WO2023194953A1 - Compositions for supplementing products with therapeutic agents and methods of use thereof - Google Patents

Compositions for supplementing products with therapeutic agents and methods of use thereof Download PDF

Info

Publication number
WO2023194953A1
WO2023194953A1 PCT/IB2023/053541 IB2023053541W WO2023194953A1 WO 2023194953 A1 WO2023194953 A1 WO 2023194953A1 IB 2023053541 W IB2023053541 W IB 2023053541W WO 2023194953 A1 WO2023194953 A1 WO 2023194953A1
Authority
WO
WIPO (PCT)
Prior art keywords
several embodiments
composition
nanoparticle
nanoparticle composition
spanning
Prior art date
Application number
PCT/IB2023/053541
Other languages
French (fr)
Inventor
Michael A. Sandoval
Brian R. SLOAT
Original Assignee
Disruption Labs, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Disruption Labs, Inc. filed Critical Disruption Labs, Inc.
Publication of WO2023194953A1 publication Critical patent/WO2023194953A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/02—Algae
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/67—Piperaceae (Pepper family), e.g. Jamaican pepper or kava
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/74—Rubiaceae (Madder family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/14—Liposomes; Vesicles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • A61K8/375—Esters of carboxylic acids the alcohol moiety containing more than one hydroxy group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4993—Derivatives containing from 2 to 10 oxyalkylene groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—Magnoliopsida [dicotyledons]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1277—Processes for preparing; Proliposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/10—General cosmetic use

Definitions

  • This disclosure relates to the fields of nanoparticles, drug delivery, and medicine.
  • nutraceuticals are used as nutraceuticals.
  • a nutraceutical also called a bioceutical, is a pharmaceutical alternative which may have physiological benefits.
  • nutraceuticals are largely unregulated, as they exist in the same category as dietary supplements and food additives by the Food and Drug Administration (FDA), under the authority of the Federal Food, Drug, and Cosmetic Act.
  • FDA Food and Drug Administration
  • nutraceutical plant extracts are now recognized to have great potential to treat a variety of diseases and conditions.
  • the area of supplementation with nutraceuticals has seen a dramatic increase in the last few years.
  • this increase in interest has led to many manufacturers rushing products to market that may be unsafe and/or that produce highly variable outcomes.
  • current delivery systems for active ingredients in plants e.g., kratom extracts, kanna extracts, kava extracts, mushroom extracts (e.g., Psilocybe cuhensisy Cannabis extracts) vary widely, making their effects unpredictable.
  • plant extracts e.g., kratom extracts
  • products comprising these plant extracts may comprise large amounts of impurities, depending on the manufacturer.
  • impurities depending on the manufacturer.
  • pure isolate forms of plant extracts may be highly hydrophobic and have different characteristics than their impure counterparts from a formulation and pharmacokinetic standpoint.
  • kratom extracts may be highly hydrophobic and have different characteristics than their impure counterparts from a formulation and pharmacokinetic standpoint.
  • currently available formulations with pure plant extracts are not without their drawbacks (suffering from, for example, poorer bioavailability).
  • currently available kratom isolate forms have low oral bioavailability due to low solubility in aqueous systems (e.g., and in the gut, etc.).
  • Current delivery systems for active ingredients can also suffer from a variety of problems.
  • current nanoparticle technology can often be too unstable for effective use.
  • Current nanoparticle formulations may distribute unevenly through a solution or a liquid medium, which may cause uneven delivery of the nanoparticle. The uneven distribution may cause the nanoparticles to form a layer or precipitate out of a solution.
  • Current nanoparticles may also separate over time. The distribution of nanoparticles and/or the active ingredients within current nanoparticle formulation may also suffer from instability.
  • Certain aspects of the disclosure comprise a nanoparticle composition, comprising a nanoparticle comprising a first active agent at a weight percent in the composition ranging from 1% to 50%; a lipid source at a weight percent in the composition ranging from 1% to 50%; optionally a surfactant at a weight percent in the composition ranging from 0% to 17.5%; and water at a weight percent in the composition ranging from 50% to about 97.5%; wherein the nanoparticles have an average size ranging from about 25 nm to about 200 nm.
  • the composition is a dried composition comprising a nanoparticle having weight ratios of a first active agent: a lipid source: and optionally a surfactant of 1 to 50:1 to 50:0 to 17.5.
  • the active agent is a pharmaceutical, nutraceutical, cosmetic, pigment, flavoring, etc.
  • the first active agent is a kratom extract, a kanna extract, a kava extract, a mushroom extract, or a Cannabis extract.
  • the first active agent is a kratom extract.
  • the composition further comprises a second active agent.
  • the second active agent is a kratom extract, a kanna extract, a kava extract, a mushroom extract, or a Cannabis extract.
  • the composition is configured such that when concentrated to dryness to afford a powder formulation of nanoparticles, the nanoparticle powder can be reconstituted to provide the nanoparticle composition.
  • modifying the mixtures of nanoparticles e.g., liposome, micelle, nanoemulsion, multi-lamellar, double liposome, solid lipid particles
  • density of the mixture of particles can provide increased stability to the actives, stability to the particles, and can be tuned for the particular liquid or carrier that the mixture is being added to for better dispersion and more stable dispersion.
  • Certain aspects of the disclosure comprise a fortified biomass comprising a biomass coated with the mixed nanoparticle composition of any aspect disclosed herein.
  • the biomass is a hemp biomass, a marijuana biomass, a moonrock, hash, mushroom biomass, kratom biomass, kana biomass, and/or kava biomass.
  • Certain aspects of the disclosure comprise a method of treating a patient in need of treatment comprising administering an effective amount of the mixed nanoparticle composition of any aspect disclosed herein or the fortified biomass of any aspect disclosed herein to the patient.
  • Certain aspects of the disclosure comprise a method of manufacturing a nanoparticle composition of an active agent comprising providing a lipid source; optionally providing a surfactant; mixing the lipid source and optionally the surfactant to provide a solution; passing the solution through a microfluidizer to provide a mixed nanoparticle composition; and mixing an active agent with the mixed nanoparticle composition.
  • the method further comprises adding one or more co-emulsifiers to the solution.
  • the method further comprises adding water to the solution.
  • Aspect 1 of the present disclosure concerns a nanoparticle composition
  • the composition comprising at least one active agent, at a weight percent in the composition ranging from 1% to 50 %, at least one lipid at a weight percent in the composition ranging from 1% to 50%, optionally at least one surfactant at a weight percent in the composition ranging from 0% to 17.5%, and water at a weight percent in the composition ranging from 50% to about 97.5%.
  • Aspect 2 concerns the nanoparticle composition of aspect 1, wherein the active agent comprises one or more pharmaceutical, nutraceutical, cosmetic, pigment, or flavoring.
  • Aspect 3 concerns the nanoparticle composition of aspect 1 or 2, wherein the active agent comprises a plant extract.
  • Aspect 4 concerns the nanoparticle composition of any one of aspects 1-3, wherein the active agent comprises a cannabis extract, a kanna extract, a kratom extract, an algae extract, and/or a mushroom extract.
  • Aspect 5 concerns the nanoparticle composition of any one of aspects 1-4, wherein the active agent comprises a small molecule.
  • Aspect 6 concerns the nanoparticle composition of any one of aspects 1-5, wherein the active agent comprises a biologic.
  • Aspect 7 concerns the nanoparticle composition of any one of aspects 1-6, wherein the active agent comprises a flavoring agent.
  • Aspect 8 concerns the nanoparticle composition of any one of aspects 1-7, wherein the active agent comprises a cosmetic.
  • Aspect 9 concerns the nanoparticle composition of any one of aspects 1-8, wherein the lipid comprises phosphatidylcholine and/or phosphatidylserine.
  • Aspect 10 concerns the nanoparticle composition of aspect 9, wherein a source of the phophatidylcholine is 20% pure, 50%, pure, or 90% pure or ranges including and/or spanning the aforementioned values.
  • Aspect 11 concerns the nanoparticle composition of aspect 9 or 10, wherein the phosphatidylcholine comprises hydrogenated soybean phosphatidylcholine (HSPC) and/or sunflower phosphatidylcholine.
  • HSPC hydrogenated soybean phosphatidylcholine
  • sunflower phosphatidylcholine HSPC
  • Aspect 12 concerns the nanoparticle composition of any one of aspects 1-11, wherein the surfactant comprises an emulsifier.
  • Aspect 13 concerns the nanoparticle composition of any one of aspects 1-12, wherein the at least one nanoparticle does not comprise a surfactant.
  • Aspect 14 concerns the nanoparticle composition of any one of aspects 1-13, wherein the composition comprises a mixture of nanoparticles selected from at least two of a multilamellar nanoparticle vesicles, unilamellar nanoparticle vesicles, multivesicular nanoparticles, emulsion particles, irregular particles with lamellar structures and bridges, partial emulsion particles, combined lamellar and emulsion particles, micelles, and/or combinations thereof.
  • Aspect 15 concerns the nanoparticle composition of any one of aspects 1-14, comprised in a liquid formulation.
  • Aspect 16 concerns the nanoparticle composition of any one of aspects 1-15, wherein the density of the nanoparticle composition is within 10 % of the density of the liquid formulation.
  • Aspect 17 concerns the nanoparticle composition of any one of aspects 1-16, further comprising at least one co-emulsifier and/or at least one preservative.
  • Aspect 18 concerns nanoparticle composition of any one of aspects 1-17, wherein the at least one nanoparticle comprises phosphatidylcholine, capric and caprylic triglycerides, one or more sterol such as cholesterol and/or a plant sterol, vitamin E, potassium sorbate, sodium benzoate, and citric acid.
  • Aspect 19 concerns a method of manufacturing a nanoparticle composition of any one of aspects 1-18, the method comprising the steps of: a. adding one or more active agents, one or more lipids, and optionally one or more surfactants to water; b. mixing the ingredients of step (a) creating a mixture; c. homogenizing the mixture creating a homogenized mixture; d. performing microfluidization on the homogenized mixture creating a microfluid; e. sonicating the microfluid creating a sonicated microfluid; f. stirring the sonicated microfluid creating a stirred microfluid; g. creating a coacervation from the stirred microfluid; and h. precipitating the coacervation.
  • Aspect 20 concerns the method of aspect 19, wherein the mixing of step (b) comprises high sheer mixing.
  • Aspect 21 concerns the method of aspect 19 or 20, wherein the homogenizing of step (c) comprises high pressure homogenization.
  • Aspect 22 concerns the method of any one of aspects 19-21, wherein the stirring of step (f) comprises mechanical stirring.
  • Aspect 23 concerns the method of any one of aspects 19-22, wherein the precipitating of step (h) comprises solvent precipitation.
  • Aspect 24 concerns the method of any one of aspects 19-23, further comprising extruding the composition using hot melt extrusion.
  • Aspect 25 concerns the method of any one of aspects 19-24, further comprising drying the nanoparticle composition.
  • Aspect 26 concerns the method of aspect 25, wherein the drying comprises lyophilizing, spray drying, fluid bed drying, and/or desiccating the nanoparticle composition.
  • Aspect 27 concerns a nanoparticle composition comprising at least one nanoparticle, the composition comprising at least one active agent, at least one lipid, and optionally at least one surfactant at a weight ratio of 1 to 50:1 to 50:0 to 17.5, wherein the composition comprise less than 10 wt. % water.
  • Aspect 28 concerns the nanoparticle composition of aspect 27, wherein the active agent comprises one or more pharmaceutical, nutraceutical, cosmetic, pigment, or flavoring.
  • Aspect 29 concerns the nanoparticle composition of aspect 27 or 28, wherein the composition comprises a mixture of nanoparticles selected from at least two of a liposome, a micelle, a nanoemulsion, a multi-lamellar particle, a double liposome particle, and a solid lipid particle.
  • Aspect 30 concerns the nanoparticle composition of any one of aspects 1-18, wherein the at least one nanoparticle comprises phosphatidylcholine, capric and caprylic triglycerides, one or more sterol such as cholesterol and/or a plant sterol, vitamin E, potassium sorbate, sodium benzoate, and/or citric acid.
  • Aspect 31 concerns a method of treating a disease, a disorder, and/or a symptom in an individual, the method comprising administering to the individual a therapeutically effective amount of the nanoparticle composition of any one of aspects 1-18 or 27-30.
  • Aspect 32 concerns the method of aspect 31, wherein the disease is an autoimmune disease, a cancer, a degenerative disease, a blood disease, an infection, and/or a deficiency disease.
  • Aspect 33 concerns the method of aspect 31 or 32, wherein the symptom comprises opioid withdrawal, pain, anxiety, depression, insomnia, inflammation, fever, fatigue, muscle aches, or a combination thereof.
  • Aspect 34 concerns the method of any one of aspects 31-33, wherein the administering step comprises local administration.
  • Aspect 35 concerns the method of any one of aspects 31-33, wherein the administering step comprises systemic administration.
  • Aspect 36 concerns the method of any one of aspects 31-33, wherein the administering step comprises oral administration.
  • Aspect 37 concerns the method of any one of aspects 31-36, wherein the therapeutically effective amount of the nanoparticle composition comprises 10 mg/kg to 200 mg/kg.
  • Aspect 38 concerns a method of distributing an active agent in a solution, the method comprising contacting the solution with the nanoparticle composition of aspects 1-18 or 27-30.
  • Aspect 39 concerns the method of aspect 38, wherein the nanoparticle composition has a density within 10% of a density of the solution.
  • Aspect 40 concerns the method of aspect 38 or 39, wherein the nanoparticle composition comprises a mixture of nanoparticles selected from at least two of a liposome, a micelle, a nanoemulsion, a multi-lamellar particle, a double liposome particle, and a solid lipid particle.
  • Aspect 41 concerns a method of adjusting a density of the nanoparticle composition of aspect 14-18, the method comprising adjusting the density by adjusting a ratio of at least two of a liposome, a micelle, a nanoemulsion, a multi-lamellar particle, a double liposome particle, and a solid lipid particle.
  • Aspect 42 concerns the method of aspect 41, wherein the ratio is adjusted by adjust the concentration of an ingredient and/or substituting an ingredient used to form the nanoparticles.
  • Aspect 43 concerns the method of aspect 42, wherein a concentration is increased of a lipid that is a solid at room temperature to increase concentration of solid lipid particles.
  • Aspect 44 concerns the method of any one of aspects 42 or 43, wherein a concentration is increased of a lipid that is a liquid at room temperature to increase concentration of liposomes.
  • Aspect 45 concerns the method of any one of aspects 42 to 44, wherein a concentration of a sterol is adjusted to adjust the density.
  • Aspect 46 concerns the method of any one of aspects 42 to 45, wherein a concentration ratio is decreased of medium chained triglycerides to phosphatidylcholine to increase concentration of liposomes.
  • FIG. 1 is a flow chart showing an embodiment of a method of preparing a composition as disclosed herein.
  • FIG. 2 is a flow chart showing another embodiment of a method for preparing a composition as disclosed herein.
  • FIG. 3 is a flow chart showing another embodiment of a method for preparing a composition as disclosed herein.
  • FIG. 4 shows the size distribution of lipid nanoparticles (LNPs) stored for two years.
  • FIG. 5 shows distribution of compounds found near expected cannabinoid elusion fractions from lipid nanoparticles (LNPs) stored for two years.
  • FIGs. 6A-6B show particle size and dissolution of nanoparticles disclosed herein compared to other marketed products.
  • FIG. 7 shows viscosity vs. concentration of lipid in the kratom mixed micelle formulation. Point at 300 g/L and 300 mPa*s is shown to guide the eye. The 300 g/L mixed micelle suspension was not successful due to high viscosity during compounding.
  • FIG. 8 shows change in CBG (cannabigerol) concentration when stored at controlled room temperature.
  • FIG. 9 shows change in Z- average particle size of CBG nanoparticles when stored at controlled room temperature.
  • FIG. 10 shows change in CBD concentration from BSD (broad spectrum hemp distillate) when stored at controlled room temperature.
  • FIG. 11 shows change in CBG (cannabigerol) concentration from BSD when stored at controlled room temperature.
  • FIG. 12 shows change in CBN (cannabinol) concentration from BSD when stored at controlled room temperature.
  • FIG. 13 shows change in CBC (cannabichromene) concentration from BSD when stored at controlled room temperature.
  • FIG. 14 shows change in Z-average particle size of BSD nanoparticles when stored at controlled room temperature.
  • FIG. 15 shows change in Z-average particle size and PDI of FSD (Full Spectrum Hemp Distillate) and THCv (tetrahydrocannabivarin) nanoparticles when stored at controlled room temperature.
  • FSD Full Spectrum Hemp Distillate
  • THCv tetrahydrocannabivarin
  • FIG. 16 shows change in Z-average particle size and PDI of FSD and THCv nanoparticles when stored at accelerated temperature.
  • nanoparticle compositions comprising a nanoparticle comprising a first active agent at a weight percent in the composition ranging from 1% to 50%; a lipid source at a weight percent in the composition ranging from 1% to 50%; optionally a surfactant at a weight percent in the composition ranging from 0% to 17.5%; and water at a weight percent in the composition ranging from 50% to about 97.5%; wherein the nanoparticles have an average size ranging from about 25 nm to about 200 nm.
  • the composition is a dried composition comprising a nanoparticle having weight ratios of a first active agent: a lipid source: and a optionally a surfactant of 1 to 50:1 to 50:0 to 17.5. It has been found that compositions disclosed herein can be configured such that when concentrated to dryness to afford a powder formulation of nanoparticles, the nanoparticle powder can be reconstituted to provide the nanoparticle composition.
  • modifying the mixtures of nanoparticles e.g., liposome, micelle, nanoemulsion, multi-lamellar, double liposome, solid lipid particles
  • density of the mixture of particles can provide increased stability to the actives, stability to the particles, and can be tuned for the particular liquid or carrier that the mixture is being added to for better dispersion and more stable dispersion.
  • A, B, and/or C includes: A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C. In other words, “and/or” operates as an inclusive or.
  • compositions and methods for their use can “comprise,” “consist essentially of,” or “consist of’ any of the ingredients or steps disclosed throughout the specification. Compositions and methods “consisting essentially of’ any of the ingredients or steps disclosed limits the scope of the claim to the specified materials or steps which do not materially affect the basic and novel characteristic of the claimed disclosure.
  • treatment shall be given its ordinary meaning and shall also include herein to generally refer to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disorder, disease, or symptom thereof and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disorder or disease and/or adverse effect attributable to the disorder or disease.
  • Treatment shall also cover any treatment of a disorder or disease in a mammal, particularly a human, and includes: (a) preventing the disorder, disease, or symptom (e.g., of the disorder or disease) from occurring in a subject which may be predisposed to the disorder, disease, or symptom but has not yet been diagnosed as having it; (b) inhibiting the disorder, disease, or symptom, e.g., arresting its development; and/or (c) relieving the disorder, disease, or symptom (e.g., causing regression of the disorder, disease, or symptom).
  • the “patient” or “subject” treated as disclosed herein may be a human patient, although it is to be understood that the principles of the presently disclosed subject matter indicate that the presently disclosed subject matter is effective with respect to all vertebrate species, including mammals, which are intended to be included in the terms “subject” and “patient.” Suitable subjects are generally mammalian subjects. The subject matter described herein finds use in research as well as veterinary and medical applications.
  • mammal as used herein includes, but is not limited to, humans, non-human primates, cattle, sheep, goats, pigs, mini-pigs (a mini-pig is a small breed of swine weighing about 35 kg as an adult), horses, cats, dog, rabbits, rodents (e.g., rats or mice), monkeys, etc.
  • Human subjects include neonates, infants, children, juveniles, adults and geriatric subjects.
  • the subject can be a subject “in need of’ the methods disclosed herein can be a subject that is experiencing a disease state and/or is anticipated to experience a disease state, and the methods and compositions of the disclosure are used for therapeutic and/or prophylactic treatment.
  • the terms “active agent”, “active compound”, “pharmaceutical composition”, “therapeutic agent”, and the like may be used interchangeably.
  • the terms generally refer to compositions having pharmacological activity or other direct effects in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure, appearance, or any function of molecules, cells, tissues, organs, or subject.
  • the terms may refer to compositions in a beverage.
  • the terms may refer to pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like.
  • the terms may refer to compositions that are hydrophobic, hydrophilic, or both.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
  • various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of a compound, which are not biologically or otherwise undesirable for use in a pharmaceutical.
  • the compounds herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in US4783443A, Johnston et al., published September 11, 1987 (incorporated by reference herein in its entirety).
  • an “effective amount” or a “therapeutically effective amount” as used herein can refer to an amount of a therapeutic agent that is effective to relieve, to some extent, or to reduce the likelihood of onset of, one or more of the symptoms of a disease or condition (e.g., disorder), and includes curing a disease or condition. “Curing” means that the symptoms of a disease or condition are eliminated; however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).
  • weight percent when referring to a component, is the weight of the component divided by the weight of the composition that includes the component, multiplied by 100%. For example, the weight percent of component A when 5 grams of component A is added to 95 grams of component B is 5% (e.g., 5 g A / (5 g A + 95 g B) x 100%).
  • dry weight % (e.g., “dry wt. %”, “dry weight percent”, etc.) of an ingredient is the weight percent of that ingredient in the composition where the weight of water has not been included in the calculation of the weight percent of that ingredient.
  • a dry weight % can be calculated for and includes either a composition that does not include water (e.g., that has been dried to, for example, a powder) or for a composition that includes water but where the amount of water is not included in the calculation.
  • the “wet weight %” (e.g., “wet wt. %”, “wet weight percent”, etc.) of an ingredient is the weight percent of that ingredient in a composition where the weight of water is included in the calculation of the weight percent of that ingredient.
  • the dry weight percent of component A when 5 grams of component A is added to 95 grams of component B and 100 grams of water is 5% (e.g., 5 g A / (5 g A + 95 g B) x 100%).
  • the wet weight percent of component A when 5 grams of component A is added to 95 grams of component B and 100 grams of water is 2.5% (e.g., 5 g A / (5 g A + 95 g B + 100 g water) x 100%).
  • weight volume percent when referring to a component, is the weight of the component in grams divided by the volume of a solution in milliliters that includes the component, multiplied by 100%.
  • weight volume percent when 5 grams of component A is added to a solution to provide 100 mL of solution is 5 w/v (%) (e.g., 5 g solute A / 100 mL solution x 100%).
  • A may be at 5 wt. % and B may be at 5 wt. %, totaling 10 wt. %.
  • the terms “or ranges including and/or spanning the aforementioned values” is meant to include any range that includes or spans the aforementioned values.
  • the wt. % of an ingredient is expressed as 1%, 5%, 10%, 20%
  • “orranges including and/or spanning the aforementioned values” this includes wt. % ranges for the ingredient spanning from 1% to 20%, 1% to 10%, 1% to 5%, 5% to 20%, 5% to 10%, and 10% to 20%.
  • polydispersity or “PDI” is used to describe the degree of nonuniformity of a size distribution of particles. Also known as the heterogeneity index, PDI is a number calculated from a two-parameter fit to the correlation data (the cumulants analysis). This index is dimensionless and scaled such that values smaller than 0.05 are mainly seen with highly monodisperse standards.
  • the term “phytocannabinoid” refers to a group of cannabinoids that occur naturally in the cannabis plant, including but not limited to, THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid), CBD (cannabidiol), CBDA (cannabidiolic acid), CBN (cannabinol), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabicyclol), CBV (cannabivarin), THCV (tetrahydrocannabivarin), CBDV (cannabidivarin), CBCV (cannabichromevarin), CBGV (cannabigerovarin), CBGM (cannabigerol monomethyl ether), CBE (cannabielsoin), and CBT (cannabicitran).
  • THC tetrahydrocannabinol
  • THCA tetrahydrocannabinolic acid
  • CBD canannabidio
  • the term “cannabinoid” refers to the chemical substance, regardless of structure or origin, that joins the cannabinoid receptors of the body and brain and that have similar effects to those produced by the cannabis plant.
  • the term “cannabinoid” includes but is not limited to Cannabichromenes (e.g., cannabichromene (CBC), cannabichromenic acid (CBCA), cannabichromevarin (CBCV), cannabichromevarinic acid (CBCVA), Cannabicyclols (e.g., cannabicyclol (CBL), cannabicyclolic acid (CBLA), cannabicyclovarin (CBLV), etc.), Cannabidiols (e.g., cannabidiol (CBD), cannabidiol monomethylether (CBDM), cannabidiolic acid (CBDA), Cannabidiol-C4 (CBD-C4), cannabidiols (CBD), cann
  • compositions comprising a nanoparticle, which may encapsulate an active agent.
  • the compositions can deliver highly pure active agents, such as pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, etc. in a nanoparticle delivery system (e.g., lipid nanoparticle, a liposomal system, oil-in-water emulsions, dry liposome particles, etc.).
  • active agents include kratom and/or kratom extracts, kanna extracts, kava extracts, Psilocybe cubensis extracts, cannabis extracts, other active agents, and/or combinations of any of the foregoing.
  • compositions disclosed herein comprise mixed nanoparticle compositions comprising active agents or combinations of active agents.
  • the disclosed compositions which may be mixed nanoparticle compositions, have certain characteristics including, but not limited to, fewer impurities, fewer variations batch-to-batch (e.g., stability, degradation profiles, efficacy), better delivery predictability, fewer side effects when administered to a subject, higher bioavailability, faster onset of activity, greater long term storage stability of the particles and the active ingredient(s), better dispersibility, greater stability of a dispersion, and better efficacy, relative to the characteristics of compositions known in the art.
  • Certain embodiments concern nanoparticles, including mixed micelle-based compositions, and their use in methods for the delivery of active compounds, which may include plant extracts (e.g., kratom extracts, hemp extracts, etc.) and/or other beneficial agents (e.g., vitamins, nutrients, other plant extracts, nutraceuticals, pharmaceuticals, flavorings, pigments, or other beneficial agents for delivery).
  • active compounds which may include plant extracts (e.g., kratom extracts, hemp extracts, etc.) and/or other beneficial agents (e.g., vitamins, nutrients, other plant extracts, nutraceuticals, pharmaceuticals, flavorings, pigments, or other beneficial agents for delivery).
  • the compositions are stable (e.g., at room temperature) for prolonged periods of time.
  • the nanoparticle compositions comprise one or more active agents (e.g., single active agents or combinations thereof).
  • the composition is comprised of high-quality, pure, and/or high-grade ingredients (e.g., highly pure) that yield a well-characterized, reproducible delivery system (e.g., comprising mixed nanoparticles).
  • the compositions have enhanced stability (e.g., are stable for long periods of time under various conditions).
  • the composition confers water solubility to hydrophobic agents, to combinations of hydrophobic agents, and/or to combinations of hydrophobic and hydrophilic agents.
  • the nanoparticle composition comprises a liposomal and/or nano-emulsion composition of an active agent.
  • compositions disclosed herein in relation to particular plant extracts (e.g., kratom extracts, cannabinoids, etc.), it is to be understood that other active agents, nutrients, and/or combinations thereof can be employed in the compositions disclosed herein.
  • hydrophilic active agents may also be provided in the disclosed nanoparticle compositions (e.g., alone, in combination with other hydrophilic active agents, and/or in combination with hydrophobic active agents).
  • the compositions disclosed herein may enhance the delivery of and/or slow or lessen the degradation of hydrophilic or hydrophobic agents (or combinations thereof).
  • nanoparticles e.g., mixed micelle-based nanoparticles
  • microparticles are also envisioned.
  • nanoparticle products which may comprise active compositions.
  • the composition comprises a nanoparticle delivery system, which may be utilized to impart apparent aqueous solubility and deliverability to an otherwise practically water insoluble molecules (e.g., hydrophobic kratom extracts, hydrophobic kanna extracts, hydrophobic kava extracts, hydrophobic mushroom extracts, hydrophobic Cannabis extracts).
  • nanoparticle delivery system which may be utilized to impart apparent aqueous solubility and deliverability to an otherwise practically water insoluble molecules (e.g., hydrophobic kratom extracts, hydrophobic kanna extracts, hydrophobic kava extracts, hydrophobic mushroom extracts, hydrophobic Cannabis extracts).
  • Attributes of some embodiments disclosed herein have been determined to be high quality and reproducible. Such reproducibility and low variations may allow the products to generate a reproducible certificate of analysis for different batches.
  • the compositions disclosed herein increase the bioavailability of active agents (e.g., pharmaceutical, nutraceutical, etc.), decrease the time for absorption of those active agents, increase the stability of the active agents or the particles comprising the active agents, increase the consistency of delivery (e.g., by limiting batch-to-batch variation), and/or increase the efficacy of the active agents (higher dosing and/or faster onset of activity).
  • active agents e.g., pharmaceutical, nutraceutical, etc.
  • the compositions (including the mixed nanoparticle compositions) disclosed herein are able to deliver active agents that are highly pure.
  • an active agent e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like
  • formulated with the nanoparticle has a purity of greater than or equal to about: 80%, 90%, 95%, 98%, 99%, 99.5%, 99.9%, 99.99%, or ranges including and/or spanning the aforementioned values.
  • some embodiments relate to delivery systems (e.g., mixed nanoparticle compositions and/or formulations comprising the same) that improve the absorption of the highly insoluble forms of an active agent (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like) or combination of agents.
  • an active agent e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like
  • the active agent encapsulated in the nanoparticle compositions disclosed herein (e.g., the starting material) has an aqueous solubility of less than or equal to about: 0.05 mg/mL, 0.01 mg/mL, 0.012 mg/mL, 0.001 mg/mL, or ranges including and/or spanning the aforementioned values, such as a range between 0.05 mg/mL to 0.001 mg/mL.
  • one or more or all of the active agents in the composition may have an aqueous solubility of less than or equal to about: 0.05 mg/mL, 0.01 mg/mL, 0.012 mg/mL, 0.001 mg/mL, or ranges including and/or spanning the aforementioned values, such as a range between 0.05 mg/mL to 0.001 mg/mL.
  • the aqueous solubility of the active agent or agents can be improved to equal to or greater than about: 1 mg/mL, 5 mg/mL, 10 mg/mL, 20 mg/mL, 30 mg/mL, 50 mg/mL, 100 mg/mL, or ranges including and/or spanning the aforementioned values.
  • the aqueous solubility of the active agent or agents may be increased to 1 mg/mL to 50 mg/mL, 10 mg/mL to 100 mg/mL, 1 mg/mL to 20 mg/mL, etc.
  • At least one active agent in the nanoparticle composition is hydrophobic.
  • at least one hydrophobic active agent used to prepare a nanoparticle composition as disclosed herein e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like
  • the solubility of the at least one active agent e.g.
  • the amount of the active agent that can be provided in an aqueous solution) used to prepare the compositions disclosed herein can be improved to equal to or greater than about: 1 mg/mL, 5 mg/mL, 20 mg/mL, 30 mg/mL, 50 mg/mL, 100 mg/mL, or ranges including and/or spanning the aforementioned values, when formulated with a nanoparticle.
  • the solubility of the at least one active agent can be improved by at least about: 50%, 100%, 150%, 200%, 500%, 1000%, 10,000%, or ranges including and or spanning the aforementioned values.
  • the solubility is measured as an amount that can be suspended for longer than 30 days and or that can be dissolved in an aqueous solution at a concentration of at least 20 mg/mL.
  • a nanoparticle composition e.g., a mixed micelle composition, a liposomal composition, solid lipid particles, oil-in-water emulsions, water-in-oil-in-water emulsions, water-in-oil emulsions, oil-in-water-in-oil emulsions, etc.
  • the nanoparticles comprise one or more active agents.
  • one or more of the active ingredients is a nutraceutical.
  • a composition comprising the nanoparticles disclosed herein comprises a therapeutically effective amount of one or more active ingredients.
  • the one or more active compounds comprise kratom extracts, kanna extracts, kava extracts, mushroom extracts (e.g., Psilocybe cubensis), Cannabis extracts, cannabinoids, and/or combinations of any of the foregoing.
  • the active ingredients provided in the nanoparticle composition may comprise an unenriched extract (e.g., a mixture of agents as extracted from a single plant source), an enriched extract that has been enriched through purification processes (to have larger amounts of certain active agents), or any individual active component of the extract (e.g., a pure or substantially pure compound).
  • the nanoparticle composition may include an unenriched kratom extract that is isolated by bulk extraction of multiple actives from kratom biomass at one time.
  • the nanoparticle composition may include actives that have been further processed to enrich the extract for particular active agents (e.g., a kratom extract enriched for 7-hydroxymitragynine or mitragynine and having a higher wt. % of 7-hydroxymitragynine or mitragynine than unprocessed kratom extract).
  • active agents e.g., a kratom extract enriched for 7-hydroxymitragynine or mitragynine and having a higher wt. % of 7-hydroxymitragynine or mitragynine than unprocessed kratom extract.
  • an active from an extract may be purified and may be pure and/or substantially pure, as disclosed elsewhere herein.
  • extracts is meant to include any of the foregoing (e.g., including a full plant extract that has not been enriched, an extract that has been enriched for particular components (e.g., particular active agents), and/or an extract that has been purified to provide, for example, highly pure individual components).
  • the nanoparticle (or a composition comprising the nanoparticle) is composed and/or comprises one or more kratom extracts.
  • the one or more kratom extracts may be from any one or more kratom strains.
  • the nanoparticle (or a composition comprising the nanoparticle) comprises one or more Sceletium extracts (e.g., Kanna extracts).
  • the nanoparticle compositions comprise one or more kava extracts.
  • the nanoparticle (or compositions comprising the nanoparticle) comprises or is composed of kava powders and/or kava active ingredients (e.g., including but not limited to alkaloids).
  • the kava extract is an alkaloid (pipermethystine, etc.), a kavalactone (e.g., Dihydrokavain, Kavain, desmehtoxyyangonin, dihydromethysticin, yangonin, methysticin, etc.) or combinations of any of the foregoing.
  • the kava extracts are extracted from kava plants (e.g., are natural extracts). In other embodiments, the kava extracts may be produced synthetically (e.g., in a laboratory). In several embodiments, the synthetic extract may share a structure with an extract that is naturally occurring. In several embodiments, the kava extracts are analogs of natural extracts of kava (e.g., produced synthetically).
  • the nanoparticle (or a composition comprising the nanoparticle) comprises one or more mushroom extracts (e.g., cordyceps, lion mane, reishi, chaga gano, psilocybin (including the compound itself, natural extract forms, synthetic forms, derivatives of psilocybin, and prodrugs of any one of the foregoing), others, and/or combinations of any of the foregoing).
  • the mixed nanoparticle (or a composition comprising it) comprises or is composed of one or more fungus extracts (e.g., a mushroom extract).
  • the mixed nanoparticle (or a composition comprising it) comprises or is composed of mushroom extracts (e.g., of mushroom powder).
  • the nanoparticle (or a composition comprising the nanoparticle) comprises or is composed of cannabinoids.
  • the nanoparticle (or a composition comprising the nanoparticle) comprises or is composed of cannabinoids derived from resin or rosin (solventless extraction of cannabinoids achieved by pressing biomass).
  • the nanoparticle (or a composition comprising the nanoparticle) comprises or is composed of cannabinoids from a crude extract of hemp or marijuana (an extraction that is not further purified).
  • the lipid particle solution is composed of cannabinoids from combinations of sources, such as hemp oil fortified with cannabinoid isolate.
  • the cannabinoids may be any of the cannabinoids disclosed elsewhere herein and/or a mixture of one or more of such cannabinoids.
  • the nanoparticle (or a composition comprising the nanoparticle) comprises a cannabichromene, a cannabicyclol, a cannabidiol, a cannabielsoin, a cannabigerol, a cannabinol, a cannabinodiol, a cannabitriol, a delta-9-tetrahydrocannabinol, another cannabinoid, a synthetic cannabinoid, and/or combinations of any of the foregoing.
  • the mixed nanoparticle composition comprises two or more cannabichromenes, cannabicyclols, cannabidiols, cannabielsoins, cannabigerols, cannabinols, cannabinodiols, cannabitriols, delta-9-tetrahydrocannabinols, other cannabinoids, synthetic cannabinoids, and/or combinations of any of the foregoing.
  • the nanoparticle composition comprises CBC, CBCA, CBCV, CBCVA, CBL, CBLA, CBLV, CBD, CBDM, CBDA, CBD-C1, CBDV, CBDVA, CBEA-B, CBE, CBEA-A, CBG, CBGM, CBGA, CBGAM, CBGV, CBGVA, CBND, CBVD, CBN, CBNM, CBN-C2, CBN-C4, CBNA, CBN-C1, CBV, 10-ethoxy-9-hydroxy-delta-6a-tetrahydrocannabinol, 8,9-dihydroxy- delta-61 -tetrahydrocannabinol, CBT, CBTV, THC, THC-C4, THCA-A, THCA-B, THCA-C4, THC-C1, THCA-C1, THCV, THCVA, OTHC, CBCF, CBF, cannabiglendol, CBR, cannb
  • the nanoparticle composition may comprise CBN, CBD, and CBG.
  • the kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts are isolated from their plant sources.
  • the kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts are isolated from their plant sources using solvent extraction.
  • the kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts are isolated from their plant sources using acid base titration.
  • the kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts are isolated from their plant sources using CO2 (supercritical or nonsupercritical), In several embodiments, the kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts, are isolated from their plant sources using cyrogenic ethanol. In several embodiments, the kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts, are isolated from their plant sources using other forms of extraction. In several embodiments, the extract is an alkaloid (e.g., a kratom alkaloid), as disclosed elsewhere herein.
  • CO2 supercritical or nonsupercritical
  • the kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts are isolated from their plant sources using cyrogenic ethanol.
  • the kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts are isolated from their plant
  • the kratom is provided as a kratom plant powder.
  • the kanna is provided as a kanna plant powder.
  • the kava is provided as a kava plant powder.
  • the mushroom is provided as a mushroom powder.
  • the Cannabis is provided as a Cannabis plant powder.
  • a kratom active e.g., alkaloid
  • a kanna active e.g., a kava active, a mushroom active
  • a Cannabis active may be provided in a salt form.
  • salt is a pharmaceutically acceptable salt.
  • the salt is the acetate or citrate salt.
  • the composition may comprise mixtures of salt forms.
  • the dry weight % of one or more active agents present in the nanoparticle compositions is equal to or at least about: 0.5%, 1%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 25%, 50%, or ranges including and/or spanning the aforementioned values.
  • the active agents are provided in an aqueous composition.
  • the wet weight % of one or more active agents e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, etc.
  • the wet weight % of one or more active agents is equal to or at least about: 0.5%, 1%, 2%, 3%, 4%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, or ranges including and/or spanning the aforementioned values.
  • the one or more active agents may be provided in the wet composition at a concentration of greater than or equal to about: 1 mg/mL, 5 mg/mL, 20 mg/mL, 30 mg/mL, 50 mg/mL, 100 mg/mL, or ranges including and/or spanning the aforementioned values.
  • the active agents are present in the aqueous nanoparticle composition at a concentration of less than or equal to about: 150 mg/mL, 100 mg/mL, 75 mg/mL, 50 mg/mL, 25 mg/mL, 20 mg/mL, 10 mg/mL, 5 mg/mL, 2.5 mg/mL or ranges including and/or spanning the aforementioned values.
  • the one or more active agents are present in the aqueous composition at a concentration of greater than or equal to about: 150 mg/mL, 100 mg/mL, 75 mg/mL, 50 mg/mL, 25 mg/mL, 20 mg/mL, 10 mg/mL, 5 mg/mL, or ranges including and/or spanning the aforementioned values.
  • the one or more active agents, collectively or individually are present in the composition at a dry wt. % of equal to or at least about: 0.5%, 1%, 5%, 7.5%, 10%, 15%, 20%, 25%, or ranges including and/or spanning the aforementioned values.
  • the one or more active agents are present in the composition at a wet wt. % of equal to or at least about: 0.1%, 0.25%, 0.5%, 1%, 2%, 3%, 4%, 5%, 7.5%, 10%, or ranges including and/or spanning the aforementioned values.
  • the composition is aqueous, while in others it has been dried into a powder (that is free of or substantially free of water).
  • the composition comprises a water content of less than or equal to 20%, 15%, 10%, 7.5%, 5%, 2.5%, 1%, or ranges including and/or spanning the aforementioned values.
  • the nanoparticle may be used to deliver combination extracts (e.g., combinations of one or more kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts), additional actives, terpenes, and/or combinations thereof (as disclosed elsewhere herein).
  • the nanoparticle composition may include one or more active agents (e.g., a single active agent or a combination of active agents).
  • the nanoparticle composition may include a single active agent or a plurality of active agents (e.g., 1, 2, 3, 4, or more).
  • the nanoparticle composition may comprise a kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts, cannabinoids and a different active (e.g., a pharmaceutical, nutraceutical, cosmetic, pigment, flavoring, a kratom extract, and/or a terpene).
  • the nanoparticle may comprise one or more therapeutic plant extracts and one or more non-plant based therapeutic agent.
  • Other combinations of therapeutics selected from kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts, and other therapeutics are also envisioned.
  • the composition comprises combinations of active compounds of varying ratios.
  • a first active compound e.g., a kratom extract, a kanna extract, a kava extract, a mushroom extract, or a Cannabis extract
  • a second active compound e.g., a different a kratom extract, a kanna extract, a kava extract, a mushroom extract, or a Cannabis extract
  • a first active compound e.g., a kratom extract, a kanna extract, a kava extract, a mushroom extract, or a Cannabis extract
  • a second active compound e.g., a different a kratom extract, a kanna extract, a kava extract, a mushroom extract, or a Cannabis extract
  • present in the composition may be about: 10: 1, 5: 1, 4: 1, 3: 1 2: 1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, or ratios including and/or spanning the aforementioned ratios.
  • the one or more non- kratom/non-kanna/non-kava active/non-mushroom active/non-Cannabis active agent(s), collectively or individually, are present in the aqueous composition at a concentration of greater than or equal to about: 100 mg/mL, 75 mg/mL, 50 mg/mL, 25 mg/mL, 20 mg/mL, 10 mg/mL, 5 mg/mL, or ranges including and/or spanning the aforementioned values.
  • the one or more non-kratom/non-kanna/non-kava active/non-mushroom active/non-Cannabis active agent(s) are present in the composition at a dry wt. % of equal to or at least about: 0.5%, 1%, 5%, 7.5%, 10%, 15%, 20%, 25%, or ranges including and/or spanning the aforementioned values.
  • the one or more non-kratom/non-kanna/non-kava active/non-mushroom active/non-Cannabis active agent(s) are present in the composition at a wet wt. % of equal to or at least about: 0.1%, 0.25%, 0.5%, 1%, 2%, 3%, 4%, 5%, 7.5%, 10%, 15%, or ranges including and/or spanning the aforementioned values.
  • the composition is aqueous (e.g., contains water) while in other embodiments, the composition is dry (lacks water or substantially lacks water). In several embodiments, the composition has been dried (e.g., has been subjected to a process to remove most or substantially all water). In several embodiments, the composition comprises nanoparticles in water (e.g., as a solution, suspension, or emulsion). In other embodiments, the composition is provided as a powder (e.g., that may be constituted or reconstituted in water). In several embodiments, as disclosed elsewhere herein, the water content (in wt.
  • the composition is less than or equal to about: 30%, 20%, 10%, 5%, 2.5%, 1%, 0.5%, 0.1%, 0%, or ranges including and/or spanning the aforementioned values.
  • the water content (in wt. %) of the composition is greater than or equal to about: 50%, 60%, 70%, 80%, 85%, 90%, 92.5%, 95%, 97.5%, or ranges including and/or spanning the aforementioned values.
  • the water is nanopure, deionized, USP grade, WFI, and/or combinations of the foregoing.
  • the composition is a dried composition comprising a nanoparticle having weight ratios of a first therapeutic active agent: a lipid source: and optionally a surfactant of 1 to 50:1 to 50:0 to 17.5.
  • the nanoparticle composition provides an oil-in-water emulsion (e.g., a nanoemulsion), water-in-oil emulsion, a water-in-oil-in-water emulsion, an oil-in-water-in-oil emulsion, a liposome (and variants including multi-lamellar, double liposome preparations, etc.), micelle, and/or solid lipid particles. Any one of these structures may be provided as a nanoparticle or microparticle.
  • the nanoparticle composition comprises a lipid source.
  • the lipid source comprises a charged lipid, which can impart a charge to the nanoparticle.
  • the lipid source comprises a neutral lipid.
  • the lipid source comprises one or more phospholipids.
  • the one or more phospholipids comprises one or more of phosphatidic acid, phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylinositol phosphate, phosphatidylinositol bisphosphate, phosphatidylinositol trisphosphate, lipoid H 100-3, phospholipon 90H, phospholipon 80H, lipoid 100-3, lipoid P75-3, or any combination of the foregoing.
  • the lipid source is a phosphatidylcholine.
  • the only lipid present is a phosphatidylcholine (e.g., the lipid source lacks phospholipids other than phosphatidylcholine or is substantially free of other phospholipids).
  • the one or more lipid source lipid(s) (collectively or individually) are present in the composition at a dry wt. % of equal to or less than about: 0%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, or ranges including and/or spanning the aforementioned values.
  • the one or more lipid source lipid(s) are present in the composition at a wet wt.
  • the one or more lipid source lipid(s) are present in the composition at a wet w/v of equal to or less than about: 0 mg/mL, 0.1 mg/mL, 0.5 mg/mL, 1.0 mg/mL, 2.5 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7.5 mg/mL, 10 mg/mL, 12.5 mg/mL, 15 mg/mL, 17.5 mg/mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 45 mg/mL, 50 mg/mL, or ranges including and/or spanning the aforementioned values.
  • the composition is aqueous, while in others it has been dried into a powder.
  • the composition is aqueous (wet), while in others it has been dried into a powder (dry).
  • the one or more lipid(s) of the lipid source are synthetic, derived from sunflower, soy, egg, or mixtures thereof.
  • the one or more lipids of the lipid source can be hydrogenated or nonhydrogenated.
  • the lipid source exceeds requirements of the United States Pharmacopeia (is USP grade) and/or is National Formulary (NF) grade.
  • the lipid source e.g., phosphatidylcholine, including hydrogenated soybean phosphatidylcholine
  • the lipid source may be of high purity.
  • the phosphatidylcholine is H100-3 grade (from Lipoid) and includes over 96.3% phosphatidylcholine (hydrogenated) or over 99% phosphatidylcholine (hydrogenated).
  • the one or more lipids of the lipid source has a purity of greater than or equal to about: 92.5%, 95%, 96%, 96.3%, 98%, 99%, 100%, or ranges including and/or spanning the aforementioned values.
  • the one or more lipids of the lipid source has a total % impurity content by weight of less than or equal to about: 8.5%, 5%, 4%, 3.7%, 2%, 1%, 0%, or ranges including and/or spanning the aforementioned values.
  • the one or more lipids of the lipid source comprises less than or equal to about 8.5%, 5%, 4%, 3.7%, 2%, 1%, or 0.1% (or ranges including and/or spanning the aforementioned values) of any one or more of saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids (C 18), arachidonic acid (ARA) (C 20:4), docosahexaenoic acid DHA (C 22:6), phosphatidic acid, phosphatidylethanolamine, and/or lysophosphatidylcholine by weight.
  • the one or more lipids of the lipid source has less than about 1.1% lysophosphatidylcholine and less than about 2.0% triglycerides by weight.
  • the lipid source e.g., phosphatidylcholine, including hydrogenated soybean phosphatidylcholine
  • the lipid source may be 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% pure, or ranges including and/or spanning the aforementioned values.
  • the nanoparticle composition comprises a surfactant. In some embodiments, the nanoparticle composition does not comprises a surfactant. In several embodiments, the surfactant is a pharmaceutically acceptable surfactant. In several embodiments, the surfactant is a food surfactant.
  • the surfactant comprises one or more of a polyoxyethylene sorbitan esters (e.g., polysorbates/tweens, including polysorbate 80, polysorbate 20, etc.), cremophor (e.g., a nonionic solubilizer and emulsifier that is made by reacting ethylene oxide with castor oil), propylene oxide-modified polymethylsiloxane, dodecyl betaine, lauramidopropyl betaine, cocoamido-2-hydroxypropyl sulfobetaine, sodium stearate (or other stearate salts), polyoxyethylene alcohol, lecithins, mono- and diglycerides of fatty acids (MDG), acetic acid esters of MDG, lactic acid esters of MDG, citric acid esters of MDG, mono- and diacetyl tartaric acid esters of MDG, sucrose esters of fatty acids, polyglycerol esters of fatty acids (e.g.
  • Natural or synthetic surfactants can be used, including polyethylene glycol and dextrans, such as cyclodextran.
  • the one or more surfactants are present in the nanoparticle composition (collectively or individually) at a dry wt. % of equal to or less than about: 0%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, or ranges including and/or spanning the aforementioned values.
  • Surfactants can include cationic, anionic, nonionic, and zwitterionic surfactants.
  • the one or more surfactants are present in the composition at a wet wt.
  • the one or more surfactants are present in the composition at a wet w/v of equal to or less than about: 0 mg/mL, 0.1 mg/mL, 0.5 mg/mL, 1.0 mg/mL, 2.5 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7.5 mg/mL, 10 mg/mL, 12.5 mg/mL, 15 mg/mL, 17.5 mg/mL, or ranges including and/or spanning the aforementioned values.
  • the surfactant exceeds requirements of the United States Pharmacopeia (is USP grade) and/or is National Formulary (NF) grade.
  • co-emulsifiers are used.
  • the co-emulsifier is a pharmaceutically acceptable co-emulsifier.
  • the co-emulsifier is selected from the group consisting of oleic acid, miglyol 812N (all versions), triglycerides, conjugated linoleic acid (CLA), cetearyl olivate, isoprpyle myristate, glyceryl stearate (e.g., glycerol monostearate), celluloses and polysaccharides (e.g., methylcellulose, propylmethylcellulose, hydroxypropyl methylcellulose, xanthan gum, etc.) and/or combinations of any of the foregoing.
  • CLA conjugated linoleic acid
  • cetearyl olivate isoprpyle myristate
  • glyceryl stearate e.g., glycerol monostearate
  • the one or more coemulsifiers are present in the nanoparticle composition (collectively or individually) at a dry wt. % of equal to or less than about: 0%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, or ranges including and/or spanning the aforementioned values.
  • the one or more co-emulsifiers are present in the composition at a wet wt. % of equal to or less than about: 0%, 0.1%, 0.5%, 1.0%, 2.5%, 4%, 5%, 6%, 7.5%, 10%, 12.5%, 15%, 17.5%, or ranges including and/or spanning the aforementioned values.
  • the one or more co-emulsifiers are present in the composition at a wet w/v of equal to or less than about: 0 mg/mL, 0.1 mg/mL, 0.5 mg/mL, 1.0 mg/mL, 2.5 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7.5 mg/mL, 10 mg/mL, 12.5 mg/mL, 15 mg/mL, 17.5 mg/mL, or ranges including and/or spanning the aforementioned values.
  • the co-emulsifiers exceeds requirements of the United States Pharmacopeia (is USP grade) and/or is National Formulary (NF) grade.
  • the co-emulsifier component comprises a medium chain triglyceride (MCT) or a MCT- substitute.
  • MCT medium chain triglyceride
  • the medium chain triglyceride comprises a fatty acid selected from one or more of caprioc acid, octanoic acid, capric acid, caprylic acid, and/or lauric acid (e.g., is formed from).
  • the medium chain triglyceride comprises a fatty acid 6-12 carbons in length (e.g., 6, 7, 8, 9, 10, 11, or 12).
  • the coemulsifier component comprises a long chain triglyceride (LCT).
  • the long chain triglyceride comprises a fatty acid greater than 12 carbons in length (e.g., greater than or equal to 13, 14, 15, 16, 17, 18, 19, or 20 carbons in length, or ranges including and/or spanning the aforementioned values).
  • the co-emulsifier component is a single lipid.
  • the co-emulsifier component is MCT.
  • the MCT is highly pure.
  • the MCT has a purity by weight % of equal to or greater than about: 90%, 95%, 97%, 98%, 99%, 100%, or ranges including and/or spanning the aforementioned values.
  • the MCT (or LCT) is present in the nanoparticle composition at dry weight % of equal to or greater than about: 10%, 20%, 30%, 35%, 40%, 45%, 50%, or ranges including and/or spanning the aforementioned values.
  • the MCT-substitute lipid is selected from one or more of oleic acid, capric acid, caprylic acid, and triglycerides of such (Captex 8000, Captex GTO, Captex 1000), glycerol monooleate, glycerol monostearate (GeleolTM Mono and Diglyceride NF), omega-3 fatty acids (a-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), Tonalin, Pronova Pure® 46:38, free fatty acid Tonalin FFA 80), conjugated linoleic acid, alpha glycerylphosphorylcholine (alpha GPC), palmitoylethanolamide (PEA), cetyl alcohol, or emulsifying wax.
  • oleic acid e.g., the non-phospholipid lipid
  • capric acid e.g., the non-phospholipid lipid
  • the one or more MCT-substitute(s) are present in the nanoparticle composition (collectively or individually) at a dry wt. % of equal to or less than about: 0.5%, 1.0%, 2.5%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 80% or ranges including and/or spanning the aforementioned values.
  • the one or more MCT-substitute(s) are present in the composition at a wet wt. % of equal to or less than about: 0.5%, 1.0% 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 30%, 40%, 60% or ranges including and/or spanning the aforementioned values.
  • the MCT-substitute has a purity of greater than or equal to about: 70%, 80%, 85%, 92.5%, 95%, 96%, 98%, 99%, 99.9%, 100%, or ranges including and/or spanning the aforementioned values. In some embodiments, the MCT-substitute has a total % impurity content by weight of less than or equal to about: 8.5%, 5%, 4%, 3.7%, 2%, 1%, 0%, or ranges including and/or spanning the aforementioned values
  • the nanoparticle composition comprises one or more sterols.
  • the one or more sterols comprises one or more cholesterols, ergosterols, hopanoids, hydroxysteroids, phytosterols (e.g., vegapure), ecdysteroids, and/or steroids.
  • the sterol comprises a cholesterol.
  • the sterol component is a single sterol.
  • the sterol component is cholesterol.
  • the cholesterol (or other sterol) is highly pure.
  • the one or more sterol(s) (e.g., cholesterol, and/or other sterols), collectively or individually, are present in the aqueous composition at a concentration of less than or equal to about: 50 mg/mL, 40 mg/mL, 20 mg/mL, 10 mg/mL, 5 mg/mL, or ranges including and/or spanning the aforementioned values.
  • the one or more sterol(s) are present in the composition at a dry wt. % of equal to or less than about: 0.25%, 0.5%, 1%, 5%, 7.5%, 10%, 15%, 20%, 25%, or ranges including and/or spanning the aforementioned values.
  • the one or more sterol(s) are present in the composition at a wet wt. % of equal to or less than about: 0.1%, 0.25%, 0.5%, 1%, 2%, 3%, 4%, 5%, 7.5%, 10%, or ranges including and/or spanning the aforementioned values.
  • the cholesterol used in the composition comprises cholesterol from one or more of sheep’s wool, synthetic cholesterol, or semisynthetic cholesterol from plant origin.
  • the sterol has a purity of greater than or equal to about: 92.5%, 95%, 96%, 98%, 99%, 99.9%, 100.0%, or ranges including and/or spanning the aforementioned values.
  • the sterol has a total % impurity content by weight of less than or equal to about: 8.5%, 5%, 4%, 3.7%, 2%, 1%, 0%, or ranges including and/or spanning the aforementioned values.
  • the sterol is cholesterol. In some embodiments, the sterol is not cholesterol. In some embodiments, the sterol is phytosterol.
  • the nanoparticle composition comprises a preservative.
  • the preservative includes one or more benzoates (such as sodium benzoate or potassium benzoate), nitrites (such as sodium nitrite), sulfites (such as sulfur dioxide, sodium or potassium sulphite, bisulphite or metabisulphite), sorbates (such as sodium sorbate, potassium sorbate), ethylenediaminetetraacetic acid (EDTA) (and/or the disodium salt thereof), polyphosphates, organic acids (e.g., citric, succinic, malic, tartaric, benzoic, lactic and propionic acids), and/or antioxidants (e.g., vitamins such as vitamin E and/or vitamin C, butylated hydroxy toluene).
  • benzoates such as sodium benzoate or potassium benzoate
  • nitrites such as sodium nitrite
  • sulfites such as sulfur dioxide, sodium or potassium sulphite, bisulphite or
  • sorbates and benzoates may be used in acidic pH formulations.
  • the one or more preservatives are present in the composition at a dry wt. % of equal to or at less than about: 0.01%, 0.1%, 0.25%, 0.5%, 1%, 5%, 7.5%, 10%, 15%, 20%, 25%, or ranges including and/or spanning the aforementioned values.
  • the one or more preservatives are present in the composition at a wet wt.
  • the one or more surfactants are present in the composition at a wet w/v of equal to or less than about: 0 mg/mL, 0.001 mg/mL, 0.1 mg/mL, 0.5 mg/mL, 1.0 mg/mL, 2.5 mg/mL, 4 mg/mL, 5 mg/mL, or ranges including and/or spanning the aforementioned values.
  • the composition is aqueous, while in others it has been dried into a powder.
  • the composition is aqueous (wet), while in others it has been dried into a powder (dry).
  • the preservatives inhibit or prevent growth of mold, bacteria, and fungus.
  • the nanoparticle composition comprises one or more flavoring agents.
  • the one or more flavoring agent(s) comprise an essential oil (or combinations of essential oils).
  • the one or more flavoring agents of the composition comprise monk fruit extract (e.g., MonkGold50), stevia, glycerin, peppermint oil or flavoring, lemon oil or flavoring, orange oil or flavoring, vanilla, taste makers, bitter blockers, or the like, or combinations thereof.
  • the one or more flavoring agent(s) (collectively or individually) are present in the composition at a dry wt.
  • the one or more flavoring agents are present in the composition at a wet wt. % of equal to or less than about: 0.001%, 0.01%, 0.025%, 0.05%, 0.1%, 0.5%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 5.0%, or ranges including and/or spanning the aforementioned values.
  • the composition is aqueous, while in others it has been dried into a powder.
  • the composition is aqueous (wet), while in others it has been dried into a powder (dry).
  • the composition comprises an active agent or combination of actives and a lipid source.
  • the nanoparticle composition comprises an active agent or combination of actives and a surfactant.
  • the nanoparticle composition comprises an active agent or combination of actives and a co-emulsifier (e.g., oleic acid, miglyol 812N (all versions), triglycerides, conjugated linoleic acid (CLA), cetearyl olivate, isoprpyle myristate, glyceryl stearate, etc.).
  • the composition further comprises a flavoring agent.
  • the composition further comprises a preservative.
  • the composition comprises, consists of, or consists essentially of one or more active agents, one or more lipid sources, one or more surfactants, one or more flavoring agents, one or more preservatives, one or more co-emulsifiers, or any combination thereof.
  • the composition comprises, consists of, or consists essentially of one or more active agents, one or more lipid sources, one or more surfactants, one or more preservatives, and one or more co-emulsifiers.
  • the composition comprises, consists of, or consists essentially of one or more active agents, one or more lipid sources, one or more surfactants, one or more flavoring agents, and one or more co-emulsifiers.
  • the composition comprises, consists of, or consists essentially of one or more active agents, one or more surfactants, and one or more co-emulsifiers. In several embodiments, the composition comprises, consists of, or consists essentially of one or more active agents, one or more lipid sources, one or more surfactants, one or more flavoring agents, and one or more preservatives. In several embodiments, the composition comprises, consists of, or consists essentially of one or more active agents, one or more lipid sources, and one or more surfactants. In several embodiments, the composition comprises, consists of, or consists essentially of one or more active agents, one or more lipid sources, one or more surfactants, and one or more preservatives.
  • the composition comprises, consists of, or consists essentially of one or more active agents, one or more surfactants, one or more flavoring agents, and one or more preservatives. In several embodiments, the compositions above do not comprise a surfactant. [0139] In several embodiments, the nanoparticle composition lacks terpenes (e.g., as impurities or additives). However, in other embodiments, one or more terpenes may be added to prepare the nanoparticle composition.
  • the one or more terpenes includes one or more of alpha fenchone, alpha terpinene, alpha terpineol, beta caryophyllene, alpha pinene, beta pinene, bisabolene, bisabolol, borneol, eucalyptol, gamma terpinene, guaiacol, humulene, linalool, myrcene, para cymene, phytol, and/or terpinolene.
  • the one or more terpenes includes one or more of 7,8-dihydro-alpha-ionone, 7,8- dihydro-beta-ionone, Acetanisole, Acetic Acid, Acetyl Cedrene, Anethole, Anisole, Benzaldehyde, Bergamotene (Alpha-cis-Bergamotene) (Alpha-trans-Bergamotene), Bisabolol (Beta-Bisabolol), Alpha Bisabolol, Borneol, Bornyl Acetate, Butanoic/Butyric Acid, Cadinene (Alpha-Cadinene) (Gamma-Cadinene), cafestol, Caffeic acid, Camphene, Camphor, Capsaicin, Carene (Delta- 3 -Carene), Carotene, Carvacrol, Dextro-Carvone, Laevo-Carvone, Alpha-Cary
  • the composition may also comprise one or more terpenes.
  • the one or more terpenes collectively or individually, are present in the aqueous composition at a concentration of less than or equal to about: 400 mg/mL, 300 mg/mL, 200 mg/mL, 150 mg/mL, 100 mg/mL, 75 mg/mL, 50 mg/mL, 25 mg/mL, or ranges including and/or spanning the aforementioned values.
  • the one or more terpenes are present in the composition at a dry wt.
  • the one or more terpenes are present in the composition at a wet wt. % of equal to or less than about: 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 30%, 40%, or ranges including and/or spanning the aforementioned values.
  • the mixed nanoparticle composition provides particles in the nano-measurement range.
  • the nanoparticle is spherical or substantially spherical.
  • a solid lipid nanoparticle possesses a solid lipid core matrix that can solubilize lipophilic molecules.
  • the lipid core is stabilized by surfactants and/or emulsifiers as disclosed elsewhere herein, while in other embodiments, surfactants are absent.
  • the size of the particle is measured as a mean diameter. In several embodiments, the size of the particle is measured by dynamic light scattering. In several embodiments, the size of the particle is measured using a zeta-sizer.
  • the size of the particle can be measured using Scanning Electron Microscopy (SEM). In several embodiments, the size of the particle is measured using a cyrogenic SEM (cryo-SEM). Where the size of a nanoparticle is disclosed elsewhere herein, any one or more of these instruments or methods may be used to measure such sizes.
  • SEM Scanning Electron Microscopy
  • cryo-SEM cyrogenic SEM
  • the nanoparticle composition comprises nanoparticles having an average size of less than or equal to about: 10 nm, 25 nm, 40 nm, 50 nm, 100 nm, 250 nm, 500 nm, 1000 nm, or ranges including and/or spanning the aforementioned values. In several embodiments, the composition comprises nanoparticles having an average size of between about 50 nm and 150 nm or between about 50 and about 250 nm.
  • the size distribution of the nanoparticles for at least 50%, 75%, 80%, 90% (or ranges including and/or spanning the aforementioned percentages) of the particles present is equal to or less than about: 20 nm, 40 nm, 60 nm, 80 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 160 nm, 180 nm, 200 nm, 300 nm, 400 nm, 500 nm, or ranges including and/or spanning the aforementioned nm values.
  • the composition comprises nanoparticles having an average size of less than or equal to about: 10 nm, 50 nm, 100 nm, 250 nm, 500 nm, 1000 nm, or ranges including and/or spanning the aforementioned values.
  • the size distribution of the nanoparticles for at least 90% of the particles present is equal to or less than about: 20 nm, 40 nm, 60 nm, 80 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 160 nm, 180 nm, 200 nm, 300 nm, 400 nm, 500 nm, or ranges including and/or spanning the aforementioned nm values.
  • the size distribution of the nanoparticles for at least 90% of the particles present is equal to or less than about: 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 160 nm, 180 nm, 200 nm, or ranges including and/or spanning the aforementioned nm values.
  • the D90 of the particles present is equal to or less than about: 80 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 160 nm, 180 nm, 200 nm, 300 nm, 400 nm, 500 nm, or ranges including and/or spanning the aforementioned values.
  • the size of the nanoparticle is the diameter of the nanoparticle as measured using any of the techniques as disclosed elsewhere herein. For instance, in some embodiments, the size of the nanoparticle is the measured using dynamic light scattering. In several embodiments, the size of the nanoparticle is the measured using a zeta sizer. In several embodiments, consistency in size over time, or within a sample, allows predictable stability for the active agent encapsulated therein.
  • the nanoparticles prepared by the methods disclosed herein have a particle size of between about 20 to about 500 nm (as measured by zeta sizing (e.g., refractive index). In several embodiments, over 50%, 75%, 95% (or ranges spanning and or including the aforementioned values) of the nanoparticles prepared by the methods disclosed herein have a particle size of between about 50 nm to about 200 nm (as measured by zeta sizing (e.g., refractive index).
  • the nanoparticles prepared by the methods disclosed herein have a particle size of between about 90 nm to about 150 nm (as measured by zeta sizing (e.g., refractive index). In several embodiments, this consistency in size allows predictable delivery to subjects. In several embodiments, the D90 particle size measurement varies between 150 and 500 nm.
  • the nanoparticle composition is an oil-in-water emulsion, water-in-oil emulsion, water-in-oil-in-water emulsion, oil-in-water-in-oil emulsion, liposome, solid lipid particles formulation, etc.
  • these may just be referred to as the composition.
  • the nanoparticle composition can be processed to comprises one or more of solid lipid nanoparticles, liposomes (and variants including multi-lamellar, double liposome preparations, etc.), niosomes, ethosomes, electrostatic particulates, microemulsions, nanoemulsions, microsuspensions, nanosuspensions, or combinations thereof.
  • polymeric nanoparticles may be formed.
  • cyclodextrin is added.
  • a solid lipid nanoparticle compositions comprises a lipid core matrix.
  • the lipid core matrix is solid.
  • the solid lipid comprises one or more ingredients as disclosed elsewhere herein.
  • the core of the solid lipid comprises one or more lipids, surfactants, active ingredients, etc.
  • the surfactant acts as an emulsifier.
  • emulsifiers can be used to stabilize the lipid dispersion (with respect to charge and molecular weight).
  • the core ingredients e.g., the components of the core
  • the core ingredients and/or the emulsifiers are present in the composition at a wet wt. % of equal to or less than about: 0.5%, 1.0% 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 30%, 40%, 60% or ranges including and/or spanning the aforementioned values.
  • the nanoparticle composition (e.g., when in water or dried) comprises multilamellar nanoparticle vesicles, unilamellar nanoparticle vesicles, multivesicular nanoparticles, emulsion particles, irregular particles with lamellar structures and bridges, partial emulsion particles, combined lamellar and emulsion particles, and/or combinations thereof.
  • the composition is characterized by having multiple types of particles (e.g., lamellar, emulsion, irregular, etc.). In other embodiments, a majority of the particles present are emulsion particles.
  • a majority of the particles present are lamellar (multilamellar and/or unilamellar). In other embodiments, a majority of the particles present are irregular particles. In still other embodiments, a minority of the particles present are emulsion particles. In several embodiments, a minority of the particles present are lamellar (multilamellar and/or unilamellar). In other embodiments, a minority of the particles present are irregular particles.
  • an aqueous nanoparticle composition as disclosed herein has a viscosity (in centipoise (cP)) of equal to or less than about: 1.0, 1.05, 1.1, 1.2, 1.5, 2.0, 5.0, 10.0, 20, 30, 50, 100, or ranges including and/or spanning the aforementioned values.
  • cP centipoise
  • the nanoparticle composition has a viscosity (in centipoise (cP)) of equal to or less than about: 1.0, 1.05, 1.1, 1.2, 1.5, 2.0, 5.0, 10.0, 20, 30, 50, 100, or ranges including and/or spanning the aforementioned values.
  • cP centipoise
  • the nanoparticle composition has a viscosity (in cP) of equal to or less than about: 1.0, 1.05, 1.1, 1.2, 1.5, 2.0, 5.0, 10.0, 20, 30, 50, 100, or ranges including and/or spanning the aforementioned values.
  • the viscosity of the CBD lipid nanoparticle aqueous solution is equal to or less than 5.0 Cp.
  • the nanoparticle delivery system described herein offers protection to active compounds against degradation in an aqueous environment for long-term storage.
  • the composition is well characterized to ensure a consistent product from batch to batch and with long-term stability.
  • the product stability is routinely tested for appearance, particle size and distribution, zeta potential, residual solvents, heavy metals, active compound concentration, and microbial testing and the values measured using these test methods varies (over a period of at least about 1 month or about 6 months at 25°C with 60% relative humidity) by less than or equal to about: 1%, 5%, 10%, 20%, 30%, or ranges including and/or spanning the aforementioned values.
  • the particle size and/or PDI varies over a period of at least about 1 month or about 6 months (at 25°C with 60% relative humidity) by less than or equal to about: 1%, 5%, 10%, 20%, 30%, or ranges including and/or spanning the aforementioned values.
  • the active agent e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like
  • concentration varies over a period of at least about 1 month or about 6 months (at 25°C with 60% relative humidity) by less than or equal to about: 1%, 5%, 10%, 15%, or ranges including and/or spanning the aforementioned values.
  • PDI and size can be measured using conventional techniques disclosed herein.
  • the formulations and/or compositions disclosed herein are stable during sterilization.
  • the sterilization may include one or more of ozonation, UV treatment, and/or heat treatment.
  • the particle size and/or PDI after sterilization varies by less than or equal to about: 1%, 5%, 10%, 20%, 30%, or ranges including and/or spanning the aforementioned values.
  • the active agent e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like
  • concentration after sterilization varies (e.g., drops) by less than or equal to about: 1%, 5%, 10%, 15%, or ranges including and/or spanning the aforementioned values.
  • the nanoparticle compositions (including after stabilization) disclosed herein have a shelf life of equal to or greater than 6 months, 12 months, 14 months, 16 months, 18 months, 19 months, or ranges including and/or spanning the aforementioned values.
  • the shelf-life can be determined as the period of time in which there is 95% confidence that at least 50% of the response (active agent(s) concentration or particle size) is within the specification limit. This refers to a 95% confidence interval and when linear regression predicts that at least 50% of the response is within the set specification limit.
  • the composition contains preservatives to protect against bacteria, mold, and fungal growth.
  • the product specification is no more than 100 cfu/gram.
  • the composition has equal to or not more than: 50 cfu/gram, 10 cfu/gram, 5 cfu/gram, 1 cfu/gram, 0.1 cfu/gram, or ranges including and/or spanning the aforementioned values.
  • the composition has equal to or not more than: 100 cfu/gram, 50 cfu/gram, 25 cfu/gram, 10 cfu/gram, 5 cfu/gram, 1 cfu/gram, 0.1 cfu/gram, or ranges including and/or spanning the aforementioned values.
  • the composition has a log reduction for the bacteria of equal to or greater than: 1, 2, 3, 4, 5, 10, or ranges including and/or spanning the aforementioned values.
  • the shelf-life can be determined as the period of time in which there is 95% confidence that at least 50% of the response (active agent(s) concentration or particle size) is within a specification limit.
  • a specification limit is a range of measured values in which a quality parameter should be within in order for products to be considered of the same quality when it was initially released. For example, where the CBD target concentration is 20 mg/mL, a specification limit may be defined as 18 to 22 mg/mL. At a time during a stability study, the CBD concentration may fall below 18 mg/mL due to chemical instability, at that time the product may be considered out of specification.
  • the shelf life determined as a time where the concentration of the active ingredient has changed (e.g., lessened) by less than or equal to 15%, 10%, 5%, 2.5%, or ranges including and or spanning the aforementioned ranges.
  • the density of the composition is purposefully modified.
  • the density is approximately 0.7 g/mL, 0.75 g/mL, 0.8 g/mL, 0.85 g/mL, 0.9 g/mL, 0.95 g/mL, 1.0 g/mL, 1.05 g/mL, 1.1 g/mL, 1.15 g/mL, 1.2 g/mL, 1.25 g/mL, 1/.3 g/mL, or ranges including and or spanning the aforementioned ranges.
  • the density of the composition is modified to approximately equal the density of an aqueous solution, a gel, a liquid, a cream, or a lotion.
  • the density is modified by adjust the ratio of different nanoparticle types (e.g., liposomes, solid lipid nanoparticles, etc.). In some embodiments, the density is modified by adjusting the ratio between a first lipid and second lipid. In some embodiments, the density is modified by adjusting the ratio between a first set of lipids and a second set of lipids. In some embodiments, concentrations of lipids with different chain lengths (e.g. 8 carbon, 10 carbon, 18 carbon lipids) are adjusted to modify the density. Such modifications described for modifying density may also influence API solubility (z.e., encapsulation), physical stability, chemical stability, particle composition
  • the composition comprises 6-7% active agent, 13-14% HSPC, 12-13% MCT, 0-1 % vitamin E, 1-2% cholesterol and/or plant sterol(s), and 66-67% trehalose. In some embodiments, the composition comprises 6-7% active agent, 27-28% lipid carrier, and 66-67% carbohydrate.
  • the particle comprises a lipid source, a surfactant, a coemulsifier, or combinations of the foregoing.
  • the particle is a nanoscale particle (e.g., a nanoparticle).
  • the particle is a microscale particle (e.g., a microparticle).
  • the individual particles within the disclosed nanoparticle compositions may not settle or sediment appreciably.
  • an appreciable amount of the composition e.g., as viewed by the naked eye
  • the composition does not settle and/or separate from an aqueous liquid upon standing.
  • the composition does not appreciably settle or separate from an aqueous liquid upon standing for equal to or at least about 1 day, at least about 1 month, about 3 months, about 6 months, about 9 months, about 1 year, or ranges including and/or spanning the aforementioned values.
  • the composition upon standing, the composition remains dispersed in an aqueous liquid for at least about 1 day, at least about 1 month, about 3 months, about 6 months, about 9 months, about 1 year, or ranges including and/or spanning the aforementioned values.
  • the homogeneity of the disclosed compositions changes by equal to or less than about: 0.5%, 1%, 5%, 7.5%, 10%, or 15% (or ranges including and/or spanning the aforementioned values) after a period of one week or one month. In this case, homogeneity is observed through images by SEM or cyro-SEM (e.g., the average size of the particles and/or the particle types).
  • the composition remains dispersed in an aqueous liquid and does not appreciably settle or separate from an aqueous liquid after at least about: 1 minute, 5 minutes, 30 minutes, or an hour in a centrifuge at a centripetal acceleration of at least about 100 m/s, at least about 1000 m/s, or at least about 10,000 m/s. In several embodiments, the composition remains dispersed in an aqueous liquid and does not appreciably settle or separate from an aqueous liquid after at least about: 1 minute, 5 minutes, 30 minutes, or an hour in a centrifuge at a centrifuge speed of 5000 RPM, 10,000 RPM, or 15,000 RPM.
  • the average size of the nanoparticles of a composition as disclosed herein is substantially constant and/or does not change significantly over time (e.g., it is a stable nanoparticle).
  • the average size of nanoparticles comprising the composition changes less than or equal to about: 1%, 5%, 10%, 20%, or ranges including and/or spanning the aforementioned values.
  • the polydispersity index (PDI) of the nanoparticles of a composition as disclosed herein is less than or equal to about: 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, or ranges including and/or spanning the aforementioned values.
  • the size distribution of the nanoparticles is highly monodisperse with a polydispersity index of less than or equal to about: 0.05, 0.10, 0.15, 0.20, 0.25, or ranges including and/or spanning the aforementioned values.
  • the zeta potential of the nanoparticles of a composition as disclosed herein is less than or equal to about: 1 mV, 3 mV, 4 mV, 5 mV, 6 mV, 7 mV, 8 mV, 10 mV, 20 mV, or ranges including and/or spanning the aforementioned values. In several embodiments, the zeta potential of the nanoparticles is greater than or equal to about: -3 mV, -
  • the zeta potential and/or diameter of the particles is acquired using a zetasizer (e.g., a Malvern ZS90 or similar instrument).
  • the nanoparticle composition has a pH of less than or equal to about: 2, 3, 4, 5, 6, 6.5, 7, 8, 9, or ranges including and/or spanning the aforementioned values. In several embodiments, the composition has a pH of greater than or equal to about: 2, 3, 4, 5, 6, 6.5, 7, 8, 9, or ranges including and/or spanning the aforementioned values. For example, in several embodiments, the composition has a pH ranging from 2 to 4, 4 to 6, 6 to 8,
  • multilamellar nanoparticles comprise equal to or at least about 5%, 8%, 9%, 10%, 15%, 25%, 50%, 75%, 85%, 95%, or 100% (or ranges spanning and/or including the aforementioned values), of the particles present in the composition (e.g., the aqueous composition)
  • the composition e.g., the aqueous composition
  • the particles present in the composition e.g., the aqueous composition
  • the composition e.g., the aqueous composition
  • between about 5% and about 10% of the particles present are multilamellar.
  • about 8.6% of the particles present are multilamellar.
  • unilamellar nanoparticles comprise equal to or at least about 5%, 8%, 9%, 10%, 15%, 20%, 25%, 50%, 75%, 85%, 95%, or 100% (or ranges spanning and/or including the aforementioned values) of the particles present in the composition (e.g., the aqueous composition). For example, in some embodiments, between about 10% and about 15% of the particles present are unilamellar. In several embodiments, about 12.88% of the particles present are unilamellar.
  • emulsion particles comprise equal to or at least about 5%, 8%, 9%, 10%, 15%, 25%, 50%, 60%, 65%, 70%, 75%, 85%, 95%, or 100% (or ranges spanning and/or including the aforementioned values) of the particles present in the composition (e.g., the aqueous composition).
  • the composition e.g., the aqueous composition.
  • between about 60% to about 75% of the particles present are emulsion particles.
  • about 69.7% of the particles present are emulsion particles.
  • micelle particles comprise equal to or at least about 5%, 8%, 9%, 10%, 15%, 25%, 50%, 60%, 65%, 70%, 75%, 85%, 95%, or 100% (or ranges spanning and/or including the aforementioned values) of the particles present in the composition (e.g., the aqueous composition).
  • liposomes comprise equal to or at least about 5%, 8%, 9%, 10%, 15%, 25%, 50%, 60%, 65%, 70%, 75%, 85%, 95%, or 100% (or ranges spanning and/or including the aforementioned values) of the particles present in the composition (e.g., the aqueous composition).
  • irregular particles comprise equal to or at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 25%, 50%, 75%, 85%, 95%, or 100% (or ranges spanning and/or including the aforementioned values) of the particles present in the composition (e.g., the aqueous composition).
  • the composition e.g., the aqueous composition.
  • between about 1% to about 5% of the particles present are irregular particles.
  • 2.73% are irregular particles.
  • combined lamellar and emulsion particles comprise equal to or at least about 5%, 6%, 7%, 8%, 9%, 10%, 15%, 25%, 50%, 75%, 85%, 95%, or 100% (or ranges spanning and/or including the aforementioned values) of the particles present in the composition (e.g., the aqueous composition).
  • the composition e.g., the aqueous composition.
  • between about 5% to about 6% of the particles present are combined lamellar and emulsion particles.
  • 6.06% of the particles are combined lamellar and emulsion particles.
  • mixed-micelle particles comprise equal to or at least about 5%, 6%, 7%, 8%, 9%, 10%, 15%, 25%, 50%, 75%, 85%, 95%, or 100% (or ranges spanning and/or including the aforementioned values) of the particles present in the composition (e.g., the aqueous composition).
  • the nanoparticle compositions can comprise combinations of multilamellar nanoparticles, unilamellar nanoparticles, emulsion nanoparticles, micelle nanoparticles, irregular particles, and/or liposomes.
  • the percentages and/or concentrations of particles present in the composition may be purposefully modified.
  • the percentage and/or concentration of the particles present in the composition are tailored to the active compound and/or the liquid comprising the particles. Such tailoring may lead to more homogenization and/or dispersion in the liquid.
  • the tailoring may stabilize dispersion in the liquid.
  • Such tailoring may also tailor to specific densities of the compositions. The densities of the compositions can be matched or different from a liquid that the compositions are contacted by or contained within.
  • the composition is biased towards one type of nanoparticle, such as solid nanoparticles or liposomes.
  • the composition may be biased by increasing or decreasing the ratio in the composition of lipids that are solid at room temperature to lipids that are liquid at room temperature.
  • Lipids that are liquid at room temperature may comprise MCT (a mixture of capric and caprylic triglycerides, which may have a ratio of c8:cl0 carbon chains of 45:55), captex 1000 (a triglyceride of capric acid).
  • Lipids that are solid at room temperature may comprise solubilizers and/or emollients.
  • Lipids that are solid at room temperature may comprise phosphatidylcholine (such as HSPC) phosphatidylethanolamine, sphingomyelin, triglycerides of oleic acid, and/or triglycerol monooleate.
  • concentration of an oil is adjusted, such as the concentration of a triglyceride, a fatty acid, a diglyceride, or a monoglyceride.
  • the concentration of a sterol such as cholesterol or a plant sterol, is adjusted.
  • the composition is biased towards liposomes by increasing the concentration of lipids that are liquid at room temperature.
  • Biasing the composition may alter characteristics of the composition including density, particle composition, solubility, pharmacokinetic properties, or other characteristics described herein. [0173] Decreasing the concentration of a co-emulsifier that is a liquid at room temperature can bias the outcome of the particles more towards liposomes while increasing the concentration of a co-emulsifier that is a liquid at room temperature can bias the outcome of the particles more towards solid lipid nanoparticles. Also, increasing the concentration of a lipid that is solid at room temperature can bias the outcome of particles more towards liposomes. As non-limiting examples, decreasing concentrations of the co-emulsifier MCT and/or increasing the concentration of HSPC will bias the outcome of the particles more towards liposomes.
  • substituting MCT with a lipid that is a liquid at room temperature and/or increasing the concentration ratio of HSPC to MCT will bias the outcome of the particles more towards liposomes.
  • substituting HSPC with a lipid that is a solid at room temperature will bias the outcome of the particles more towards solid lipid nanoparticles.
  • the composition comprises high purity triglycerides, such as oleic acid and/or conjugated linoleics.
  • the composition may be formulated, such as by changing the composition or concentration of lipids, for specific delivery or specific metabolism.
  • the composition may comprise medium chain triglycerides to bias the composition towards phase 1 liver metabolism.
  • the composition is formulated for a specific absorption mechanism, such as lymphatic absorption or liver first pass.
  • lipid-based particle composition comprising: a nanoparticle comprising an active compound that is of sufficient purity that it exists in a solid and/or powdered state prior to formulation in the nanoparticle composition at a weight percent in the composition ranging from 1% to 10%; a phosphatidylcholine at a weight percent in the composition ranging from 2.5% to 15%; a sterol at a weight percent in the composition ranging from 0.5% to 5%; and a medium chain triglyceride at a weight percent in the composition ranging from 2.5% to 15%.
  • the composition comprises water at a weight percent in the composition ranging from 60% to about 80%.
  • the nanoparticles have an average size ranging from about 75 nm to about 175 nm. In some embodiments, upon storage for a period of one month, the average size of the nanoparticles changes by less than about 20%.
  • the nanoparticle composition is in the form of liposomes and/or an oil-in-water nano-emulsion. In some embodiments, an appreciable amount of the nanoparticle composition does not settle and/or separate from the water upon standing for a period of at least about 12 hours, 24 hours, 3 days, 5 days, a week, 2 weeks, 3 weeks, 5 weeks, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months. In some embodiments, the composition is configured such that when concentrated to dryness to afford a powder formulation of nanoparticles, the nanoparticle powder can be reconstituted to provide the nanoparticle composition. In some embodiments, the composition has a Tmax for CBD of less than 4.5 hours.
  • the average size of the nanoparticles changes by less than about 20%.
  • the polydispersity of the nanoparticles in the composition is less than or equal to 0.15.
  • the polydispersity of the nanoparticles changes by less than or equal to 10%.
  • the polydispersity of the nanoparticles changes by less than or equal to 0.1.
  • the composition has a shelf life of greater than 18 months at 25°C and 60% relative humidity.
  • the D90 of the nanoparticles changes less than or equal to 10%.
  • the composition has a concentration max (Cmax) of 80 ng/ml after an oral dose of 15 mg/kg.
  • the nanoparticle composition is in the form and/or comprises one or more of liposomes, an oil-in-water nano-emulsion (and/or microparticle emulsion), and/or solid lipid particles.
  • an appreciable amount of the particles in the composition do not settle and/or do not separate (e.g., upon visual inspection) from the water upon standing for a period of at least about 12 hours.
  • the particles when suspended in water, the particles remain substantially homogenously distributed in the water upon standing for a period of at least about 12 hours, 24 hours, 3 days, 5 days, a week, 2 weeks, 3 weeks, 5 weeks, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months.
  • the nanoparticles have an average size ranging from about 10 nm to about 500 nm.
  • the composition comprises nanoparticles having an average size of less than or equal to about: 10 nm, 50 nm, 100 nm, 250 nm, 500 nm, 1000 nm, or ranges including and/or spanning the aforementioned values.
  • the composition comprises microparticles having an average size of less than or equal to about: 1000 nm, 1.5 pm, 2 pm, 3 pm, 5 pm, 10 pm or ranges including and/or spanning the aforementioned values.
  • the dried powder composition comprises microparticles that form nanoparticles (as disclosed herein) when reconstituted.
  • these dried powder compositions comprise particles having an average size of less than or equal to about: 250 nm, 500 nm, 1000 nm, 1.5 pm, 2 pm, 3 pm, 5 pm, 10 pm, 50 pm, or ranges including and/or spanning the aforementioned values.
  • the average size of the nanoparticles (or microparticles) increases by less than about 10%.
  • the nanoparticle composition is configured such that when concentrated to dryness to afford dry particles (e.g., from any one of the oil-in-water emulsion (e.g., a nanoemulsion or microemulsion), liposome solution, and/or solid lipid particle) as a powder, the dry nanoparticles can be reconstituted to provide a reconstituted particle based solution (e.g., the nanoparticle composition).
  • the average size of the nanoparticles increases or decreases by less than about 15% and/or by less than about 100%.
  • excipients may be added to the liposomes, oil-in-water nano-emulsions (and/or microparticle emulsions), and/or a solid lipid particle.
  • the excipient comprises trehalose.
  • the active compounds may be encapsulated in one or more of the nanoparticles described herein.
  • the active compounds may be pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like.
  • the active compound comprises a therapeutic.
  • the therapeutic may be an analgesic, an anesthetic, an antibacterial agent, an anticonvulsant, an antidementia agent, an antidepressant, an antidote, a deterrent, a toxicologic agent, an antiemetic, an antifungal, an antigout agent, an anti-inflammatory agent, an antimigraine agent, an antimyasthenic agent, an antineoplastic agent, an antiparasitic agent, an antiparkinson agent, an antipsychotic, an antipasticity agent, an antiviral, an anxiolytic, a bipolar agent, a blood glucose regulator, a blood product, a blood modifier, a blood volume expander, a cardiovascular agent, a central nervous system agent, a dental agent, an oral agent, a dermatological agent, an enzyme replacement agent, an enzyme modifying agent, a gastrointestinal agent, a genitourinary agent, a hormonal agent, a hormone stimul
  • a therapeutic may
  • the hormonal agent, a hormone stimulant, a hormone replacement, a hormone modifying agent, and/or hormone surpressant may act on the adrenal system, the pituitary system, the prostaglandin system, sex hormone, the thyroid, and/or the parathyroid.
  • the active compound may comprise a small molecule.
  • the active compound may comprise a biologic.
  • the active compound may comprise a biomolecule.
  • the active compound may comprise a macromolecule.
  • the active compound comprises a nucleic acid, a protein, a lipid, a carbohydrate, or a combination thereof.
  • the active compound comprises a cell or a derivative of a cell.
  • the active compound comprises antisense RNA.
  • the active compound comprises an siRNA, a miRNA, a IncRNA, or a combination thereof.
  • the active compound comprises a nucleic acid vector.
  • the active compound is selected from the group consisting of Cannabidiol, Cannabigerol, Cannabinol, Cannabichromene, Tetrahydrocannabivarin, Tetrahydrocannabinol, Full extracts of hemp, Specific ratios of isolated cannabinoids, Cannabigerolic acid, Cannabidolic acid, Mitragynine, Payantheine, Mitraphylline, Speciociliantine, Speciogynine, Cholecalciferol, Ergocalciferol, D,L-Alpha-Tocopherol, Menaquinone, Ascorbyl palmitate, Retinyl palmitate, Beta-Sitosterol, Plant Sterol Rich Extracts, Cholesterol, Ubiquinone, Phosphatidylcholine, Phosphatidylserine, Eicosapentaenoic/Docosahexaenoic Acid Mix
  • the active compound comprises kratom extracts, kanna extracts, kava extracts, mushroom extracts (e.g., Psilocybe cuhensisy Cannabis extracts, cannabinoids, other therapeutic agents, phytocannabinoids, fish oils, vitamin D, other vitamins, and/or combinations of any of the foregoing.
  • the active compounds may be prepared using the thoroughness and diligence of pharmaceutical drug development to consumer products.
  • the one or more therapeutic agents include one or more kratom extracts.
  • the one or more therapeutic agents include one or more plant extracts or fungus extracts (e.g., mushroom extracts).
  • the one or more therapeutic agents may comprise, consist of, or consist essentially of kratom extracts, kanna extracts, kava extracts, mushroom extracts (e.g., Psilocybe cubensisy Cannabis extracts, cannabinoids, and/or combinations of any of the foregoing.
  • Kratom or Mitragyna speciosa, is a tropical evergreen tree in the coffee family. This tree is native to Southeast Asia and is indigenous to Thailand, Indonesia, Malaysia, Sri, Malaysia, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri, Sri,
  • Kratom strains may be selected from the group consisting of Maeng da, Indo, Bas/red vein, Green Malay, Super Green Malaysian, Red Kali Kratom, Green Vein Kali, White Vein Kali, Red Indo Kratom, Green Indo Kratom, White Vein Indo Kratom, White Vein Thai Kratom, Gold Reserve Kratom Extract, Ultra Enhanced Indo Extract, ISOL-8 Extract, Natural Enhanced True Thai, Natural Enhanced White Sumatra, other kratoms, or combinations of any of the foregoing.
  • nanoparticles are composed of and/or comprise kratom powders and/or one or more kratom active ingredients.
  • the kratom active ingredients include, but are not limited to, alkaloids, mitaphylline, 7-OH-mitragynine, paynantheine, speciogynine, mitragynine, other kratom active agents, and/or combinations of any of the foregoing.
  • a kratom extract may be an alkaloid from kratom.
  • the kratom extract is an alkaloid selected from the group consisting of Ajmalicine or Raubasine (a cerebrocirculant, antiaggregant, anti-adrenergic (at alpha- 1), sedative, anticonvulsant, smooth muscle relaxer), akuammigine, ciliaphylline (antitussive, analgesic), corynantheidine (p-opioid antagonist, also found in yohimbe), corynoxeine (calcium channel blocker), corynoxine A and/or B (dopamine mediating anti-locomotives, epicatechin (antioxidant, antiaggregant, antibacterial, antidiabetic, antihepatitic, anti-inflammatory, anti-leukemic, antimutagenic, antiperoxidant, antiviral, potential cancer preventative, alpha-amylase inhibitor), 9-hydroxycorynantheidine (partial opioid agonist), 7-hydroxymitragynine (analgesic, anti
  • the kratom extracts are extracted from kratom (e.g., are natural extracts). In other embodiments, the kratom extracts may be produced synthetically (e.g., in a laboratory). In several embodiments, the synthetic extract may share a structure with an extract that is naturally occurring. In several embodiments, the kratom extracts are analogs of natural extracts of kratom (e.g., produced synthetically).
  • the kratom extract is an alkaloid extracted from kratom (e.g., is a natural extract). In other embodiments, the kratom extract is a kratom alkaloid produced synthetically (e.g., in a laboratory). In several embodiments, the synthetic extract may share a structure with an extract that is naturally occurring. In several embodiments, the kratom alkaloid is an analogs of natural extracts of kratom (e.g., produced synthetically).
  • Sceletium tortuosum is a succulent plant commonly found in South Africa, which is also known as Kanna, Channa, Kougoed.
  • Sceletium species including S. crassicaule, S. emarcidum, S. exalatum, S. expansum, S. rigidum, S. strictum, S. tortuosum and S. various.
  • the one or more kanna extracts may be from any one or more of these kanna plants.
  • the kanna plant has been used by South African scenicists and hunter-gatherers as a mood-altering substance. Traditionally, dried Sceletium was chewed and the saliva swallowed.
  • the nanoparticle compositions comprise one or more kanna extracts.
  • the kanna extracts are from one or more Sceletium species.
  • the one or more species are selected from the Tortuosum family (Sceletium tortuosum; Sceletium crassicaule; Sceletium strictum; Sceletium expansum, Sceletium varians, etc.) or the Emarcidum family (Sceletium emarcidum; Sceletium exalatum, Sceletium rigidum, etc.).
  • extracts from combinations of Sceletium species are used, other Sceletium species, or combinations of any of the foregoing.
  • the nanoparticle (or a composition comprising the nanoparticle) comprises or is composed of Sceletium extracts. In several embodiments, the nanoparticle (or a composition comprising the nanoparticle) comprises or is composed of Sceletium powders and/or one or more Sceletium active ingredients (e.g., including but not limited to alkaloids). In several embodiments, the kanna extract is an alkaloid (or a combination thereof).
  • the kanna extract is an alkaloid selected from the group consisting of joubertiamine dehydrojoubertiamine dihydrojoubertiamine joubertinamine, O-methyldehydrojoubertiamine, O-methyljouberiamine, O- methyldihydrojoubertiamine, 3’-methoxy-4’-o-methyl joubertiamine, 4-(3,4- dimehoxyphenyl)-4-[2-acetylmethylamino)ethyl]cyclohexanone, 4-(3-methoxy-4-hydroxy- phenyl)-4-[2-(aceylmethylamino)ethyl]cyclohexadienone, sceletium alkaloid A4, touruosamine, N-formyltortuosamine, N-acetyltortuosamine, or combinations of any of the foregoing.
  • the alkaloid is a 3a-aryl-cis-octahydroindole class (e.g. mesembrine), C-seco mesembrine alkaloids (e.g. joubertiamine), an alkaloid containing a 2,3- disubstituted pyridine moiety and 2 nitrogen atoms (e.g. sceletium A4), a ring C-seco Sceletium alkaloid A4 group (e.g. tortuosamine), or combinations of the foregoing.
  • the kanna (e.g., Sceletium) extracts are extracted from Sceletium (e.g., are natural extracts).
  • the Sceletium extracts may be produced synthetically (e.g., in a laboratory).
  • the synthetic extract may share a structure with an extract that is naturally occurring.
  • the Sceletium extracts are analogs of natural extracts of Sceletium (e.g., produced synthetically).
  • solutions of lipid particles are composed and or comprise kava extracts.
  • Kava Piper methysticum is a plant found in the south Pacific. The root of the plant can be used to produce a drink with sedative, anesthetic, and euphoriant properties.
  • Kava has a number of active kavalactones ingredients. Consumption of kava extracts produced with excessive amounts of poor-quality kava products, may be linked to an increased risk of adverse health outcomes, including potential liver injury.
  • delivery of these kava extracts using traditional methods and current formulations is highly inefficient, highly uncontrolled, has potential side-effects, and may suffer from with low reliability, and/or high variability batch- to-batch.
  • the nanoparticle compositions disclosed herein solve one or more of these problems or others.
  • the mushroom extracts are from a mushroom species that produces psilocybin (e.g., a psilocybin mushroom).
  • the mushroom species is selected from the group consisting of Mitragyna speciosa, Psilocybe azurescens, Psilocybe semilanceata, Psilocybe cyanescens, or combinations thereof.
  • the mushroom extract is an alkaloid.
  • the alkaloid is psilocin (3-[2 (dimethylamino)ethyl]-4-indolol), psilocybin ([3-(2-dimethylaminoethyl)-l H- indol-4-yl] dihydrogen phosphate), baeocystin, norbaeocystin, bufotenin, aeruginascin, or combinations of any of the foregoing.
  • the mushroom extracts are extracted from mushrooms (e.g., are natural extracts). In other embodiments, the mushroom extracts may be produced synthetically (e.g., in a laboratory). In several embodiments, the synthetic extract may share a structure with an extract that is naturally occurring. In several embodiments, the mushroom extracts are analogs of natural extracts of mushrooms (e.g., produced synthetically).
  • the cannabinoids are highly pure isolates derived from hemp or marijuana plant. Cannabinoids may also be from other sources, for example, ones derived from terpenes and natural sources that do not include hemp. Examples include “citrus CBD” “terpene CBD” and pharmaceutical “synthetic” CBD. In several embodiments, the cannabinoids are derived from broad spectrum hemp and/or cannabis oil, full spectrum hemp and/or cannabis oil, distillates from hemp and/or cannabis oil and combinations thereof.
  • the active agent may comprise or may be a full spectrum or broad spectrum plant extract (e.g., from kratom, kanna, kava, mushroom, Cannabis).
  • the active agent comprises rosin.
  • the rosin is extract that is produced after pressing cannabis or hemp flower using a high-pressure press.
  • the rosin is a broad spectrum extract.
  • the active agent may comprise full spectrum extract, broad spectrum extract, crude, distillates, oils, and isolates, and combinations thereof.
  • the composition is a non-THC containing composition.
  • the total potential THC does not to exceed 0.3 weight % of the phytocannabinoid, where the total potential THC is defined as THCa x 0.877 + 9- THC + 8-THC.
  • the total potential THC does not to exceed 0.3 weight % of the phytocannabinoid, where the total potential THC is defined as THCa + 9-THC.
  • the nanoparticle composition may comprise other active agent (e.g., agents that are not a kratom active, a kanna active, a kava active, a mushroom active, or a Cannabis active).
  • the non-kratom/non-kanna/non-kava active/non-mushroom active/non-Cannabis active agent is one or more of a vitamin, a nutrient, a different plant extract, a nutraceutical, a pharmaceutical, or another beneficial agent.
  • the non-kratom/non-kanna/non-kava active/non-mushroom active/non-Cannabis active agent is hydrophilic. In several embodiments, the non-kratom/non-kanna/non-kava active/non-mushroom active/non- Cannabis active agent is hydrophobic. In several embodiments, the non-kratom/non- kanna/non-kava active/non-mushroom active/non-Cannabis active agent is amphiphilic.
  • the non-kratom/non-kanna/non-kava active/non- mushroom active/non-Cannabis active agent is selected from the group consisting of Noopept (N-phenylacetyl-L-prolyglygice ethyl ester), melatonin, glutathione, gamma-glutamylcysteine (GGC), gamma-aminobutyric acid (GABA), valerian root, magnesium, theanine, 5-HTP, tyrosine, taurine, zinc, alpha fenchone, alpha terpinene, alpha terpineol, beta caryophyllene, alpha pinene, beta pinene, bisabolene, bisabolol, borneol, eucalyptol, gamma terpinene, guaiacol, humulene, linalool, myrcene, para c
  • Noopept N-phen
  • these non-kratom/non-kanna/non-kava active/non-mushroom active/non-Cannabis active agent may be provided in combination with actives at the concentrations disclosed herein.
  • when a hydrophilic composition is used it is mixed with the aqueous soluble ingredients before mixing with the lipid ingredients.
  • the active compound comprises at least one cosmetic ingredient.
  • CTFA International Cosmetic Ingredient Dictionary and Handbook (2004 and 2008) describes a wide variety of non-limiting cosmetic ingredients that can be used in the context of the present disclosure, including as active compounds.
  • the active compound comprises a fragrance, flavor, dye, etc.
  • fragrance agents artificial and natural; e.g., gluconic acid, phenoxyethanol, and triethanolamine
  • dyes and color ingredients e.g., Blue 1, Blue 1 Lake, Red 40, titanium dioxide, D&C blue no. 4, D&C green no. 5, D&C orange no. 4, D&C red no. 17, D&C red no. 33, D&C violet no. 2, D&C yellow no. 10, and D&C yellow no.
  • flavoring agents / aroma agents e.g., Stevia rebaudiana (sweetleaf) extract, and menthol
  • adsorbents e.g., Stevia rebaudiana (sweetleaf) extract, and menthol
  • lubricants solvents
  • moisturizers including, e.g., emollients, humectants, film formers, occlusive agents, and agents that affect the natural moisturization mechanisms of the skin
  • water-repellants e.g., UV absorbers (physical and chemical absorbers such as para-aminobenzoic acid (“PABA”) and corresponding PABA derivatives, titanium dioxide, zinc oxide, etc.), essential oils, vitamins (e.g., A, B, C, D, E, and K), trace metals (e.g., zinc, calcium and selenium), anti-irritants (e.g., steroids and non-steroidal anti-inflammatories), botanical extracts (e.g., Aloe ver
  • the active compound includes at least one UV absorption and/or reflecting agent.
  • UV absorption and/or reflecting agents that can be used in combination with the compositions of the present disclosure include chemical and physical sunblocks.
  • chemical sunblocks include para-aminobenzoic acid (PABA), PABA esters (glyceryl PABA, amyldimethyl PABA and octyldimethyl PABA), butyl PABA, ethyl PABA, ethyl dihydroxypropyl PABA, benzophenones (oxybenzone, sulisobenzone, benzophenone, and benzophenone- 1 through 12), cinnamates (octyl methoxycinnamate (octinoxate), isoamyl p-methoxycinnamate, octylmethoxy cinnamate, cinoxate, diisopropyl methyl cinnamate, DEA-me
  • PABA para-aminobenzoic
  • the active compound comprises at least one moisturizing agent.
  • moisturizing agents that can be used with the compositions of the present invention include amino acids, chondroitin sulfate, diglycerin, erythritol, fructose, glucose, glycerin, glycerol polymers, glycol, 1,2,6-hexanetriol, honey, hyaluronic acid, hydrogenated honey, hydrogenated starch hydrolysate, inositol, lactitol, maltitol, maltose, mannitol, natural moisturizing factor, PEG- 15 butanediol, polyglyceryl sorbitol, salts of pyrrolidone carboxylic acid, potassium PCA, propylene glycol, saccharide isomerate, sodium glucuronate, sodium PCA, sorbitol, sucrose, trehalose, urea, and xylitol.
  • acetylated lanolin examples include acetylated lanolin, acetylated lanolin alcohol, alanine, algae extract, Aloe barbadensis, Aloe barbadensis extract, Aloe barbadensis gel, Althea officinalis extract, apricot (P imus armeniaca) kernel oil, arginine, arginine aspartate, Arnica montana extract, aspartic acid, avocado (Persea gratissima) oil, barrier sphingolipids, butyl alcohol, beeswax, behenyl alcohol, beta-sitosterol, birch (Betula alba) bark extract, borage (Borago officinalis) extract, butcherbroom (Ruscus aculeatus) extract, butylene glycol, Calendula officinalis extract, Calendula officinalis oil, candelilla (Euphorbia cerifera) wax, canola oil
  • the active compound comprises at least one antioxidant.
  • antioxidants that can be used with the compositions of the present invention include acetyl cysteine, ascorbic acid polypeptide, ascorbyl dipalmitate, ascorbyl methylsilanol pectinate, ascorbyl palmitate, ascorbyl stearate, BHA, BHT, t-butyl hydroquinone, cysteine, cysteine HCI, diamylhydroquinone, di-t-butylhydroquinone, dicetyl thiodipropionate, dioleyl tocopheryl methylsilanol, disodium ascorbyl sulfate, distearyl thiodipropionate, ditridecyl thiodipropionate, dodecyl gallate, erythorbic acid, esters of ascorbic acid, ethyl ferulate, ferulic acid, gall
  • the active compound comprises at least one essential oil.
  • Essential oils include oils derived from herbs, flowers, trees, and other plants. Such oils are typically present as tiny droplets between the plant’s cells, and can be extracted by several methods known to those of skill in the art (e.g., steam distilled, enfleurage, maceration, solvent extraction, or mechanical pressing). When these types of oils are exposed to air they tend to evaporate. As a result, many essential oils are colorless, but with age they can oxidize and become darker. Essential oils are insoluble in water and are soluble in alcohol, ether, fixed oils (vegetal), and other organic solvents. Typical physical characteristics found in essential oils include boiling points that vary from about 160 to 240°C and densities ranging from about 0.759 to about 1.096.
  • Essential oils typically are named by the plant from which the oil is found.
  • rose oil or peppermint oil are derived from rose or peppermint plants, respectively.
  • Non-limiting examples of essential oils that can be used in the context of the present invention include sesame oil, macadamia nut oil, tea tree oil, evening primrose oil, Spanish sage oil, Spanish rosemary oil, coriander oil, thyme oil, pimento berries oil, rose oil, anise oil, balsam oil, bergamot oil, rosewood oil, cedar oil, chamomile oil, sage oil, clary sage oil, clove oil, cypress oil, eucalyptus oil, fennel oil, sea fennel oil, frankincense oil, geranium oil, ginger oil, grapefruit oil, jasmine oil, juniper oil, lavender oil, lemon oil, lemongrass oil, lime oil, mandarin oil, marjoram oil, myrrh oil, neroli oil, orange oil,
  • the active agent comprises an algae extract.
  • the algae extract may comprise ashwagandha and/or astoxantin.
  • the active compound is encapsulated by a nanoparticle at a concentration of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, or ranges including and/or spanning the aforementioned values, per kg of the nanoparticle.
  • the nanoparticle composition aids in absorption, bioavailability, or other pharmacokinetic properties of the active compound when administered to an individual, including by orally ingestion.
  • the compositions disclosed herein allow the active compound to be delivered to and/or absorbed through the gut.
  • some embodiments pertain to the use of the nanoparticle based nanodelivery system to protect the active compound from degradation and/or precipitation in a solution comprising the active compound (e.g., in an aqueous composition for administration to a subject).
  • use of the delivery systems, including the nanoparticles, disclosed herein result in improved bioavailability and/or absorption rate. For instance, in some embodiments, the Cmax of an active compound is increased using a disclosed embodiment, the Tmax of an active compound is decreased using an embodiment as disclosed herein, and/or the AUC of an active compound is increased using a disclosed embodiment.
  • the pharmacokinetic outcomes disclosed elsewhere herein can be achieved using aqueous nanoparticle compositions or powdered nanoparticle compositions (e.g., where the powder is supplied by itself, in a gel capsule, as an additive to food, etc.).
  • the Cmax of the active agent is increased using the disclosed embodiments relative to other delivery vehicles (e.g., after administration to a subject).
  • the Cmax is increased relative to the active agent (e.g., pharmaceuticals, nutraceuticals, and the like) alone or comparator embodiments (e.g., oil-based products) by equal to or at least about: 15%, 20%, 50%, 100%, 150%, 200%, or ranges including and/or spanning the aforementioned values.
  • the active agent Cmax is increased (relative to a comparator oil-based product) by equal to or at least about: 5%, 10%, 20%, 30%, 50%, 100%, or ranges including and/or spanning the aforementioned values.
  • the active agent Cmax is increased (relative to a comparator oil-based product) by equal to or at least about: 10 ng/mL, 20 ng/mL, 30 ng/mL, 40 ng/mL, 50 ng/mL, 60 ng/mL, 70 ng/mL, 80 ng/mL, 90 ng/mL, or ranges including and/or spanning the aforementioned values.
  • the Cmax of the active agent is equal to or at least about: 0.5 pg/L, 1 pg/L, 2 pg/L, 3 pg/L, 4 pg/L, 5 pg/L, 6 pg/L, or ranges including and/or spanning the aforementioned values.
  • active agent e.g., pharmaceuticals, nutraceuticals, and the like
  • the Cmax of the active agent is equal to or at least about: 0.5 pg/L, 1 pg/L, 2 pg/L, 3 pg/L, 4 pg/L, 5 pg/L, 6 pg/L, or ranges including and/or spanning the aforementioned values.
  • the Cmax is equal to or at least about: 40 ng/mL, 50 ng/mL, 60 ng/mL, 70 ng/mL, 80 ng/mL, 90 ng/mL, 100 ng/mL, 150 ng/mL, 200 ng/mL, or ranges including and/or spanning the aforementioned values.
  • active agent e.g., pharmaceuticals, nutraceuticals, and the like
  • the Cmax is equal to or at least about: 40 ng/mL, 50 ng/mL, 60 ng/mL, 70 ng/mL, 80 ng/mL, 90 ng/mL, 100 ng/mL, 150 ng/mL, 200 ng/mL, or ranges including and/or spanning the aforementioned values.
  • the Cmax for a disclosed embodiment is increased relative to an equal dose of an active agent (e.g., pharmaceuticals, nutraceuticals, and the like) in an oil-based comparator vehicle.
  • an active agent e.g., pharmaceuticals, nutraceuticals, and the like
  • the Cmax for a disclosed embodiment is increased relative to an oil-based comparator vehicle by equal to or at least about: 15%, 20%, 50%, 100%, 150%, 200%, or ranges including and/or spanning the aforementioned values.
  • these pharmacokinetic results can be achieved using aqueous compositions or powdered compositions (where the powder is supplied by itself, in a gel capsule, as an additive to food, etc.).
  • the Cmax using a disclosed embodiment is 1.25 times higher than when using a comparator delivery system (e.g., the Cmax of the comparator x 1.25). In some instances, the Cmax using a disclosed embodiment is equal to or at least about 1.25 times higher, 1.5 times higher, 2 times higher, 3 times higher (or ranges including or spanning the aforementioned values) than when using a comparator delivery system.
  • the Tmax for an active agent using a disclosed embodiment is shortened relative to other vehicles.
  • the Tmax is equal to or at less than about: 30 minutes, 1 hours, 2 hours, 3 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 8 hours, or ranges including and/or spanning the aforementioned values.
  • the Tmax is equal to or at less than about: 30 minutes, 1 hours, 2 hours, 3 hours, 4 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 8 hours, or ranges including and/or spanning the aforementioned values. In several embodiments, after a dose of active agent provided in an embodiment as disclosed herein to a subject, the Tmax is between about 4 hours and about 6.5 hours or between about 3 hours and about 7 hours.
  • the Tmax is equal to or less than about: 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, or ranges including and/or spanning the aforementioned values.
  • the AUC is equal to or at least about: 50 ng/mL*hr, 100 ng/mL*hr, 200 ng/mL*hr, 300 ng/mL*hr, 400 ng/mL*hr, 450 ng/mL*hr, 500 ng/mL*hr, 550 ng/mL*hr, 600 ng/mL*hr, 650 ng/mL*hr, 700 ng/mL*hr, 800 ng/mL*hr, 1000 ng/mL*hr, or ranges including and/or spanning the aforementioned values.
  • active agent e.g., pharmaceuticals, nutraceuticals, and the like
  • the AUC is equal to or at least about: 50 ng/mL*hr, 100 ng/mL*hr, 200 ng/mL*hr, 300 ng/mL*hr, 400 ng/mL*hr, 450 ng/mL*hr,
  • the half-life for an active agent (e.g., pharmaceuticals, nutraceuticals, and the like) (ti/2) in vivo using a disclosed embodiment can be shorter relative to other vehicles.
  • the ti/2 of active agent is equal to or at less than about: 4 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, or ranges including and/or spanning the aforementioned values.
  • the ti/2 of active agent is between about 4 hours and about 6.5 hours or between about 3 hours and about 7 hours.
  • the ti/2 for a disclosed embodiment is decreased relative to an active agent alone or an oil-based comparator vehicle by equal to or at least about: 15%, 20%, 50%, 100%, 150%, 200%, or ranges including and/or spanning the aforementioned values.
  • the ti/2 of active agent for a disclosed embodiment is decreased relative to the active alone or an oil-based comparator vehicle by equal to or at least about: 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, or ranges including and/or spanning the aforementioned values.
  • the ti/2 is a fraction of that achieved using a comparator delivery system. In some instances, the time to ti/2 using a disclosed embodiment is 0.5 times, 0.7 times, 0.8 times, 0.9 times, or 0.95 times the ti/2 of a comparator delivery system (or ranges including or spanning the aforementioned values).
  • the nanoparticle composition is stable.
  • the polydispersity of the nanoparticles changes less than or equal to about: 1%, 5%, 10%, 20%, or ranges including and/or spanning the aforementioned values.
  • the soluble fraction of active agent e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like
  • the soluble fraction of active agent in the formulation changes less than or equal to about: 1%, 5%, 10%, 20%, 30%, or ranges including and/or spanning the aforementioned values.
  • the PDI of nanoparticles comprising the composition changes by less than or equal to about: 1%, 5%, 10%, 20%, or ranges including and/or spanning the aforementioned values.
  • the PDI of nanoparticles comprising the composition changes by less than or equal to about: 0.05, 0.1, 0.2, 0.3, 0.4, or ranges including and/or spanning the aforementioned values.
  • the particle size of the nanoparticles of a composition as disclosed herein does not change and/or changes less than 5% during a period of greater than or equal to about: 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 10 hours, or ranges including and/or spanning the aforementioned values.
  • the particle size of the nanoparticles disclosed herein when exposed to simulated intestinal fluid (e.g., at a concentration of 20 mg/mL), does not change and/or changes less than 5% during a period of greater than or equal to about: 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 10 hours, or ranges including and/or spanning the aforementioned values.
  • the average particle size of nanoparticles comprising the composition changes by less than or equal to about: 1%, 5%, 10%, 20%, 50%, or ranges including and/or spanning the aforementioned values.
  • the PDI of nanoparticles comprising the composition changes by less than or equal to about: 1%, 5%, 10%, 20%, or ranges including and/or spanning the aforementioned values.
  • the PDI of nanoparticles comprising the composition changes by less than or equal to about: 0.01, 0.05, 0.1, 0.2, 0.3, or ranges including and/or spanning the aforementioned values.
  • the average particle size of nanoparticles comprising the composition changes by less than or equal to about: 1%, 5%, 10%, 20%, 50%, or ranges including and/or spanning the aforementioned values.
  • the PDI of nanoparticles comprising the composition changes by less than or equal to about: 1%, 5%, 10%, 20%, 100%, 150%, or ranges including and/or spanning the aforementioned values.
  • the PDI of nanoparticles comprising the composition changes by less than or equal to about: 0.01, 0.05, 0.1, 0.2, 0.3, or ranges including and/or spanning the aforementioned values.
  • the composition particle size remains consistent (a size change of less than or equal to about: 0%, 0.5%, 1%, 2%, 3%, 5%, or ranges including and/or spanning the aforementioned values) for a period of at least about 30 days when stored at room temperature, refrigeration, and up to 40°C.
  • the active agent e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like
  • concentration in the composition remains consistent (a loss of less than or equal to about: 0.5%, 1%, 2%, 3%, 5%, or ranges including and/or spanning the aforementioned values) for a period of at least about 30 days, 60 days, 90 days, or 120 days when stored at room temperature, refrigeration, and up to 40°C.
  • the composition when stored at room temperature, refrigeration, and up to 40°C, the composition is stable (e.g., the particle size or active agent concentration in the nanoparticles remains consistent and/or has a change of less than or equal to about: 0.5%, 1%, 2%, 5%, or ranges including and/or spanning the aforementioned values) for a period of at least about: 2 weeks, 30 days, 2 months, 3 months, 6 months, 9 months, 1 year, or ranges including and/or spanning the aforementioned measures of time.
  • the method of using the nanoparticle composition and/or of treating a subject with the nanoparticle composition includes administering to a subject in need of treatment (e.g., orally, topically, etc.) an effective amount of the composition.
  • the composition e.g., delivery system
  • improves the stability of the active agent e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like
  • the active agent e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like
  • the bioavailability of the active agent (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like) relative to the initial administered dose is greater than or equal to about: 10%, 20%, 50%, 75%, or ranges including and/or spanning the aforementioned values.
  • the oral bioavailability of the active agent (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like ) delivered (as measured using AUC) is higher using an embodiment disclosed herein relative to oral delivery of the active alone.
  • the oral bioavailability is improved over the active alone by greater than or equal to about: 10%, 50%, 75%, 100%, 200%, or ranges including and/or spanning the aforementioned values.
  • solutions of particles are composed of non-lipid ingredients, such as polymers and/or cyclodextrin.
  • solutions are cannabinoids, mushrooms, and kratom extracts or powders are prepared without particles.
  • the composition is prepared by adding one or more of an active compound, a lipid source, a surfactant, a co-emulsifier, a preservative, a flavoring agent, or combinations of any of the foregoing to water.
  • the composition is prepared using high sheer inline mixing (including for example via Silverson).
  • the composition is prepared using an overhead mixer (such as, for example, a IKA and/or Silverson).
  • the composition is prepared using high pressure homogenization.
  • the composition is prepared using microfluidization.
  • the composition is prepared using sonication.
  • the composition is prepared using mechanical stirring. In several embodiments, the composition is prepared using coacervation. In several embodiments, the composition is prepared using solvent precipitation. In several embodiments, the composition is prepared using hot melt extrusion (HME) tablet manufacturing. In several embodiments, the composition is prepared using one or more of the techniques or steps described above or elsewhere herein together. In several embodiments, the composition is prepared with methods excluding any one or more of these steps or techniques. [0219] In several embodiments, the nanoparticle compositions herein are lyophilized (e.g., to provide a powder). In several embodiments, where lyophilization is used to prepare a mixed micelle-based powder, one or more lyoprotectant agents may be added.
  • an individual lyoprotectant agent may be present at a dry wt. % equal to or less than the dry weight of the lipophilic ingredients.
  • the lyoprotectant agent(s) (collectively or individually) may be present at a dry wt. % equal to or less than about: 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, or ranges including and/or spanning the aforementioned values.
  • the lyoprotectant agent(s) may be present at a wet wt. % of equal to or less than about: 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 30%, or ranges including and/or spanning the aforementioned values.
  • the lyoprotectant is selected from the group consisting of lactose, dextrose, trehalose, arginine, glycine, histidine, and/or combinations thereof.
  • the nanoparticle compositions herein are spray dried (e.g., to provide a powder).
  • the nanoparticle compositions are spray dried and not lyophilized.
  • the nanoparticle composition is spray dried, fluid bed dried, desiccated, and/or lyophilized.
  • the composition is prepared by forming a lipid-in-oil emulsion.
  • an oil-in-water emulsion can be prepared without the use of organic solvents as shown in FIG. 1 (e.g., in an organic solvent-free method).
  • solid ingredients 101 are added and dissolved into liquid ingredients 102.
  • the lipid e.g., phosphatidylcholine, including phosphatidylcholine of any purity disclosed herein
  • the lipid e.g., phosphatidylcholine, including phosphatidylcholine of any purity disclosed herein
  • the addition of water 103 e.g., having a temperature of equal to or at least about: 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 80°C, or ranges including and/or spanning the aforementioned values
  • additional mixing 104 achieves an oil-in-water emulsion 105.
  • the oil-in-water emulsion is then subject to high-shear mixing to form nanoparticle compositions.
  • high-shear mixing 106 is performed using a high shear dispersion unit or an in-line mixer can be used to prepare the emulsions.
  • the particles can be made by solvent evaporation and/or solvent precipitation. In several embodiments, high sheer mixing is not required.
  • the lipid-in-oil emulsion is formed by dissolving ingredients 201, such as, one or more of a lipid (e.g., phosphatidylcholine, including phosphatidylcholine or any purity disclosed herein), a surfactant, one or more active compounds, and/or a preservative in a solvent 202.
  • a lipid e.g., phosphatidylcholine, including phosphatidylcholine or any purity disclosed herein
  • the solvent can include one or more organic solvents, including but not limited to, ethanol, chloroform, and/or ethyl acetate.
  • the solvents are class II solvents, class III solvents (e.g., at least class II and/or class III by the ICH Q3C standard), or mixtures thereof.
  • the solution of ingredients and solvent is dried 203.
  • the ingredients are provided as lipids and or liposomes as a thin film.
  • the solvent is removed from the composition by subjecting the solution to heat under vacuum to promote evaporation.
  • the film may further be dried under nitrogen gas.
  • the lipid film is hydrated 205 with warm aqueous solution to form an oil-in-water emulsion.
  • high-shear mixing is performed 206 using a high shear dispersion unit or an in-line mixer can be used to prepare the emulsions.
  • the dried composition, comprising the nanoparticle is reconstituted.
  • the nanoparticle composition such as the percentage and/or concentration of the types of nanoparticles, may change when dried.
  • the nanoparticle composition, such as the percentage and/or concentration of the types of nanoparticles may change when reconstituted.
  • the nanoparticle composition such as the percentage and/or concentration of the types of nanoparticles, may not change when dried.
  • the nanoparticle composition, such as the percentage and/or concentration of the types of nanoparticles may not change when reconstituted.
  • the lipid-in-water emulsion is subject to high pressure homogenization using a microfluidizer.
  • high sheer mixing can be used to reduce the particle size.
  • the oil-in- water emulsion is processed to a nanoparticle (e.g., about 20 to about 500 nm, etc.) using the microfluidizer or other high sheer processes.
  • the oil-in-water emulsion is processed to a nanoparticle having a size from about 80 nm to 180 nm in diameter or about 100 run to about 150 nm in diameter. In several embodiments, high sheer mixing is not used.
  • the lipid-in-water emulsion is passed through the microfluidizer a plurality of times (e.g., equal to or at least 1 time, 2 times, 3 times, 4 times, 5 times, 10 times, or ranges including and/or spanning the aforementioned values).
  • the emulsion is passed through the microfluidizer at a pressure of equal to or less than about: 5,000 PSI, 15,000 PSI, 20,000 PSI, 25,000 PSI, 30,000 PSI, or ranges including and/or spanning the aforementioned values.
  • the emulsion is passed through the microfluidizer at a temperature of equal to or at least about: 30°C, 40°C, 50°C, 65°C, 80°C, or ranges including and/or spanning the aforementioned values.
  • the emulsion is passed through the microfluidizer at least about room temperature (e.g., about 20°C or about 25°C) and/or without any heating and/or temperature control.
  • the emulsion is passed through the microfluidizer at a temperature of equal to or less than about 80°C.
  • the microfluidizer includes an interaction chamber consisting of 75 pm to 200 pm pore sizes and the emulsion is passed through this chamber.
  • the pore size of the microfluidizer are less than or equal to about: 75 pm, 100 pm, 150 pm, 200 pm, 250 pm, 300 pm, or ranges including and/or spanning the aforementioned values.
  • the nanoparticle composition is prepared by high shear mixing, sonication, or extrusion.
  • the nanoparticle composition is characterized by an ability to pass through a 0.2 pm filter while preserving the nanoparticle structure (e.g., a change in average nanoparticle size of no greater than 10 nm, 20 nm, or 30 nm).
  • a change in average nanoparticle size of no greater than 10 nm, 20 nm, or 30 nm e.g., a change in average nanoparticle size of no greater than 10 nm, 20 nm, or 30 nm.
  • after passage through a 0.2 pm there is a change in average diameter of the particles of equal to or at less than about: 1%, 5%, 10%, 20%, or ranges including and/or spanning the aforementioned values.
  • after passage through a 0.2 pm there is a change in PDI of the particles of equal to or at less than about: 1%, 5%, 10%, 20%, or ranges including and/or spanning the aforementioned values.
  • the active nanoparticle composition imparts solubility to hydrophobic active agents (e.g., kratom, CBD, other phytocannabinoids, etc.) in a delivery system that is easily dispersible in aqueous solutions.
  • hydrophobic active agents e.g., kratom, CBD, other phytocannabinoids, etc.
  • CBD oils do not disperse well in aqueous solutions and have poor oral absorption.
  • CBD particle formulations made using methods other than those disclosed herein have inconsistent particle size and may not be stable with storage over time.
  • Some embodiments, as disclosed elsewhere herein pertain to a method of manufacturing a lipid-based particle composition.
  • one or more active compounds e.g., CBD
  • one or more lipophilic components of the composition to provide a solution.
  • one or more lipid components are added.
  • one or more sterols are added.
  • one or more phospholipids are added.
  • one or more flavoring and/or preservatives are added.
  • water is added.
  • the lipophilic ingredients are combined and the hydrophilic ingredients are combined separately.
  • the lipophilic ingredients are then added to the hydrophilic ingredients.
  • the solution is passed through a microfluidizer and/or a high sheer homogenizer. In some embodiments, the process affords a particle composition.
  • the nanoparticle delivery systems (comprising e.g., a kava extract, kana extract, kratom extract, psilocybin mushroom extract, a cannabinoid, and/or combinations of any of the foregoing) disclosed herein are reproducibly manufacturable.
  • the active compound including for example kratom, kanna, kava, mushrooms, and/or Cannabis
  • pre-processing allows greater encapsulation efficiency and stability by precipitating “other” plant material away from extracts.
  • pre-processing may provide enhanced consumer experience due to less impurity/non-actives in the formulation.
  • “salt” byproducts are removed directly/indirectly by various extraction techniques.
  • pre-processing techniques include ethanol and co-solvent precipitation, filtration, activated charcoal soaking + filtration; chromatography, etc. By way of removing solvent such as ethanol, rotary evaporation may be used.
  • preprocessing allows a formulator to use any kind of kratom extract or biomass regardless of prior extraction techniques. Extract and formulations are incredibly sensitive to presence of salt and pH.
  • the preprocessing includes one or more of the following steps.
  • Kratom raw material extract e.g., an unenriched extract
  • kratom leaves e.g., kratom powder
  • the unenriched kratom extract comprises “salt” byproducts of kratom actives.
  • free base actives are prepared by adding a base (e.g., a sodium or potassium carbonate, bicarbonate, etc.). Upon preparation of the free bases, remaining salts (and other insoluble) are precipitated by adding solvent. In several embodiments, remaining solids are removed directly /indirectly by filtration (or other various solid removal techniques disclosed herein).
  • preprocessing techniques include ethanol and co- solvent precipitation, filtration, activated charcoal soaking + filtration; chromatography, etc.
  • solvent such as ethanol
  • rotary evaporation may be used.
  • Other forms of solvent removal are possible.
  • Other forms of removing active and non-active plant material are disclosed elsewhere herein (including solvent extraction, acid/base titration, CO2 extraction (both supercritical and non), cryogenic ethanol extraction, etc.
  • pre-processing (prior to use in the composition) allows a formulator to use any kind of kratom extract or biomass regardless of prior extraction techniques.
  • extract and formulations are incredibly sensitive to presence of salt and pH. Thus preprocessing may lead to higher stability and/or yield of formulations.
  • the preprocessing includes one or more of the following steps.
  • dissolve (or suspend) kratom extract (and/or leaf powder) in organic nonpolar or polar solvent e.g., hexane, chloroform, dichloromethane, and ethanol.
  • organic nonpolar or polar solvent e.g., hexane, chloroform, dichloromethane, and ethanol.
  • perform crystallization or precipitation e.g., ethanol.
  • dissolve kratom extract (and/or leaf powder) in organic solvent e.g., ethanol.
  • incubate in cold storage -20C, -80C, or 2-8C
  • the salt present in the kratom extract is an alkaloid salt.
  • the alkaloid is alkaloid citrate, alkaloid acetate, alkaloid chloride, alkaloid sodium salt e.g. gluconate, etc. (depending on its extraction technique).
  • the solution prior to precipitation, the solution comprises one or more of the following salts (e.g., of impurities), the active ingredients (and/or active ingredients of salts), and various other insolubles, etc.
  • the solution is decanted or filtered to remove solids (e.g., the insoluble including salts).
  • the mother liquor is suspended and/or the kratom extract is solubilized in buffer such as carbonate or sodium at various pH ranges (titration optional) including 5-6, 6-7, 7-8, 8-9, 9-10, 11-12 (e.g., to convert into free base bioactive ingredients such as alkaloids).
  • extraction free base with a polar or non-polar solvent like (e.g., hexane, chloroform, dichloromethane, and ethanol).
  • filtration, decant, and/or isolation technique In several embodiments, evaporate (e.g., rotary evaporation) to remove precipitation solvent.
  • the solvent is incubated in cold-chain storage (-20C, -80C, or 2-8C) prior to filtration and solvent evaporation.
  • salt separation and/or purification during preprocessing may include one or more of size exclusion, ion exchanger in presence of neutral organic compounds may also be a suitability method of purifications, evaporation and distillation membrane extraction, liquid-liquid extraction, solid phase extraction, immobilized liquid extraction, sorptive extraction, charged resin, and/or gel filtration.
  • pharmaceutical acceptable applications may also be used such as high purity filter media such as diatomite filter aids.
  • Example may include Celpure®, AW Celite®, Harborlite®, etc.
  • dialysis methods may also be used.
  • activated charcoal is used to treat a solution comprising the extract.
  • acidic conditions may be used for preprocessing.
  • polar, aprotic solvent like DMSO may also be used to solubilize hydrophobic substances like alkaloids during preprocessing.
  • DMSO and may be acidified or basified to maximize solubility and stability of alkaloids and other compounds.
  • One or more benefits of the preprocessing step may include better formulations, better encapsulation, purer compositions, industrial isolation for raw material, certified reference material/standards, manufacturer of finished intermediate and/or raw materials, or other benefits.
  • the formulation is provided as a suspension type (e.g., to formulate kratom leaf powder formulations).
  • formulations containing kratom leaf powder will provide greater regulatory certainty if extracts are considered controlled substance and/or drugs.
  • formulating with leaf powder may create a suspensions.
  • pre-processing may also be beneficial. However, in not all embodiments is preprocessing used.
  • compositions and methods of administering the compositions relate to compositions and methods of administering the compositions.
  • compositions which may comprise the nanoparticles and active compounds of the disclosure, may be administered via a route of administration.
  • the composition is administered by more than one route of administration.
  • the composition is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.
  • the appropriate dosage may be determined based on the type of disease to be treated, severity and course of the disease, the clinical condition of the individual, the individual's clinical history and response to the treatment, and the discretion of the attending physician.
  • the composition is administered at a dose of between 1 mg/kg and 5000 mg/kg. In some embodiments, the composition is administered at a dose of at least, at most, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
  • the quantity to be administered depends on the treatment effect desired.
  • An effective dose is understood to refer to an amount necessary to achieve a particular effect. In the practice in certain embodiments, it is contemplated that doses in the range from 10 mg/kg to 200 mg/kg can affect the protective capability of these agents.
  • doses include doses of about 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, and 200, 300, 400, 500, 1000 pg/kg, mg/kg, pg/day, or mg/day or any range derivable therein.
  • doses can be administered at multiple times during a day, and/or on multiple days, weeks, or months.
  • the effective dose of the composition is one which can provide a sample level of the active compound at a concentration of about 1 pM to 150 pM.
  • the effective dose provides a sample level of about 4 pM to 100 pM.; or about 1 pM to 100 pM; or about 1 pM to 50 pM; or about 1 pM to 40 pM; or about 1 pM to 30 pM; or about 1 pM to 20 pM; or about 1 pM to 10 pM; or about 10 pM to 150 pM; or about 10 pM to 100 pM; or about 10 pM to 50 pM; or about 25 pM to 150 pM; or about 25 pM to 100 pM; or about 25 pM to 50 pM; or about 50 pM to 150 pM; or about 50 pM to 100 pM (or any range derivable therein).
  • the dose can provide
  • the sample level may be analyzed from any biological sample, such as a blood sample, urine sample, skin sample, saliva sample, or the like.
  • the active agent that is administered to a subject is metabolized in the body to a metabolized active agent, in which case the blood levels may refer to the amount of that agent.
  • the blood levels discussed herein may refer to the unmetabolized active agent.
  • Precise amounts of the active composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting dose include physical and clinical state of the patient, the route of administration, the intended goal of treatment (alleviation of symptoms versus cure) and the potency, stability and toxicity of the particular therapeutic substance or other therapies a subject may be undergoing.
  • administrations of the composition e.g., 2, 3, 4, 5, 6 or more administrations.
  • the administrations can be at 1, 2, 3, 4, 5, 6, 7, 8, to 5, 6, 7, 8, 9, 10, 11, or 12 week intervals, including all ranges there between.
  • compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, subcutaneous, or intraperitoneal routes.
  • parenteral administration e.g., formulated for injection via the intravenous, intramuscular, subcutaneous, or intraperitoneal routes.
  • such compositions can be prepared as either liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and, the preparations can also be emulsified.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including, for example, aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • compositions will typically be via any common route. This includes, but is not limited to oral, or intravenous administration. Alternatively, administration may be by orthotopic, intradermal, subcutaneous, intramuscular, intraperitoneal, or intranasal administration. Such compositions would normally be administered as pharmaceutically acceptable compositions that include physiologically acceptable carriers, buffers or other excipients.
  • solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically or prophylactic ally effective.
  • the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above.
  • the method of treating comprises selecting patient for treatment.
  • the method of threating comprises administering to the patient an effective amount of a formulation comprising a nanoparticle composition comprising an active agent (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like).
  • an active agent e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like.
  • compositions as described herein may be used to induce at least one effect, e.g. therapeutic effect, that may be associated with at least one active agent (e.g., pharmaceuticals, nutraceuticals, and the like), which is capable of inducing, enhancing, arresting or diminishing at least one effect, by way of treatment or prevention of unwanted conditions or diseases in a subject.
  • active agent e.g., pharmaceuticals, nutraceuticals, and the like
  • the at least one active agent may be selected amongst therapeutic agents, such as agents capable of inducing or modulating a therapeutic effect when administered in a therapeutically effective amount.
  • compositions disclosed herein e.g., mixed nanoparticle compositions including a kava extract, kana extract, kratom extract, psilocybin mushroom extract, a cannabinoid, and/or combinations of any of the foregoing
  • the subject is treated by administering an effective amount of a composition as disclosed herein to the subject.
  • the disease or condition to be treated via administration of a composition as disclosed herein may include one or more of opioid withdrawal, pain relief, anxiety relief, depression, insomnia, inflammation, fever, fatigue, muscle aches, etc.
  • the nanoparticle composition e.g., those including one or more active agents
  • the nanoparticle composition (e.g., those comprising cannabinoids, such as CBD, non-cannabinoids, and combinations thereof as disclosed elsewhere herein) is provided for use in a method of treating a subject suffering from a condition selected from pain associated disorders, inflammatory disorders and conditions, symptoms of vomiting and nausea, intestine and bowl disorders, disorders and conditions associated with anxiety, disorders and conditions associated with psychosis, disorders and conditions associated with seizures and/or convulsions, sleep disorders and conditions, disorders and conditions which require treatment by immunosuppression, disorders and conditions associated with elevated blood glucose levels, disorders and conditions associated with nerve system degradation, inflammatory skin disorders and conditions, disorders and conditions associated with artery blockage, disorders and conditions associated with bacterial infections, disorders and conditions associated with fungal infections, proliferative disorders and conditions, and disorders and conditions associated with inhibited bone growth, post trauma disorders and others, a patient in need of appetite suppression or stimulation.
  • the method comprises administering to the subject an effective amount of a composition of this disclosure.
  • the nanoparticle compositions (e.g., those including a kava extract, kana extract, kratom extract, psilocybin mushroom extract, a cannabinoid, and/or combinations of any of the foregoing) described herein may be used for inducing, enhancing, arresting or diminishing at least one effect, by way of treatment or prevention of unwanted conditions or diseases in a subject.
  • the active agent may be selected amongst therapeutic agents, such as agents capable of inducing or modulating a therapeutic effect when administered in a therapeutically effective amount, and non-therapeutic agents, such as agents which by themselves do not induce or modulate a therapeutic effect but which may endow the pharmaceutical composition with a selected desired characteristic.
  • a nanoparticle compositions as disclosed herein may be selected to treat, prevent or ameliorate any pathology or condition.
  • administering of a therapeutic amount of the composition or system described herein, whether in a concentrate form or in a diluted formulation form, is effective to ameliorate undesired symptoms associated with a disease, to prevent the manifestation of such symptoms before they occur, to slow down the progression of the disease, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the disease, to delay the onset of said progressive stage, to lessen the severity or cure the disease, to improve survival rate or more rapid recovery, or to prevent the disease from occurring or a combination of two or more of the above.
  • the compositions disclosed herein may be provided in a number of different forms for administration and/or ingestion.
  • the compositions are stable during ozonation sterilization, UV sterilization, heat sterilization, filtration sterilization, and/or gamma irradiation during beverage preparation and packaging.
  • the particle size and/or PDI after sterilization varies by less than or equal to about: 1%, 5%, 10%, 20%, 30%, or ranges including and/or spanning the aforementioned values.
  • the active agent e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like
  • concentration after sterilization drops by less than or equal to about: 1%, 5%, 10%, 15%, or ranges including and/or spanning the aforementioned values.
  • the beverages comprising nanoparticle compositions have a shelf life of equal to or greater than 6 months, 12 months, 14 months, 16 months, 18 months, 19 months, 24 months, or ranges including and/or spanning the aforementioned values.
  • the compositions are provided in a sterilized beverage.
  • the sterilized beverage may be a cold beverage (e.g., juices, sports drinks, energy drinks, protein drinks, nutritional drinks, sodas, etc.).
  • the cold beverage may be a carbonated beverage.
  • the cold beverage may be an alcoholic beverage.
  • the compositions may be provided in hot beverages (e.g., coffee, tea, etc.).
  • the particle size and/or PDI varies by less than or equal to about: 1%, 5%, 10%, 20%, 30%, or ranges including and/or spanning the aforementioned values.
  • the active agent e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like
  • concentration drops by less than or equal to about: 1%, 5%, 10%, 15%, or ranges including and/or spanning the aforementioned values.
  • compositions also encompass methods for administering the disclosed compositions.
  • Multiple techniques of administering the nanoparticle compositions as disclosed herein exist including, but not limited to, oral, sublingual, buccal, rectal, topical, vaginal, aerosol, injection and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injections.
  • administration is performed through oral pathways, which administration includes administration in an emulsion, capsule, tablet, film, chewing gum, suppository, granule, pellet, spray, syrup, or other such forms.
  • oral formulations may comprise of DMSO and NMP.
  • the nanoparticles may be used to deliver extracts, combination extracts (e.g., combinations of one or more kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts), additional actives, terpenes, and/or combinations thereof (as disclosed elsewhere herein) to a biomass.
  • combination extracts e.g., combinations of one or more kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts
  • additional actives terpenes, and/or combinations thereof (as disclosed elsewhere herein)
  • the biomass may be fortified with extracts additional terpenes, and/or combinations thereof (as disclosed elsewhere herein).
  • a kratom biomass may be supplemented with a kratom extract.
  • a hemp biomass may be supplemented with other cannabinoids, noncannabinoid therapeutics (including kratom extracts, kanna extracts, etc.), and/or combinations of any one of the foregoing.
  • the fortification is accomplished by spraying a liquid solution onto the biomass (or other consumer product).
  • a product that is fortified with an active is provided.
  • these fortifying therapeutic agents can be used to enhance health benefits of the consumer product (e.g., biomass), to change the flavor profile of the consumer product (e.g., biomass), to change the physiological effects of the consumer product (e.g., biomass), and/or to provide other benefits.
  • the topical formulation may include SLM2026 (skin lipid matrix including Aqua (Water), Caprylic/Capric Triglyceride, Hydrogenated Phosphatidylcholine, Pentylene Glycol, Glycerin, Butyrospermum Parkii (Shea) Butter, Squalane, Ceramide NP), SLM2038 (skin lipid matrix including Aqua (and) Caprylic/Capric Triglyceride (and) Hydrogenated Phosphatidylcholine (and) Pentylene Glycol (and) Glycerin (and) Butyrospermum Parkii Butter (and) Squalane), or other formulated emulsion systems.
  • SLM2026 skin lipid matrix including Aqua (Water), Caprylic/Capric Triglyceride, Hydrogenated Phosphatidylcholine, Pentylene Glycol, Glycerin, Butyrospermum Parkii Butter (and) Squalane
  • SLM2038 skin lipid matrix including
  • topical permeation enhancers may be included and may be selected from, but not inclusive of, the following: dimethyl sulfoxide, dimethyl sulfone, ethanol, propylene glycol, dimethyl isosorbide, polyvinyl alcohol, CapryolTM 90, Labrafil Ml 944 CS, Labrasol, Labrasol ALF, LauroglycolT M90, Transcutol HP, Capmul S12L, Campul PG-23 EP/NF, Campul PG-8 NF.
  • the topical may include one or more of Lipoid’s Skin Lipid Matrix 2026 technology, lipid/oil based ingredients or oil soluble ingredients, and includes Captex 170 EP as a skin permeation enhancer, argan oil, menthol, arnica oil, camphor, grapefruit seed oil, For example, dimethyl sulfoxide, dimethyl isosorbide, topical analgesics such as lidocaine, wintergreen oil, and terpenes such as guaiacol. In several embodiments, any one or more of these ingredients is present in the topical composition at a dry wt.
  • any one or more of these ingredients is present in the topical at a wet wt. % of equal to or at least about: 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 30%, or ranges including and/or spanning the aforementioned values.
  • the nanoparticle compositions disclosed herein can be in admixture with a suitable carrier, diluent, or excipient such as sterile water, physiological saline, glucose, or the like, and can contain auxiliary substances such as wetting or emulsifying agents, pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired.
  • a suitable carrier diluent, or excipient
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired.
  • Such preparations can include liposomes, microemulsions, micelles, and/or unilamellar or multilamellar vesicles.
  • the nanoparticle composition is configured for oral ingestion.
  • the nanoparticle formulation is provided as a drinkable solution, such as a beverage, elixir, tonic, or the like.
  • the nanoparticle formulation is provided as a powder that can be constituted in a liquid (e.g., water, juice, coffee) and ingested orally.
  • the nanoparticle compositions can be provided as a tablet, capsule, pressed tablet, aqueous or oil suspension, dispersible powder or granule (as a food additive, drink additive, etc.), emulsion, hard or soft capsule, syrup or elixir.
  • Compositions intended for oral use can include one or more of the following agents: sweeteners, flavoring agents, coloring agents and preservatives.
  • the compositions are provided in ready-to-drink formulations, such as protein drinks, energy drinks, sodas, juices, coffees, etc.
  • Formulations for oral use can also be provided as gelatin capsules.
  • a powder composition as disclosed herein is added to the gelatin capsule.
  • the active ingredient(s) in the nanoparticle compositions disclosed herein are mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules.
  • the active compounds can be dissolved or suspended in suitable liquids, such as water.
  • Stabilizers and microspheres formulated for oral administration can also be used.
  • Capsules can include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • trehalose can be added.
  • trehalose is present in the nanoparticle composition at a dry wt. % of equal to or less than about: 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, or ranges including and/or spanning the aforementioned values.
  • the trehalose is present in the composition at a wet wt. % of equal to or at least about: 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 30%, or ranges including and/or spanning the aforementioned values.
  • Dry powder formulations or liquid embodiments may also be used in a variety of consumer products.
  • dry powders can be added (e.g., scooped, from a packet, squirted from a dispenser, etc.) into any consumer product (e.g., a hot or cold beverage).
  • liquid solutions or powdered nanoparticle formulations can be coated onto and/or added into a consumer product (e.g., sprayed and/or squirted from a dispenser, through dipping, soaking, rolling, dusting, etc.).
  • the consumer product is a food product (e.g., candies, lollipops, edibles, food, ingestible, buccal adhesives, or others).
  • the consumer product is a biomass.
  • the biomass is a hemp biomass (e.g., the buds and/or nugs of the hemp plant), a marijuana biomass (e.g., the buds and/or nugs of the marijuana plant), a mushroom biomass (plant or powdered plant, cordyceps, lion mane, reishi, chaga gano, psilocybin, or combinations thereof), and/or kratom biomass (plant or powdered plant, Maeng da, Indo, Bali/red vien, Green Malay, or combinations thereof).
  • hemp biomass e.g., the buds and/or nugs of the hemp plant
  • a marijuana biomass e.g., the buds and/or nugs of the marijuana plant
  • a mushroom biomass plant or powdered plant, cordyceps, lion mane, reishi, chaga gano, psilocybin, or combinations thereof
  • kratom biomass plant or powdered plant, Maeng da, Indo, Bali/red vien, Green Mal
  • the biomass is a moonrock (e.g., a marijuana nug dipped in or sprayed with concentrate (e.g., solvent extracted marijuana) and/or hash oil; a moon rock may be further rolled in and/or coated with kief).
  • the biomass is a rosin.
  • the biomass is hash.
  • the biomass is bubble hash.
  • Bubble hash is a cannabis concentrate comprising trichomes, or resinous glands, that have been separated from the plant (e.g., using ice water, agitation, and a sieve).
  • the nanoparticles e.g., of the compositions disclosed herein supplement and/or fortify the consumer product (e.g., biomass) with an active agent from the nanoparticles.
  • the active agent is delivered to the user in a greater quantity than would be achieved using (e.g., consuming) the biomass alone.
  • the nanoparticle compositions may be used to improve a condition.
  • an improvement in a condition can be a reduction in disease symptoms or manifestations (e.g., opioid withdrawal symptoms, pain, anxiety & stress, mood disorders (e.g., depression), seizures, malaise, inflammation, insomnia, etc.).
  • Actual dosage levels of active ingredients in an active composition of the presently disclosed subject matter can be varied so as to administer an amount of the active compound(s) that is effective to achieve the desired response for a particular subject and/or application.
  • the selected dosage level will depend upon a variety of factors including, but not limited to, the activity of the composition, composition, route of administration, combination with other drugs or treatments, severity of the condition being treated, and the physical condition and prior medical history of the subject being treated.
  • a minimal dose is administered, and dose is escalated in the absence of dose-limiting toxicity to a minimally effective amount. Determination and adjustment of an effective dose, as well as evaluation of when and how to make such adjustments, are contemplated herein.
  • an aqueous nanoparticle composition comprising an active agent (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like) as disclosed herein may be administered using an atomizer.
  • an atomizer nozzles are used in oral spray, such as the binaca spray.
  • an atomizer nozzle is used in a nasal spray. This result is surprising, as the extracts disclosed herein would be typically be understood to clog atomizer nozzles.
  • the nanoparticles or compositions may be used as coatings.
  • coating is performed with an aqueous or solvent solution of the nanoparticles.
  • the solution may be sprayed (e.g., via a spray nozzle, atomizer, etc.) or otherwise coated (e.g., dip-coated, etc.) onto the biomass hemp biomass, marijuana biomass, mushroom biomass, kratom biomass, kava biomass, kanna biomass, or combinations thereof.
  • pharmaceutical coating equipment e.g., that used to coat tablets, beads, drug layered/coated films
  • fluid bed technology, film bed technology, dry powder laying technology, and/or combinations thereof are used to coat the biomass.
  • film coating is used.
  • the biomass prior to coating with a liquid solution of nanoparticles, the biomass is dried completely. Then, after coating, the fortified biomass is dried. In other implementations, freshly harvested biomass is solution coated (e.g., prior to drying). After coating and/or spraying with the lipid particles, the biomass can then be dried together with the nanoparticles to provide a fortified biomass.
  • a powder can be used to coat the biomass.
  • a powder nanoparticle formulation is dusted or coated onto either dried or freshly harvested biomass. Additional drying may be performed to afford a consumable fortified product.
  • an additional drying step may optionally be performed (though it may not be required).
  • the dried fortified biomass is suitable for use by a user.
  • the powdered biomass of one plant may be used to coat the biomass of another plant (e.g., kanna on a kratom biomass, kratom on hemp biomass, kratom on kanna biomass, etc.).
  • the fortified biomass is further processed prior to use (e.g., in dried or undried form).
  • milling is used to reduce the size of the coated biomass particles.
  • the milling is a two stage process with a first course milling and then a fine milling.
  • the average particle size of the fortified biomass is such that greater than 50% pass through screen having a mesh size of less than or equal to 100, 150, 200, or ranges spanning and/or including the aforementioned values.
  • the average particle size of the fortified biomass is less than or equal to about: 1000 pm, 500 pm, 200 pm, or ranges including and/or spanning the aforementioned values.
  • the fortified biomass is suitable for delivery to a user.
  • the biomass is smoked or vaporized and inhaled where active agents from the biomass (including the fortifying agents) are delivered as smoke or vapor to the lungs.
  • the fortified biomass is suitable for delivery to a user via the gastrointestinal tract (e.g., as an edible, a food ingredient, a gummy, a coated candy, etc.).
  • coatings can be applied to candies, lollipops, edibles, food, ingestible, buccal adhesives, or others.
  • the lipid particle formulation can be remote loaded with active agents (kratom extracts, cannabinoids, non-cannabinoid therapeutics, terpenes, etc.).
  • active agents kratom extracts, cannabinoids, non-cannabinoid therapeutics, terpenes, etc.
  • a liquid formulation of lipid particles is adding to an active agent.
  • the active agent incorporates into the particles by hydrophobic/hydrophilic interactions, electrostatic interactions, etc.
  • a remote loaded product could be coated onto biomass (as disclosed above), dried, and/or milled to provide a fortified, finished product.
  • the lipid particle can be provided with or without an active agent inside prior to remote loading.
  • the remote loaded active is THC.
  • the lipid particles can be transported (e.g., across state lines or through territories) even through jurisdictions where some cannabinoids (e.g., d9-THC) are not legal.
  • the therapeutic agent can be remote loaded and used to, for example, fortify biomass (or otherwise be delivered to a user).
  • the pharmaceutical lipid-based particle compositions can be provided as a tablet, aqueous or oil suspension, dispersible powder or granule (as a food additive, drink additive, etc.), emulsion, hard or soft capsule, syrup or elixir.
  • Compositions intended for oral use can include one or more of the following agents: sweeteners, flavoring agents, coloring agents and preservatives.
  • Formulations for oral use can also be provided as gelatin capsules. In some embodiments, a powder composition as disclosed herein is added to the gelatin capsule.
  • the active ingredient(s) in the nanoparticle compositions disclosed herein are mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules.
  • an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin
  • the active compounds can be dissolved or suspended in suitable liquids, such as water.
  • Stabilizers and microspheres formulated for oral administration can also be used.
  • Capsules can include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • liquid formulations can be added measured and poured into any consumer product.
  • the consumer product can include one or more alcoholic beverages, milks (dairy, but also nuts “milks” such as almond juice, etc.), coffee, sodas, tea, fermented beverages, wines, nutritional supplements, smoothies, simple water, sports drinks, sparkling water, or the like.
  • the consumer product can include one or more eye drops, mouth wash, lotions/creams/serums, lip balms, hair care products, deodorant, nasal solutions, enema solutions, liquid soaps, solid soaps, or the like.
  • the consumer product can include one or more food products.
  • the consumer product can include desserts.
  • the consumer product can include single serving products of multi-serving products (e.g., family size).
  • the consumer product can include one or more dried products (e.g., flour, coffee creamer, protein shakes, nutritional supplements, etc.).
  • these dried products can be configured to be reconstituted for use.
  • the consumer product can include one or more the dried product can be added to other dietary supplements (e.g., multivitamins, gummies, etc.).
  • Some embodiments also encompass methods for making (as disclosed elsewhere herein) and for administering the disclosed compositions.
  • Multiple techniques of administering the lipid-based particle compositions as disclosed herein exist including, but not limited to, oral, rectal, topical, aerosol, injection and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections.
  • administration is performed through oral pathways, which administration includes administration in an emulsion, capsule, tablet, film, chewing gum, suppository, granule, pellet, spray, syrup, or other such forms.
  • topical permeation enhancers may be included and may be selected from, but not inclusive of, the following: dimethyl sulfoxide, dimethyl sulfone, ethanol, propylene glycol, dimethyl isosorbide, polyvinyl alcohol, CapryolTM 90, Labrafil Ml 944 CS, Labrasol, Labrasol ALF, LauroglycolT M90, Transcutol HP, Capmul S12L, Campul PG-23 EP/NF, Campul PG-8 NF.
  • the topical may include one or more of Lipoid’s Skin Lipid Matrix 2026 technology, lipid/oil based ingredients or oil soluble ingredients, and includes Captex 170 EP as a skin permeation enhancer, argan oil, menthol, arnica oil, camphor, grapefruit seed oil, dimethyl sulfoxide, dimethyl isosorbide, topical analgesics such as lidocaine, wintergreen oil, and terpenes such as guaiacol. In some embodiments, any one or more of these ingredients is present in the topical composition at a dry wt.
  • any one or more of these ingredients is present in the topical at a wet wt. % of equal to or at least about: 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 30%, or ranges including and/or spanning the aforementioned values.
  • compositions and methods have been disclosed. Although this disclosure has been described in terms of certain illustrative embodiments and uses, other embodiments and other uses, including embodiments and uses which do not provide all of the features and advantages set forth herein, are also within the scope of this disclosure. Components, elements, features, acts, or steps can be arranged or performed differently than described and components, elements, features, acts, or steps can be combined, merged, added, or left out in various embodiments. All possible combinations and subcombinations of elements and components described herein are intended to be included in this disclosure. No single feature or group of features is necessary or indispensable.
  • the agents in some aspects of the disclosure may be formulated into preparations for local delivery (such as to a specific location of the body, such as a specific tissue or cell type) or systemic delivery, in solid, semi-solid, gel, liquid or gaseous forms such as tablets, capsules, powders, granules, ointments, solutions, depositories, inhalants and injections allowing for oral, parenteral or surgical administration. Certain aspects of the disclosure also contemplate local administration of the compositions by coating medical devices and the like.
  • Suitable carriers for parenteral delivery via injectable, infusion or irrigation and topical delivery include distilled water, physiological phosphate-buffered saline, normal or lactated Ringer's solutions, dextrose solution, Hank's solution, or propanediol.
  • sterile, fixed oils may be employed as a solvent or suspending medium.
  • any biocompatible oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the carrier and agent may be compounded as a liquid, suspension, polymerizable or non-polymerizable gel, paste or salve.
  • the actual dosage amount of a composition administered to a patient or subject can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration.
  • the practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject.
  • the pharmaceutical compositions are administered in the form of injectable compositions either as liquid solutions or suspensions; solid forms suitable or solution in, or suspension in, liquid prior to injection may also be prepared. These preparations also may be emulsified.
  • the composition comprises a pharmaceutically acceptable carrier.
  • the composition may contain 10 mg or less, 25 mg, 50 mg or up to about 100 mg of human serum albumin per milliliter of phosphate buffered saline.
  • Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like.
  • non-aqueous solvents examples include propylene glycol, polyethylene glycol, vegetable oil and injectable organic esters such as ethyloleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, saline solutions, parenteral vehicles such as sodium chloride, Ringer's dextrose, etc.
  • Intravenous vehicles include fluid and nutrient replenishers.
  • Preservatives include antimicrobial agents, antgifungal agents, anti-oxidants, chelating agents and inert gases. The pH and exact concentration of the various components the pharmaceutical composition are adjusted according to well-known parameters.
  • compositions are suitable for oral administration.
  • Oral formulations include such typical excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like.
  • the compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders.
  • the pharmaceutical compositions may include classic pharmaceutical preparations.
  • compositions according to certain aspects may be via any common route so long as the target tissue is available via that route. This may include oral, nasal, buccal, rectal, vaginal or topical administration. Alternatively, administration may be by orthotopic, intradermal, subcutaneous, intramuscular, intraperitoneal or intravenous injection. Such compositions would normally be administered as pharmaceutically acceptable compositions that include physiologically acceptable carriers, buffers or other excipients. For treatment of conditions of the lungs, aerosol delivery can be used. Volume of the aerosol may be between about 0.01 ml and 0.5 ml, for example.
  • Precise amounts of the pharmaceutical composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting the dose include the physical and clinical state of the patient, the route of administration, the intended goal of treatment (e.g., alleviation of symptoms versus cure) and the potency, stability and toxicity of the particular active substance. It is contemplated that other agents may be used in combination with certain aspects of the present embodiments to improve the therapeutic efficacy of treatment.
  • the first group is treated with a kratom extract containing mixed nanoparticle composition as disclosed herein (orally).
  • the second group of patients is treated orally with a kratom extract oil based comparator composition orally.
  • the third group of patients is treated with a placebo orally.
  • the first group of patients experiences milder withdrawal symptoms than the second group as measured by a self-evaluation and evaluation from a doctor.
  • the patients in the first group report less feelings of nervousness, less feelings of restlessness, less feelings of impending danger, panic or doom, less trouble concentrating, and less trouble sleeping.
  • After oral ingestion the patients in the first group have lower heart rates and less trembling than those in the second group. The results show statistically significant improvements in the first group relative to either the second group or the third group.
  • the patients in the second group show statistically significant improvement over the placebo, but not to the degree achieved reported by the first group.
  • the patients in the second group have statistically higher reports of side effects associated with treatment than either the first or the third group.
  • the patients in the second group show statistically significant improvement over the placebo, but not to the degree achieved reported by the first group.
  • the patients in the second group have statistically higher reports of side effects associated with treatment than either the first or the third group.
  • the first group is treated with a kratom extract containing mixed nanoparticle composition as disclosed herein orally.
  • the second group of patients is treated orally with a kratom based comparator composition orally.
  • the third group of patients is treated with a placebo orally.
  • the first group of patients experiences recovery from each of the symptoms of anxiety faster than the second group and to a higher degree as measured by a self-evaluation.
  • the patients in the first group report less feelings of nervousness, less feelings of restlessness, less feelings of impending danger, panic or doom, less trouble concentrating, less trouble sleeping.
  • After oral ingestion the patients in the first group have lower heart rates and less trembling than those in the second group. The results show statistically significant improvements in the first group relative to either the second group or the third group.
  • the standards analyzed with samples include 100 ng/mL each of CBD and 7-OH-CBD. Peaks observed in swine plasma have been identified as a glucuronide conjugates of CBD and 7-OH CBD. The exact mass and fragmentation is consistent with the structure of CBD-glucuronide (CBD-gluc) and 7-OH-CBD glucuronide (7-OH-CBD-gluc). Neutral loss fragments of 176 for CBD-gluc and 194 for 7-OH-CBD-gluc, confirm the presence of glucuronides. Additional metabolites were detected in the samples. A peak at 5.6min has a molecular weight of 344.2 (CBD + 30) consistent with oxidation to a carboxylic acid.
  • Samples were prepared by pooling aliquots from plasma samples from swing that received spray dried cannabidiol LNP powder at 4, 5, and 6 hr time points. Total volume of pooled plasma sample was 150 pL and was precipitated with 1:3 volume of acetonitrile, vortexed and centrifuged at 5,000 rpm for 5 min. After centrifugation, 300 pL of supernatant was removed and dried under a gentle stream of nitrogen. Dried samples were then reconstituted in 100 pL water/acetonitrile (50/50). Samples were injected on Agilent QTOF 6550 mass spectrometer equipped with Agilent 1260 HPLC. Data were acquired using HRMS and auto MS/MS to evaluate fragments and propose structures. Data analysis was performed by SeventhWave Laboratories (BASi).
  • LC/MS conditions were as follows: HPLC: Agilent 1260 Infinity; Mobile Phases: lOmM ammonium formate in water and acetonitrile; Column: Waters Atlantis C18 3pM, 2.1x150 mm (PN: 186001299); Injection volume: 10 pL; Flow Rate: 300 pL/min; Gradient: 0-0.5 min - 25% B (in some embodiments B comprises acetonitrile), 0.5-8 min - 25- 90% B, 8-11 min - 90% B, 11-11.5 min - 25% B, 11.5-15 min - 25% B; Mass Spectrometer: Agilent 6550 ifunnel QTOF.
  • Cannabidiol LNPs and empty LNPs under various conditions, including acidic, basic, oxidative conditions, and high temperature/high humidity were performed.
  • the degradations evaluated analytical method for the utility to detect degradants and impurities found in Cannabidiol and Empty LNPs. The results were to determine if Cannabidiol LNP converts to D9-THC under acidic conditions or if degradation occurs under basic, oxidative conditions, and high temperature/high humidity.
  • Cannabidiol and empty LNPs were stressed according to the following separate conditions: 0.01 M hydrochloric acid, 0.01 M sodium hydroxide, 0.1% hydrogen peroxide.
  • Cannabidiol and empty LNPs were stressed either at room temperature (25C/60% relative humidity) or an accelerated temperature (40C/75% relative humidity). Lipid encapsulated nanoparticles (without cannabidiol) were stressed under similar conditions. Cannabidiol solubilized in 200-Proof USP ethanol was also stressed with 0.01M hydrochloric acid at 25C/60% RH and 40C/75% RH as a positive control. Test articles were analyzed by Ultra Performance Liquid Chromatography (UPLC) using the cannabinoids method described herein. Cannabidiol LNPs were prepared using manufacturing described herein at an R&D scale.
  • UPLC Ultra Performance Liquid Chromatography
  • ingredients include: cannabidiol API (2.0%), sunflower phosphatidylcholine (10.0%), capric and caprylic triglycerides (9.3%), cholesterol (1.0%), vitamin E (0.1%), potassium sorbate (0.1%), sodium benzoate (0.1%), citric acid (0.1%), and water for injection (77.3%).
  • cannabidiol API (2.0%)
  • sunflower phosphatidylcholine (10.0%)
  • capric and caprylic triglycerides 9.3%
  • cholesterol 1.0%)
  • vitamin E 0.1%)
  • potassium sorbate 0.1%)
  • sodium benzoate 0.1%)
  • citric acid 0.1%)
  • water for injection 77.3%
  • APLgrade, crystalline, synthetic cannabidiol was purchased from Benuvia Manufacturing (Round Rock, Texas) Catalog Number: ITI-GMP-002, Lot Number: RM19084.
  • the Cannabidiol LNP Characteristics were white, free of sedimenting particulates with a pH of 4.406, a density of 0.998 g/mL, a Z-average of 86.51 nm, and a PDI of 0.181.
  • 0.01M hydrochloric acid samples were prepared by adding 5 mL of lipid encapsulated cannabidiol to 4.9 mL of water for injection. 0.1 mL of IM hydrochloric acid (JT Baker) was added to achieve a final concentration of 0.01M hydrochloric acid. The 10 mL of sample was divided into 2 x 5 mL samples in amber vials and crimp sealed. A sample was stored at either 25C/60% RH or 40C/75% RH.
  • 0.01M sodium hydroxide samples were prepared by adding 5 mL of lipid encapsulated cannabidiol to 4.9 mL of water for injection. 0.1 mL of IM sodium hydroxide (JT Baker) was added to achieve a final concentration of 0.01M sodium hydroxide. The 10 mL of sample was divided into 2 x 5 mL samples in amber vials and crimp sealed. A sample was stored at either 25C/60% RH or 40C/75% RH.
  • 0.1% hydrogen peroxide samples were prepared by adding 5 mL of lipid encapsulated cannabidiol to 4.967 mL of water for injection. 0.033 mL of 30% hydrogen peroxide (JT Baker) was added to achieve a final concentration of 0.1% hydrogen peroxide. The 10 mL of sample was divided into 2 x 5 mL samples in amber vials and crimp sealed. A sample was stored at either 25C/60% RH or 40C/75% RH.
  • a control sample was prepared by adding 5 mL of lipid encapsulated cannabidiol to 5.0 mL of water for injection. The 10 mL sample was divided into 2 x 5 mL samples and stored at either 25C/60% RH or 40C/75% RH.
  • Lipid encapsulated nanoparticles without cannabidiol were prepared and stressed under identical conditions.
  • Cannabinoid reference standards were fully separated by Reverse Phase UPLC (Thermo Vanquish Horizon). Cannabidiol (Crystalline) was formulated as LNPs or Ethanol solutions and subjected to degradation by the acid, base, oxidative, or high temperature/high humidity conditions previously described. Degradants and/or impurities that eluted or eluted near cannabinoid reference standards were evaluated by ultra-performance liquid chromatography method with diode array detection (UPLC-DAD), Spectra, Retention Time, and NMR analysis.
  • UPLC-DAD ultra-performance liquid chromatography method with diode array detection
  • cannabidiol would convert to d9-THC under acidic conditions when formulated in LNPs, similar to what commonly occurs in alcohol-based compositions.
  • use of the LNPs did not show degradation to d9-THC under acidic conditions.
  • CBN is a common oxidative byproduct of Delta-9 THC although spectra and retention time analysis for this particular sample was not supportive of this conclusion. Accordingly, use of the LNPs containing cannabidiol provided significant protection of the cannabidiol under acidic conditions.
  • Embodiments herein provide a stable good manufacturing practice (GMP) material that has been stored for 24 month at room temperature and analyzed using the analytical method disclosed herein.
  • the GMP material is characterized as follows: Days since manufacture (DOM): 745 days, Storage: 25C/60% RH, Appearance: White, free of sedimenting particulates, pH: 4.801, Density: 0.996 grams/mL, Z-average: 130.6 nm, PDI: 0.119, Cannabidiol Source: Plant Extract (Isolate), Target Assay: 20 mg/g Cannabidiol.
  • Cannabidiol LNPs cannabidiol API (2.0%), sunflower phosphatidylcholine (10.0%), capric and caprylic triglycerides (9.3%), cholesterol (1.0%), vitamin E (0.1%), potassium sorbate (0.1%), sodium benzoate (0.1%), citric acid (0.1%), and water for injection (77.3%)) at 25C/60% RH for over 2 years
  • Cannabidiol and particle size was within specifications, as shown in FIG. 4.
  • the formation of Delta-9-THC was not observed after long-term storage at room temperature as shown in FIG. 5. Up to 8 degradants were observed all of which have similar UV spectras as cannabinoids.
  • a degradant was observed closely eluting near THCV (3.826 vs 3.621 minutes) with lambda maxes of 203.87 vs. 208.84 nm. 3.826 minute degradant was determined to be cannabidiol hydroxy quinone although in very small amounts.
  • a degradation product also eluted 6.282 minutes near Delta-8-THC compared to 6.518 minutes for reference.
  • a peak eluting at 6.503 minutes was determined to be unknown rather than Delta-8 THC.
  • a degradation product eluting at 3.066 minutes before cannabidiol (3.286 minutes) was identified as "unknown" although the retention time was similar to CBG.
  • the lambda max of the unknown degradant was 208.70 nm compared to 205.99 nm for reference material.
  • the lack of D9-THC and the maintenance of particle size for over 2 years of storage at 25C/60% RH demonstrates that the LNPs provide significant protection of the active agent encapsulated therein.
  • the typical base formulation composition includes phosphatidylcholine source (typically sunflower), sterol source (typically plant sterols or cholesterol), triglyceride source (medium or long chain from coconut, seeds, PUFA, etc.), and purified water.
  • Ratios of excipients (lipids, sterols, and fatty acids) including additional inactive ingredients are added on a case by case basis depending on the intended use or application. The ratio and type of excipients can be selected based on the type of active ingredient to be encapsulated.
  • Ingredients may include the use of reducing agents, antioxidants, acidifiers, flavoring agents, and antimicrobial preservatives (natural or synthetic).
  • the mixed nanoparticle formulations may contain phosphatidylcholine, surfactant, and various inactive and functional ingredients.
  • Embodiments including pharmaceutical compositions for drug delivery applications, all excipients including lipids, cholesterol and triglycerides are sourced from pharmaceutical suppliers that provide GMP, USP, NF, and/or Multi-Compendial graded material.
  • Water for injection USP/EP
  • Antimicrobial preservatives common to drug products for most routes of administration including parabens, phenols, acids, and alcohols can be used in platform technologies at acceptable levels. All excipients can be GRAS and found in FDA’s inactive list of excipients.
  • Certain ingredients used in the compositions can be found on the FDA’s IID list. Examples include: 12 drug products (intravenous, topicals, vaginal) that contain cholesterol; 5 drug products (intravenous) that contain some form of phosphatidylcholine; 2 drug products (sublingual and topical) that containing forms of caprylic/capric triglycerides; 21 drug products (oral, injection, sublingual, topical) that contain Medium Chain Triglycerides.
  • Lipid-based cannabidiol formulations were placed in a traditional dialysis setup, where the pore size of the membrane was small enough to contain the particles whereas ‘free drug’ can freely diffuse through non-reactive pores, and the dialysis tube was placed in an aqueous diluent at 37°C with agitation. Cannabidiol was measured at predefined time points to evaluate release media over time. Cannabidiol was not detected in the release media. Sample and separate method was also performed using centrifugation.
  • Nanoparticle compositions (active agent (2.0%), sunflower phosphatidylcholine (10.0%), capric and caprylic triglycerides (9.3%), cholesterol (1.0%), vitamin E (0.1%), potassium sorbate (0.1%), sodium benzoate (0.1%), citric acid (0.1%), and water for injection (77.3%)) comprising the following active agents were evaluated for stability by monitoring particle size distribution and polydispersity over time when stored at controlled room temperature (25°C/60% relative humidity or accelerated conditions (40°C/60% relative humidity).
  • Active ingredients Cannabidiol, Cannabigerol, Cannabinol, Cannabichromene, Tetrahydrocannabivarin, Tetrahydrocannabinol, Full extracts of hemp, Specific ratios of isolated cannabinoids, Cannabigerolic acid, Cannabidolic acid, Mitragynine, Payantheine, Mitraphylline, Speciociliantine, Speciogynine, Cholecalciferol, Ergocalciferol, D,L-Alpha- Tocopherol, Menaquinone, Ascorbyl palmitate, Retinyl palmitate, Beta-Sitosterol, Plant Sterol Rich Extracts, Cholesterol, Ubiquinone, Phosphatidylcholine, Phosphatidylserine, Eicosapentaenoic/Docosahexaenoic Acid Mixtures, Oleic Acid, Conjugated Linoleic Acid,
  • the physical characteristics of the particle have been predictive of stability for encapsulated actives. This is especially true for poorly water soluble compounds like cannabinoids. No phase separation occurred for nanoparticles encapsulating the actives provided above. Further, the measured particle size for each of the encapsulated actives was within acceptable limits. The consistency in size over time, or within a sample even at the time of manufacture, is predictive of stability over time for the active agent encapsulated therein.
  • Table 1 [0327] The particle size and poly dispersity index for each formulation in Table 1 are shown in Table 2. With an increase in total surfactant concentration (increasing from formulation 1 to formulation 3) the Z-average particle size decreases from 187.0 nm to 67.6 nm. The change in polydispersity index measured for each formulation did not correlate to increasing total surfactant concentration.
  • a formulation at 300 g/L of lipids was found to be too viscous during compounding.
  • Formulations 8 and 10 did not decrease in mitragynine concentration when stored for 5 months at controlled room temperature (25°C/60% relative humidity), indicating the formulations were chemically stable. Flavor of the mitragynine speciosa extract formulations improves as lipid concentration increases. The high bitterness of Mitragynine speciosa extracts was masked with high lipid content.
  • Formulations provided in Table 5 were evaluated for particle size and poly dispersity index as shown in Table 6. From Table 6, a Z-Average particle size minima can be seen with formulations of pH ⁇ 4.0. Comparatively more basic formulations tend to have decreased physical stability, which is evidenced by an increased particle size even at relatively low lipid concentrations (formulations 6 and 7). Formulations with less acid have a higher tendency to gel over time. The inclusion of acids and bases has a strong impact on flavor. Bitterness reducers such as acetate and malic acid improve the flavor of the formulation, but acetate imparts instability while malic acid does not. This would suggest an ideal pH range of between 3 and 4. Table 6
  • Formulations provided in Table 7 were evaluated for particle size and poly dispersity index as shown in Table 8. Incorporation temperatures at 45 °C and 55 °C have large Z- Average particle sizes than formulations prepared at 65 °C. This is also evidenced by reduced physical stability at higher temperatures resulting in increased optical opacity and increased tendency to gel over time (data not shown). Incorporation temperatures of 70°C and higher were attempted, but high optical opacity and low recovered mitragynine concentrations were observed.
  • Formulations were evaluated for particle size, mitragynine concentration initially and after 5 months of storage at controlled room temperature, and taste. Flavor oil was found to not impact Z- Average particle size or poly dispersity index. Both parameters remained fairly consistent between all flavors tested. After storage at controlled room temperature for 5 months, mitragynine concentration was comparable to that measured at stability set down (TO), indicating the formulations, irrespective of flavor oil type, were stable.
  • TO stability set down
  • the particle size, poly dispersity index, and Mitragynine concentration for each formulation in Table 9 is shown in Table 10.
  • Table 11 [0337] Formulations provided in Table 11 were evaluated for particle size and poly dispersity index as shown in Table 12. The Z-average particle size and poly dispersity index data demonstrate comparable particle characteristics are achievable with different encapsulated ingredients.
  • Nanoparticle formulations containing ribose alone, ribose and niacinamide, or niacinamide alone were formed into spray dried powders.
  • Formulations containing either ribose alone, niacinamide alone, or both ribose and niacinamide with varying amounts of various lipids and other excipients were prepared using a solvent- free manufacturing process. Water-soluble components were dissolved in water at 65°C with magnetic stirring. High shear mixing was applied at 65°C and lipids and excipients were added. High shear mixing was maintained until a stable suspension was formed. The suspension was then microfluidized for 5 passes using an MP110 microfluidizer at 30,000 psi.
  • formulations were diluted with an equal volume containing the excipient type such that the excipient is at the stated final concentration.
  • Up to 25% ethanol e.g., 10%, 15%, 20%, 25%
  • Formulations were spray dried on a Buchi B290 benchtop spray dryer. The inlet temperature was set at 125 °C, the aspirator set to 100%, the pump rate set to 10%, and nitrogen flow set to 60 mmHg. Powder was collected was measured for residual moisture and recovered yield was calculated.
  • Table 13 shows formulation conditions evaluated. Table 13
  • CBN isolate containing nanoparticles were prepared using the solvent free manufacturing process described in Example 1.
  • a 15-liter batch containing 2.0% CBN isolate was prepared and 15 grams was filled into 20 mL dropper cap bottles for stability testing, samples were stored at controlled room temperature (25°C/60% relative humidity) for 365 days and at accelerated conditions (40°C/75% relative humidity) for 90 days. Shown in Table 15 are the CBN concentrations for each storage condition at the start and end of the stability study.
  • CBG isolate containing nanoparticles were prepared using the solvent free manufacturing process described in Example 1.
  • a 15-liter batch containing 2.0% CBG isolate was prepared and 15 grams was filled into 20 mL dropper cap bottles for stability testing. Samples were stored at controlled room temperature (25°C/60% relative humidity) for 365 days. Shown in FIGs. 8 and 9 are the change in CBG concentration and Z-average particle size over the 365-day storage period.
  • BSD Broad Spectrum Hemp Distillate
  • CBG cannabinoid
  • CBN cannabinoids
  • CBC cannabinoids
  • Samples were stored at controlled room temperature (25°C/60% relative humidity) for 365 days and at accelerated conditions (40°C/75% relative humidity) for 180 days. Shown in FIGs. 10 - 13 are changes in CBD, CBG, CBN, and CBC, respectively, over 365 days of storage at controlled room temperature.
  • Shown in Table 16 are the changes in cannabinoids over 180 days of storage at accelerated temperature. Shown in FIG. 14 is the change in Z-average particle size over 12 months of storage for a 50-liter batch of encapsulated BSD nanoparticles at controlled room temperature.
  • CBD concentration varied from 19.8 mg/gram to 22.9 mg/gram (FIG. 10).
  • the overall change in CBD concentration at the end of the 365 days was +16%.
  • the minor cannabinoids (CBG, CBN, and CBC) varied in concentration from 0.74 mg/gram to 0.973 mg/gram.
  • the change in the CBG concentration was +12%, the CBN concentration was +15% and the CBC concentration was +15% over the 365 days of controlled room temperature storage (FIGs. 11 - 13).
  • FSD Fluorescence Spectrum Hemp Distillate
  • THCv tetrahydrocannabivarinand isolate containing nanoparticles
  • a 50-liter batch containing 2.0% Full Spectrum Hemp Distillate and 0.32% THCv isolate was prepared and 30 grams was filled into 30 mL dropper cap bottles for stability testing.
  • the FSD was found to contain CBD as a major cannabinoid, and CBG, CBN, and CBC as minor cannabinoids.
  • Delta-9 THC was detectable in the FSD raw material at or below the LOQ (limit of quantitation) in the encapsulated FSD nanoparticles. Delta-9 THC is not reported in the data below.
  • THCv cannabinoid concentration decreased by 11.2% by 3 months storage at accelerated temperature and by 25.7% by 6 months of storage.
  • Storage at 40°C/75% is generally understood to increase degradation kinetics by a factor of 4 compared to controlled room temperature based on the Arrhenius equation. Therefore, THCv stability is expected to be between 1 and 2 years of storage at controlled room temperature. This agrees well with observed stability at 25°C/60% relative humidity showing 14.1% degradation after 12 months.

Abstract

Several embodiments pertain to nanoparticle-based compositions and their use in methods for the delivery of active agents to subjects and to products. In several embodiments, the compositions are stable for prolonged periods of time and provide enhanced bioavailability and/or dispersibility.

Description

COMPOSITIONS FOR SUPPLEMENTING PRODUCTS WITH THERAPEUTIC AGENTS AND METHODS OF USE THEREOF
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to US Provisional Application Nos. 63/329,193 filed April 8, 2022. The contents of which is incorporated into the present application by reference.
BACKGROUND
I. Field of the Disclosure
[0002] This disclosure relates to the fields of nanoparticles, drug delivery, and medicine.
II. Background
[0003] Currently, a number of plant extracts and fungus extracts are used as nutraceuticals. A nutraceutical, also called a bioceutical, is a pharmaceutical alternative which may have physiological benefits. In the U.S. currently, nutraceuticals are largely unregulated, as they exist in the same category as dietary supplements and food additives by the Food and Drug Administration (FDA), under the authority of the Federal Food, Drug, and Cosmetic Act.
[0004] The delivery of nutraceutical plant extracts is now recognized to have great potential to treat a variety of diseases and conditions. Thus, the area of supplementation with nutraceuticals has seen a dramatic increase in the last few years. However, this increase in interest has led to many manufacturers rushing products to market that may be unsafe and/or that produce highly variable outcomes. For example, current delivery systems for active ingredients in plants (e.g., kratom extracts, kanna extracts, kava extracts, mushroom extracts (e.g., Psilocybe cuhensisy Cannabis extracts) vary widely, making their effects unpredictable. For example, plant extracts (e.g., kratom extracts) are not well-regulated. Thus, products comprising these plant extracts may comprise large amounts of impurities, depending on the manufacturer. In the case of kratom, for example, this leads to a risk of serious side-effects, including seizures, hallucinations, chills, vomiting, liver damage or even death.
[0005] Compounding this issue, pure isolate forms of plant extracts (e.g., kratom extracts, kanna extracts, kava extracts, Psilocybe cubensis extracts, Cannabis extracts, etc.) may be highly hydrophobic and have different characteristics than their impure counterparts from a formulation and pharmacokinetic standpoint. Thus, currently available formulations with pure plant extracts are not without their drawbacks (suffering from, for example, poorer bioavailability). For instance, currently available kratom isolate forms have low oral bioavailability due to low solubility in aqueous systems (e.g., and in the gut, etc.). These problems can also be found in kratom extracts, kanna extracts, kava extracts, Psilocybe cubensis extracts, Cannabis extracts, etc.
[0006] Current delivery systems for active ingredients can also suffer from a variety of problems. For example, current nanoparticle technology can often be too unstable for effective use. Current nanoparticle formulations may distribute unevenly through a solution or a liquid medium, which may cause uneven delivery of the nanoparticle. The uneven distribution may cause the nanoparticles to form a layer or precipitate out of a solution. Current nanoparticles may also separate over time. The distribution of nanoparticles and/or the active ingredients within current nanoparticle formulation may also suffer from instability.
[0007] Several embodiments disclosed herein solve these or other problems by providing novel and innovative nanoparticle compositions and methods for generating such compositions.
BRIEF SUMMARY
[0008] Certain aspects of the disclosure comprise a nanoparticle composition, comprising a nanoparticle comprising a first active agent at a weight percent in the composition ranging from 1% to 50%; a lipid source at a weight percent in the composition ranging from 1% to 50%; optionally a surfactant at a weight percent in the composition ranging from 0% to 17.5%; and water at a weight percent in the composition ranging from 50% to about 97.5%; wherein the nanoparticles have an average size ranging from about 25 nm to about 200 nm. In some aspects, the composition is a dried composition comprising a nanoparticle having weight ratios of a first active agent: a lipid source: and optionally a surfactant of 1 to 50:1 to 50:0 to 17.5. In some aspects, the active agent is a pharmaceutical, nutraceutical, cosmetic, pigment, flavoring, etc. In some aspects, the first active agent is a kratom extract, a kanna extract, a kava extract, a mushroom extract, or a Cannabis extract. In some aspects, the first active agent is a kratom extract. In some aspects, the composition further comprises a second active agent. In some aspects, the second active agent is a kratom extract, a kanna extract, a kava extract, a mushroom extract, or a Cannabis extract. In some aspects, the composition is configured such that when concentrated to dryness to afford a powder formulation of nanoparticles, the nanoparticle powder can be reconstituted to provide the nanoparticle composition. Disclosed herein, it has been found that modifying the mixtures of nanoparticles (e.g., liposome, micelle, nanoemulsion, multi-lamellar, double liposome, solid lipid particles) and/or density of the mixture of particles can provide increased stability to the actives, stability to the particles, and can be tuned for the particular liquid or carrier that the mixture is being added to for better dispersion and more stable dispersion.
[0009] Certain aspects of the disclosure comprise a fortified biomass comprising a biomass coated with the mixed nanoparticle composition of any aspect disclosed herein. In some aspects, the biomass is a hemp biomass, a marijuana biomass, a moonrock, hash, mushroom biomass, kratom biomass, kana biomass, and/or kava biomass.
[0010] Certain aspects of the disclosure comprise a method of treating a patient in need of treatment comprising administering an effective amount of the mixed nanoparticle composition of any aspect disclosed herein or the fortified biomass of any aspect disclosed herein to the patient.
[0011] Certain aspects of the disclosure comprise a method of manufacturing a nanoparticle composition of an active agent comprising providing a lipid source; optionally providing a surfactant; mixing the lipid source and optionally the surfactant to provide a solution; passing the solution through a microfluidizer to provide a mixed nanoparticle composition; and mixing an active agent with the mixed nanoparticle composition. In some aspects, the method further comprises adding one or more co-emulsifiers to the solution. In some aspects, the method further comprises adding water to the solution.
[0012] Aspect 1 of the present disclosure concerns a nanoparticle composition comprising at least one nanoparticle, the composition comprising at least one active agent, at a weight percent in the composition ranging from 1% to 50 %, at least one lipid at a weight percent in the composition ranging from 1% to 50%, optionally at least one surfactant at a weight percent in the composition ranging from 0% to 17.5%, and water at a weight percent in the composition ranging from 50% to about 97.5%.
[0013] Aspect 2 concerns the nanoparticle composition of aspect 1, wherein the active agent comprises one or more pharmaceutical, nutraceutical, cosmetic, pigment, or flavoring.
[0014] Aspect 3 concerns the nanoparticle composition of aspect 1 or 2, wherein the active agent comprises a plant extract. [0015] Aspect 4 concerns the nanoparticle composition of any one of aspects 1-3, wherein the active agent comprises a cannabis extract, a kanna extract, a kratom extract, an algae extract, and/or a mushroom extract.
[0016] Aspect 5 concerns the nanoparticle composition of any one of aspects 1-4, wherein the active agent comprises a small molecule.
[0017] Aspect 6 concerns the nanoparticle composition of any one of aspects 1-5, wherein the active agent comprises a biologic.
[0018] Aspect 7 concerns the nanoparticle composition of any one of aspects 1-6, wherein the active agent comprises a flavoring agent.
[0019] Aspect 8 concerns the nanoparticle composition of any one of aspects 1-7, wherein the active agent comprises a cosmetic.
[0020] Aspect 9 concerns the nanoparticle composition of any one of aspects 1-8, wherein the lipid comprises phosphatidylcholine and/or phosphatidylserine.
[0021] Aspect 10 concerns the nanoparticle composition of aspect 9, wherein a source of the phophatidylcholine is 20% pure, 50%, pure, or 90% pure or ranges including and/or spanning the aforementioned values.
[0022] Aspect 11 concerns the nanoparticle composition of aspect 9 or 10, wherein the phosphatidylcholine comprises hydrogenated soybean phosphatidylcholine (HSPC) and/or sunflower phosphatidylcholine.
[0023] Aspect 12 concerns the nanoparticle composition of any one of aspects 1-11, wherein the surfactant comprises an emulsifier.
[0024] Aspect 13 concerns the nanoparticle composition of any one of aspects 1-12, wherein the at least one nanoparticle does not comprise a surfactant.
[0025] Aspect 14 concerns the nanoparticle composition of any one of aspects 1-13, wherein the composition comprises a mixture of nanoparticles selected from at least two of a multilamellar nanoparticle vesicles, unilamellar nanoparticle vesicles, multivesicular nanoparticles, emulsion particles, irregular particles with lamellar structures and bridges, partial emulsion particles, combined lamellar and emulsion particles, micelles, and/or combinations thereof.
[0026] Aspect 15 concerns the nanoparticle composition of any one of aspects 1-14, comprised in a liquid formulation.
[0027] Aspect 16 concerns the nanoparticle composition of any one of aspects 1-15, wherein the density of the nanoparticle composition is within 10 % of the density of the liquid formulation. [0028] Aspect 17 concerns the nanoparticle composition of any one of aspects 1-16, further comprising at least one co-emulsifier and/or at least one preservative.
[0029] Aspect 18 concerns nanoparticle composition of any one of aspects 1-17, wherein the at least one nanoparticle comprises phosphatidylcholine, capric and caprylic triglycerides, one or more sterol such as cholesterol and/or a plant sterol, vitamin E, potassium sorbate, sodium benzoate, and citric acid.
[0030] Aspect 19 concerns a method of manufacturing a nanoparticle composition of any one of aspects 1-18, the method comprising the steps of: a. adding one or more active agents, one or more lipids, and optionally one or more surfactants to water; b. mixing the ingredients of step (a) creating a mixture; c. homogenizing the mixture creating a homogenized mixture; d. performing microfluidization on the homogenized mixture creating a microfluid; e. sonicating the microfluid creating a sonicated microfluid; f. stirring the sonicated microfluid creating a stirred microfluid; g. creating a coacervation from the stirred microfluid; and h. precipitating the coacervation.
[0031] Aspect 20 concerns the method of aspect 19, wherein the mixing of step (b) comprises high sheer mixing.
[0032] Aspect 21 concerns the method of aspect 19 or 20, wherein the homogenizing of step (c) comprises high pressure homogenization.
[0033] Aspect 22 concerns the method of any one of aspects 19-21, wherein the stirring of step (f) comprises mechanical stirring.
[0034] Aspect 23 concerns the method of any one of aspects 19-22, wherein the precipitating of step (h) comprises solvent precipitation.
[0035] Aspect 24 concerns the method of any one of aspects 19-23, further comprising extruding the composition using hot melt extrusion.
[0036] Aspect 25 concerns the method of any one of aspects 19-24, further comprising drying the nanoparticle composition.
[0037] Aspect 26 concerns the method of aspect 25, wherein the drying comprises lyophilizing, spray drying, fluid bed drying, and/or desiccating the nanoparticle composition. [0038] Aspect 27 concerns a nanoparticle composition comprising at least one nanoparticle, the composition comprising at least one active agent, at least one lipid, and optionally at least one surfactant at a weight ratio of 1 to 50:1 to 50:0 to 17.5, wherein the composition comprise less than 10 wt. % water.
[0039] Aspect 28 concerns the nanoparticle composition of aspect 27, wherein the active agent comprises one or more pharmaceutical, nutraceutical, cosmetic, pigment, or flavoring.
[0040] Aspect 29 concerns the nanoparticle composition of aspect 27 or 28, wherein the composition comprises a mixture of nanoparticles selected from at least two of a liposome, a micelle, a nanoemulsion, a multi-lamellar particle, a double liposome particle, and a solid lipid particle.
[0041] Aspect 30 concerns the nanoparticle composition of any one of aspects 1-18, wherein the at least one nanoparticle comprises phosphatidylcholine, capric and caprylic triglycerides, one or more sterol such as cholesterol and/or a plant sterol, vitamin E, potassium sorbate, sodium benzoate, and/or citric acid.
[0042] Aspect 31 concerns a method of treating a disease, a disorder, and/or a symptom in an individual, the method comprising administering to the individual a therapeutically effective amount of the nanoparticle composition of any one of aspects 1-18 or 27-30.
[0043] Aspect 32 concerns the method of aspect 31, wherein the disease is an autoimmune disease, a cancer, a degenerative disease, a blood disease, an infection, and/or a deficiency disease.
[0044] Aspect 33 concerns the method of aspect 31 or 32, wherein the symptom comprises opioid withdrawal, pain, anxiety, depression, insomnia, inflammation, fever, fatigue, muscle aches, or a combination thereof.
[0045] Aspect 34 concerns the method of any one of aspects 31-33, wherein the administering step comprises local administration.
[0046] Aspect 35 concerns the method of any one of aspects 31-33, wherein the administering step comprises systemic administration.
[0047] Aspect 36 concerns the method of any one of aspects 31-33, wherein the administering step comprises oral administration.
[0048] Aspect 37 concerns the method of any one of aspects 31-36, wherein the therapeutically effective amount of the nanoparticle composition comprises 10 mg/kg to 200 mg/kg. [0049] Aspect 38 concerns a method of distributing an active agent in a solution, the method comprising contacting the solution with the nanoparticle composition of aspects 1-18 or 27-30.
[0050] Aspect 39 concerns the method of aspect 38, wherein the nanoparticle composition has a density within 10% of a density of the solution.
[0051] Aspect 40 concerns the method of aspect 38 or 39, wherein the nanoparticle composition comprises a mixture of nanoparticles selected from at least two of a liposome, a micelle, a nanoemulsion, a multi-lamellar particle, a double liposome particle, and a solid lipid particle.
[0052] Aspect 41 concerns a method of adjusting a density of the nanoparticle composition of aspect 14-18, the method comprising adjusting the density by adjusting a ratio of at least two of a liposome, a micelle, a nanoemulsion, a multi-lamellar particle, a double liposome particle, and a solid lipid particle.
[0053] Aspect 42 concerns the method of aspect 41, wherein the ratio is adjusted by adjust the concentration of an ingredient and/or substituting an ingredient used to form the nanoparticles.
[0054] Aspect 43 concerns the method of aspect 42, wherein a concentration is increased of a lipid that is a solid at room temperature to increase concentration of solid lipid particles.
[0055] Aspect 44 concerns the method of any one of aspects 42 or 43, wherein a concentration is increased of a lipid that is a liquid at room temperature to increase concentration of liposomes.
[0056] Aspect 45 concerns the method of any one of aspects 42 to 44, wherein a concentration of a sterol is adjusted to adjust the density.
[0057] Aspect 46 concerns the method of any one of aspects 42 to 45, wherein a concentration ratio is decreased of medium chained triglycerides to phosphatidylcholine to increase concentration of liposomes.
[0058] It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the disclosure, and vice versa. Furthermore, compositions of the disclosure can be used to achieve methods of the disclosure. [0059] Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0060] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.
[0061] FIG. 1 is a flow chart showing an embodiment of a method of preparing a composition as disclosed herein.
[0062] FIG. 2 is a flow chart showing another embodiment of a method for preparing a composition as disclosed herein.
[0063] FIG. 3 is a flow chart showing another embodiment of a method for preparing a composition as disclosed herein.
[0064] FIG. 4 shows the size distribution of lipid nanoparticles (LNPs) stored for two years.
[0065] FIG. 5 shows distribution of compounds found near expected cannabinoid elusion fractions from lipid nanoparticles (LNPs) stored for two years.
[0066] FIGs. 6A-6B show particle size and dissolution of nanoparticles disclosed herein compared to other marketed products.
[0067] FIG. 7 shows viscosity vs. concentration of lipid in the kratom mixed micelle formulation. Point at 300 g/L and 300 mPa*s is shown to guide the eye. The 300 g/L mixed micelle suspension was not successful due to high viscosity during compounding.
[0068] FIG. 8 shows change in CBG (cannabigerol) concentration when stored at controlled room temperature.
[0069] FIG. 9 shows change in Z- average particle size of CBG nanoparticles when stored at controlled room temperature.
[0070] FIG. 10 shows change in CBD concentration from BSD (broad spectrum hemp distillate) when stored at controlled room temperature.
[0071] FIG. 11 shows change in CBG (cannabigerol) concentration from BSD when stored at controlled room temperature.
[0072] FIG. 12 shows change in CBN (cannabinol) concentration from BSD when stored at controlled room temperature. [0073] FIG. 13 shows change in CBC (cannabichromene) concentration from BSD when stored at controlled room temperature.
[0074] FIG. 14 shows change in Z-average particle size of BSD nanoparticles when stored at controlled room temperature.
[0075] FIG. 15 shows change in Z-average particle size and PDI of FSD (Full Spectrum Hemp Distillate) and THCv (tetrahydrocannabivarin) nanoparticles when stored at controlled room temperature.
[0076] FIG. 16 shows change in Z-average particle size and PDI of FSD and THCv nanoparticles when stored at accelerated temperature.
DETAILED DESCRIPTION
[0077] Disclosed herein are nanoparticle compositions, comprising a nanoparticle comprising a first active agent at a weight percent in the composition ranging from 1% to 50%; a lipid source at a weight percent in the composition ranging from 1% to 50%; optionally a surfactant at a weight percent in the composition ranging from 0% to 17.5%; and water at a weight percent in the composition ranging from 50% to about 97.5%; wherein the nanoparticles have an average size ranging from about 25 nm to about 200 nm. In some aspects, the composition is a dried composition comprising a nanoparticle having weight ratios of a first active agent: a lipid source: and a optionally a surfactant of 1 to 50:1 to 50:0 to 17.5. It has been found that compositions disclosed herein can be configured such that when concentrated to dryness to afford a powder formulation of nanoparticles, the nanoparticle powder can be reconstituted to provide the nanoparticle composition. Also, it has been found that modifying the mixtures of nanoparticles (e.g., liposome, micelle, nanoemulsion, multi-lamellar, double liposome, solid lipid particles) and/or density of the mixture of particles can provide increased stability to the actives, stability to the particles, and can be tuned for the particular liquid or carrier that the mixture is being added to for better dispersion and more stable dispersion.
I. Definitions
[0078] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the measurement or quantitation method.
[0079] The use of the word “a” or “an” when used in conjunction with the term “comprising” may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” [0080] The phrase “and/or” means “and” or “or”. To illustrate, A, B, and/or C includes: A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C. In other words, “and/or” operates as an inclusive or.
[0081] The words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. When used in the context of a compound, composition or device, the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components.
[0082] The compositions and methods for their use can “comprise,” “consist essentially of,” or “consist of’ any of the ingredients or steps disclosed throughout the specification. Compositions and methods “consisting essentially of’ any of the ingredients or steps disclosed limits the scope of the claim to the specified materials or steps which do not materially affect the basic and novel characteristic of the claimed disclosure.
[0083] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject matter belongs. The terminology used in the description of the subject matter herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the subject matter.
[0084] The terms “treatment,” “treating,” “treat” and the like shall be given its ordinary meaning and shall also include herein to generally refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disorder, disease, or symptom thereof and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disorder or disease and/or adverse effect attributable to the disorder or disease. “Treatment” shall also cover any treatment of a disorder or disease in a mammal, particularly a human, and includes: (a) preventing the disorder, disease, or symptom (e.g., of the disorder or disease) from occurring in a subject which may be predisposed to the disorder, disease, or symptom but has not yet been diagnosed as having it; (b) inhibiting the disorder, disease, or symptom, e.g., arresting its development; and/or (c) relieving the disorder, disease, or symptom (e.g., causing regression of the disorder, disease, or symptom). [0085] The “patient” or “subject” treated as disclosed herein may be a human patient, although it is to be understood that the principles of the presently disclosed subject matter indicate that the presently disclosed subject matter is effective with respect to all vertebrate species, including mammals, which are intended to be included in the terms “subject” and “patient.” Suitable subjects are generally mammalian subjects. The subject matter described herein finds use in research as well as veterinary and medical applications. The term “mammal” as used herein includes, but is not limited to, humans, non-human primates, cattle, sheep, goats, pigs, mini-pigs (a mini-pig is a small breed of swine weighing about 35 kg as an adult), horses, cats, dog, rabbits, rodents (e.g., rats or mice), monkeys, etc. Human subjects include neonates, infants, children, juveniles, adults and geriatric subjects. The subject can be a subject “in need of’ the methods disclosed herein can be a subject that is experiencing a disease state and/or is anticipated to experience a disease state, and the methods and compositions of the disclosure are used for therapeutic and/or prophylactic treatment.
[0086] As used herein, the terms “active agent”, “active compound”, “pharmaceutical composition”, “therapeutic agent”, and the like may be used interchangeably. The terms generally refer to compositions having pharmacological activity or other direct effects in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure, appearance, or any function of molecules, cells, tissues, organs, or subject. The terms may refer to compositions in a beverage. The terms may refer to pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like. The terms may refer to compositions that are hydrophobic, hydrophilic, or both.
[0087] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.
[0088] The term “pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of a compound, which are not biologically or otherwise undesirable for use in a pharmaceutical. In many cases, the compounds herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in US4783443A, Johnston et al., published September 11, 1987 (incorporated by reference herein in its entirety).
[0089] An “effective amount” or a “therapeutically effective amount” as used herein can refer to an amount of a therapeutic agent that is effective to relieve, to some extent, or to reduce the likelihood of onset of, one or more of the symptoms of a disease or condition (e.g., disorder), and includes curing a disease or condition. “Curing” means that the symptoms of a disease or condition are eliminated; however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).
[0090] As used herein, the term “weight percent” (or wt. %, weight %, percent by weight, etc.), when referring to a component, is the weight of the component divided by the weight of the composition that includes the component, multiplied by 100%. For example, the weight percent of component A when 5 grams of component A is added to 95 grams of component B is 5% (e.g., 5 g A / (5 g A + 95 g B) x 100%).
[0091] As used herein, the “dry weight %” (e.g., “dry wt. %”, “dry weight percent”, etc.) of an ingredient is the weight percent of that ingredient in the composition where the weight of water has not been included in the calculation of the weight percent of that ingredient. A dry weight % can be calculated for and includes either a composition that does not include water (e.g., that has been dried to, for example, a powder) or for a composition that includes water but where the amount of water is not included in the calculation.
[0092] As used herein, the “wet weight %” (e.g., “wet wt. %”, “wet weight percent”, etc.) of an ingredient is the weight percent of that ingredient in a composition where the weight of water is included in the calculation of the weight percent of that ingredient. For example, the dry weight percent of component A when 5 grams of component A is added to 95 grams of component B and 100 grams of water is 5% (e.g., 5 g A / (5 g A + 95 g B) x 100%). Alternatively, the wet weight percent of component A when 5 grams of component A is added to 95 grams of component B and 100 grams of water is 2.5% (e.g., 5 g A / (5 g A + 95 g B + 100 g water) x 100%).
[0093] As used herein, the term “weight volume percent” (or weight volume percentage, w/v, w/v (%), etc.), when referring to a component, is the weight of the component in grams divided by the volume of a solution in milliliters that includes the component, multiplied by 100%. For example, the w/v of component A when 5 grams of component A is added to a solution to provide 100 mL of solution is 5 w/v (%) (e.g., 5 g solute A / 100 mL solution x 100%).
[0094] When referring to an amount present for one or more ingredients, the term “collectively or individually” (and variations thereof) means that the amount is intended to signify that the ingredients combined may be provided in the amount disclosed, or each individual ingredient may be provided in the amount disclosed. For example, if agents A and B are referred to as collectively or individually being present in a composition at a wt. % of 5%, that means that A may be at 5 wt. % in the composition, B may be at 5 wt. % in the composition, or the combination of A and B may be present at a total of 5 wt. % (A + B = 5 wt. %). Alternatively, where both A and B are present, A may be at 5 wt. % and B may be at 5 wt. %, totaling 10 wt. %.
[0095] When referring to the amount present for one or more ingredients, the terms “or ranges including and/or spanning the aforementioned values” (and variations thereof) is meant to include any range that includes or spans the aforementioned values. For example, when the wt. % of an ingredient is expressed as 1%, 5%, 10%, 20%, “orranges including and/or spanning the aforementioned values,” this includes wt. % ranges for the ingredient spanning from 1% to 20%, 1% to 10%, 1% to 5%, 5% to 20%, 5% to 10%, and 10% to 20%.
[0096] As used herein, “polydispersity” or “PDI” is used to describe the degree of nonuniformity of a size distribution of particles. Also known as the heterogeneity index, PDI is a number calculated from a two-parameter fit to the correlation data (the cumulants analysis). This index is dimensionless and scaled such that values smaller than 0.05 are mainly seen with highly monodisperse standards.
[0097] As used herein, the term “phytocannabinoid” refers to a group of cannabinoids that occur naturally in the cannabis plant, including but not limited to, THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid), CBD (cannabidiol), CBDA (cannabidiolic acid), CBN (cannabinol), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabicyclol), CBV (cannabivarin), THCV (tetrahydrocannabivarin), CBDV (cannabidivarin), CBCV (cannabichromevarin), CBGV (cannabigerovarin), CBGM (cannabigerol monomethyl ether), CBE (cannabielsoin), and CBT (cannabicitran).
[0098] As used herein, the term “cannabinoid” refers to the chemical substance, regardless of structure or origin, that joins the cannabinoid receptors of the body and brain and that have similar effects to those produced by the cannabis plant. As used herein, the term “cannabinoid” includes but is not limited to Cannabichromenes (e.g., cannabichromene (CBC), cannabichromenic acid (CBCA), cannabichromevarin (CBCV), cannabichromevarinic acid (CBCVA), Cannabicyclols (e.g., cannabicyclol (CBL), cannabicyclolic acid (CBLA), cannabicyclovarin (CBLV), etc.), Cannabidiols (e.g., cannabidiol (CBD), cannabidiol monomethylether (CBDM), cannabidiolic acid (CBDA), Cannabidiol-C4 (CBD-C4), cannabidiorcol (CBD-C1), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), etc.), Cannabielsoins (e.g., Cannabielsoic Acid (CBEA), Cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEA-B), cannabielsoin (CBE), cannabielsoin acid A (CBEA-A), etc.), Cannabigerols (e.g., cannabigerol (CBG), cannabigerol monomethylether (CBGM), cannabigerolic acid (CBGA), cannabigerolic acid monomethylether (CBGAM), cannabigerovarin (CBGV), cannabigerovarinic acid (CBGVA), etc.), Cannabinols and cannabinodiols (e.g., cannabinodiol (CBND), cannabinodivarin (CBVD), cannabinol (CBN) cannabinol methylether (CBNM), cannabinol-C2 (CBN-C2), cannabinol-C4 (CBN-C4), cannabinolic acid (CBNA), cannabiorcool (CBN-C1), cannabivarin (CBV), etc.), Cannabitriols (e.g., 10-ethoxy-9-hydroxy-delta-6a-tetrahydrocannabinol, 8,9-dihydroxy-delta- 61 -tetrahydrocannabinol, 8,9-Dihydroxy-A6a(10a)-tetrahydrocannabinol (8,9-Di-OH-CBT-Cs), cannabitriol (CBT), cannabitriolvarin (CBTV), Ethoxy-cannabitriolvarin (CBTVE), etc.), tetrahydrocannabinols (e.g., tetrahydrocannabinol (THC), tetrahydrocannabinol-C4 (THC- C4), delta-9-tetrahydrocannabinol (A9-THC), delta-9-tetrahydrocannabinol-C4 (A9-THC-C4), delta-9-tetrahydrocannabinolic acid A (THCA-A), Tetrahydrocannabinolic Acid (THCA), delta-9-tetrahydrocannabinolic acid B (THCA-B) delta-9-tetrahydrocannabinolic acid-C4 (THCA-C4), Tetrahydrocannbinol C4 (THC-C4), delta-9-tetrahydrocannabiorcol (THC-C1), delta-9-tetrahydrocannabiorcolic acid (THCA-C1), delta-9-tetrahydrocannabivarin (THCV), delta-9-tetrahydrocannabivarinic acid (THCVA), delta-9-cis-tetrahydrocannabinol (cis-THC), trihydroxy-delta-9-tetrahydrocannabinol (triOH-THC), etc.), and/or other cannabinoids (e.g., 10-Oxo-delta-6a-tetrahydrocannabinol (OTHC), cannabichromanon (CBCF), cannbifuran (CBF), cannabiglendol, cannabiripsol (CBR), cannbicitran, dehydrocannabifuran (DCBF), 3,4,5,6-tetrahydro-7-hydroxy-alpha-alpha-2-trimethyl-9-n-propyl-2,6-methano-2H-l- benzoxocin-5 -methanol (OH-iso-HHCV), A7-cis-iso-tetrahydrocannabivarin, A8- tetrahydrocannabinolic acid (A8-THCA), tetrahydrocannabiorcolic acid (THCA-C4), Cannabivarinodiolic (CBNDVA), Cannabivarinodiol (CBNDV), A8-tetrahydrocannabinol (A8- THC), Cannabivarinselsoin (CBEV), Cannabivarinselsoinic Acid (CBEVA), Cannabielvarinsoin (CBLV), Cannabielvarinsoinic Acid (CBLVA), Cannabivarinic Acid (CBNVA), Cannabiorcol (CBN-Ci), Cannabinodiolic Acid (CBNDA), and/or 3, 4,5,6- tetrahydro-7-hydroxy-alpha-alpha-2-trimethyl-9-n-propyl-2,6-methano-2H-l-benzoxocin-5- methanol (OH-iso-HHCV). Cannabinoids can also include cannabinoids derived from sources other than hemp or marijuana, such as oranges. Cannabinoids can also include synthetic (e.g., not naturally occurring) chemicals.
[0099] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term “including” should be read to mean “including, without limitation,” “including but not limited to,” or the like; the term “having” should be interpreted as “having at least;” the term “includes” should be interpreted as “includes but is not limited to;” the term “example” is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like “preferably,” “preferred,” “desired,” or “desirable,” and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of any embodiment disclosed herein, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the disclosure. Likewise, a group of items linked with the conjunction “or” should not be read as requiring mutual exclusivity among that group, in some embodiments, but rather should be read as “and/or”.
[0100] Additionally, the phrase “consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of’ excludes any element not specified. [0101] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.
[0102] The section headings used herein are for organizational purposes only and are not to be construed as limiting the described subject matter in any way. All literature and similar materials cited in this application, including but not limited to, patents, patent applications, articles, books, treatises, and internet web pages are expressly incorporated by reference in their entirety for any purpose. When definitions of terms in incorporated references appear to differ from the definitions provided in the present teachings, the definition provided in the present teachings shall control. It will be appreciated that there is an implied “about” prior to the temperatures, concentrations, times, etc. discussed in the present teachings, such that slight and insubstantial deviations are within the scope of the present teachings herein. In this application, the use of the singular includes the plural unless specifically stated otherwise.
II. Compositions
[0103] Certain embodiments disclosed herein concern compositions comprising a nanoparticle, which may encapsulate an active agent. The compositions, in some embodiments, can deliver highly pure active agents, such as pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, etc. in a nanoparticle delivery system (e.g., lipid nanoparticle, a liposomal system, oil-in-water emulsions, dry liposome particles, etc.). Some active agents include kratom and/or kratom extracts, kanna extracts, kava extracts, Psilocybe cubensis extracts, cannabis extracts, other active agents, and/or combinations of any of the foregoing. Compositions disclosed herein, in some embodiments, comprise mixed nanoparticle compositions comprising active agents or combinations of active agents. In several embodiments, the disclosed compositions, which may be mixed nanoparticle compositions, have certain characteristics including, but not limited to, fewer impurities, fewer variations batch-to-batch (e.g., stability, degradation profiles, efficacy), better delivery predictability, fewer side effects when administered to a subject, higher bioavailability, faster onset of activity, greater long term storage stability of the particles and the active ingredient(s), better dispersibility, greater stability of a dispersion, and better efficacy, relative to the characteristics of compositions known in the art.
[0104] Certain embodiments concern nanoparticles, including mixed micelle-based compositions, and their use in methods for the delivery of active compounds, which may include plant extracts (e.g., kratom extracts, hemp extracts, etc.) and/or other beneficial agents (e.g., vitamins, nutrients, other plant extracts, nutraceuticals, pharmaceuticals, flavorings, pigments, or other beneficial agents for delivery). In several embodiments, the compositions are stable (e.g., at room temperature) for prolonged periods of time.
[0105] Several embodiments disclosed herein pertain to formulations, including mixed nanoparticle compositions, for the delivery of one or more active agents (e.g., active agents) to subjects. Several embodiments pertain to methods of use and making the composition. In several embodiments, the nanoparticle compositions comprise one or more active agents (e.g., single active agents or combinations thereof). In several embodiments, the composition is comprised of high-quality, pure, and/or high-grade ingredients (e.g., highly pure) that yield a well-characterized, reproducible delivery system (e.g., comprising mixed nanoparticles). In several embodiments, the compositions have enhanced stability (e.g., are stable for long periods of time under various conditions). In several embodiments, the composition confers water solubility to hydrophobic agents, to combinations of hydrophobic agents, and/or to combinations of hydrophobic and hydrophilic agents. In several embodiments, the nanoparticle composition comprises a liposomal and/or nano-emulsion composition of an active agent.
[0106] While some embodiments are disclosed herein in relation to particular plant extracts (e.g., kratom extracts, cannabinoids, etc.), it is to be understood that other active agents, nutrients, and/or combinations thereof can be employed in the compositions disclosed herein. In several embodiments, for example, hydrophilic active agents may also be provided in the disclosed nanoparticle compositions (e.g., alone, in combination with other hydrophilic active agents, and/or in combination with hydrophobic active agents). Advantageously, the compositions disclosed herein may enhance the delivery of and/or slow or lessen the degradation of hydrophilic or hydrophobic agents (or combinations thereof). Additionally, while some embodiments are disclosed in relation to nanoparticles (e.g., mixed micelle-based nanoparticles), as disclosed elsewhere herein, microparticles are also envisioned.
[0107] Certain embodiments disclosed herein comprise nanoparticle products, which may comprise active compositions. In several embodiments, the composition comprises a nanoparticle delivery system, which may be utilized to impart apparent aqueous solubility and deliverability to an otherwise practically water insoluble molecules (e.g., hydrophobic kratom extracts, hydrophobic kanna extracts, hydrophobic kava extracts, hydrophobic mushroom extracts, hydrophobic Cannabis extracts). Attributes of some embodiments disclosed herein have been determined to be high quality and reproducible. Such reproducibility and low variations may allow the products to generate a reproducible certificate of analysis for different batches.
[0108] In several embodiments, the compositions disclosed herein (e.g., mixed nanoparticle compositions and/or formulations comprising them) increase the bioavailability of active agents (e.g., pharmaceutical, nutraceutical, etc.), decrease the time for absorption of those active agents, increase the stability of the active agents or the particles comprising the active agents, increase the consistency of delivery (e.g., by limiting batch-to-batch variation), and/or increase the efficacy of the active agents (higher dosing and/or faster onset of activity). [0109] As disclosed elsewhere herein, in some embodiments, the compositions (including the mixed nanoparticle compositions) disclosed herein are able to deliver active agents that are highly pure. In several embodiments, an active agent (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like) formulated with the nanoparticle has a purity of greater than or equal to about: 80%, 90%, 95%, 98%, 99%, 99.5%, 99.9%, 99.99%, or ranges including and/or spanning the aforementioned values.
[0110] As disclosed herein, some embodiments relate to delivery systems (e.g., mixed nanoparticle compositions and/or formulations comprising the same) that improve the absorption of the highly insoluble forms of an active agent (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like) or combination of agents. In several embodiments, the active agent encapsulated in the nanoparticle compositions disclosed herein (e.g., the starting material) has an aqueous solubility of less than or equal to about: 0.05 mg/mL, 0.01 mg/mL, 0.012 mg/mL, 0.001 mg/mL, or ranges including and/or spanning the aforementioned values, such as a range between 0.05 mg/mL to 0.001 mg/mL. In several embodiments, where a combination of active agents is encapsulated in the nanoparticle compositions disclosed herein, one or more or all of the active agents in the composition may have an aqueous solubility of less than or equal to about: 0.05 mg/mL, 0.01 mg/mL, 0.012 mg/mL, 0.001 mg/mL, or ranges including and/or spanning the aforementioned values, such as a range between 0.05 mg/mL to 0.001 mg/mL. In several embodiments, the aqueous solubility of the active agent or agents (and/or the amount of active agent or agents that can be provided in an aqueous solution) can be improved to equal to or greater than about: 1 mg/mL, 5 mg/mL, 10 mg/mL, 20 mg/mL, 30 mg/mL, 50 mg/mL, 100 mg/mL, or ranges including and/or spanning the aforementioned values. For example, the aqueous solubility of the active agent or agents may be increased to 1 mg/mL to 50 mg/mL, 10 mg/mL to 100 mg/mL, 1 mg/mL to 20 mg/mL, etc.
[0111] In several embodiments, at least one active agent in the nanoparticle composition (and/or combination of active agents provided in the mixed nanoparticle composition) is hydrophobic. In several embodiments, at least one hydrophobic active agent used to prepare a nanoparticle composition as disclosed herein (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like) has an aqueous solubility of less than or equal to about: 0.05 mg/mL, 0.01 mg/mL, 0.012 mg/mL, 0.001 mg/mL, or ranges including and/or spanning the aforementioned values. In several embodiments, the solubility of the at least one active agent (e.g. the amount of the active agent that can be provided in an aqueous solution) used to prepare the compositions disclosed herein (e.g., a cannabinoid, etc.) can be improved to equal to or greater than about: 1 mg/mL, 5 mg/mL, 20 mg/mL, 30 mg/mL, 50 mg/mL, 100 mg/mL, or ranges including and/or spanning the aforementioned values, when formulated with a nanoparticle. In several embodiments, the solubility of the at least one active agent (such as CBD) can be improved by at least about: 50%, 100%, 150%, 200%, 500%, 1000%, 10,000%, or ranges including and or spanning the aforementioned values. In several embodiments, the solubility is measured as an amount that can be suspended for longer than 30 days and or that can be dissolved in an aqueous solution at a concentration of at least 20 mg/mL.
[0112] In several embodiments, as disclosed elsewhere herein, a nanoparticle composition (e.g., a mixed micelle composition, a liposomal composition, solid lipid particles, oil-in-water emulsions, water-in-oil-in-water emulsions, water-in-oil emulsions, oil-in-water-in-oil emulsions, etc.) is provided to aid in the delivery of active agents. As disclosed elsewhere herein, in several embodiments, the nanoparticles comprise one or more active agents. In several embodiments, one or more of the active ingredients is a nutraceutical. In several embodiments, a composition comprising the nanoparticles disclosed herein comprises a therapeutically effective amount of one or more active ingredients. In several embodiments, the one or more active compounds comprise kratom extracts, kanna extracts, kava extracts, mushroom extracts (e.g., Psilocybe cubensis), Cannabis extracts, cannabinoids, and/or combinations of any of the foregoing.
[0113] In several embodiments, the active ingredients provided in the nanoparticle composition may comprise an unenriched extract (e.g., a mixture of agents as extracted from a single plant source), an enriched extract that has been enriched through purification processes (to have larger amounts of certain active agents), or any individual active component of the extract (e.g., a pure or substantially pure compound). Using kratom as an example, the nanoparticle composition may include an unenriched kratom extract that is isolated by bulk extraction of multiple actives from kratom biomass at one time. Alternatively, the nanoparticle composition may include actives that have been further processed to enrich the extract for particular active agents (e.g., a kratom extract enriched for 7-hydroxymitragynine or mitragynine and having a higher wt. % of 7-hydroxymitragynine or mitragynine than unprocessed kratom extract). In several embodiments, alternatively, an active from an extract may be purified and may be pure and/or substantially pure, as disclosed elsewhere herein. For brevity, when a composition or particle disclosed herein is described as including plant extracts, the term “extracts” is meant to include any of the foregoing (e.g., including a full plant extract that has not been enriched, an extract that has been enriched for particular components (e.g., particular active agents), and/or an extract that has been purified to provide, for example, highly pure individual components).
[0114] In several embodiments, the nanoparticle (or a composition comprising the nanoparticle) is composed and/or comprises one or more kratom extracts. In several embodiments, the one or more kratom extracts may be from any one or more kratom strains. In several embodiments, the nanoparticle (or a composition comprising the nanoparticle) comprises one or more Sceletium extracts (e.g., Kanna extracts).
[0115] In several embodiments, as disclosed elsewhere herein, the nanoparticle compositions comprise one or more kava extracts. In several embodiments, the nanoparticle (or compositions comprising the nanoparticle) comprises or is composed of kava powders and/or kava active ingredients (e.g., including but not limited to alkaloids). In several embodiments, the kava extract is an alkaloid (pipermethystine, etc.), a kavalactone (e.g., Dihydrokavain, Kavain, desmehtoxyyangonin, dihydromethysticin, yangonin, methysticin, etc.) or combinations of any of the foregoing. In several embodiments, the kava extracts are extracted from kava plants (e.g., are natural extracts). In other embodiments, the kava extracts may be produced synthetically (e.g., in a laboratory). In several embodiments, the synthetic extract may share a structure with an extract that is naturally occurring. In several embodiments, the kava extracts are analogs of natural extracts of kava (e.g., produced synthetically).
[0116] In several embodiments, the nanoparticle (or a composition comprising the nanoparticle) comprises one or more mushroom extracts (e.g., cordyceps, lion mane, reishi, chaga gano, psilocybin (including the compound itself, natural extract forms, synthetic forms, derivatives of psilocybin, and prodrugs of any one of the foregoing), others, and/or combinations of any of the foregoing). In several embodiments, the mixed nanoparticle (or a composition comprising it) comprises or is composed of one or more fungus extracts (e.g., a mushroom extract). In several embodiments, the mixed nanoparticle (or a composition comprising it) comprises or is composed of mushroom extracts (e.g., of mushroom powder).
[0117] In several embodiments, as disclosed elsewhere herein, the nanoparticle (or a composition comprising the nanoparticle) comprises or is composed of cannabinoids. In several embodiments, the nanoparticle (or a composition comprising the nanoparticle) comprises or is composed of cannabinoids derived from resin or rosin (solventless extraction of cannabinoids achieved by pressing biomass). In several embodiments, the nanoparticle (or a composition comprising the nanoparticle) comprises or is composed of cannabinoids from a crude extract of hemp or marijuana (an extraction that is not further purified). In several embodiments, the lipid particle solution is composed of cannabinoids from combinations of sources, such as hemp oil fortified with cannabinoid isolate. The cannabinoids (including phytocannabinoids) may be any of the cannabinoids disclosed elsewhere herein and/or a mixture of one or more of such cannabinoids.
[0118] In several embodiments, the nanoparticle (or a composition comprising the nanoparticle) comprises a cannabichromene, a cannabicyclol, a cannabidiol, a cannabielsoin, a cannabigerol, a cannabinol, a cannabinodiol, a cannabitriol, a delta-9-tetrahydrocannabinol, another cannabinoid, a synthetic cannabinoid, and/or combinations of any of the foregoing. In several embodiments, the mixed nanoparticle composition comprises two or more cannabichromenes, cannabicyclols, cannabidiols, cannabielsoins, cannabigerols, cannabinols, cannabinodiols, cannabitriols, delta-9-tetrahydrocannabinols, other cannabinoids, synthetic cannabinoids, and/or combinations of any of the foregoing. In several embodiments, the nanoparticle composition comprises CBC, CBCA, CBCV, CBCVA, CBL, CBLA, CBLV, CBD, CBDM, CBDA, CBD-C1, CBDV, CBDVA, CBEA-B, CBE, CBEA-A, CBG, CBGM, CBGA, CBGAM, CBGV, CBGVA, CBND, CBVD, CBN, CBNM, CBN-C2, CBN-C4, CBNA, CBN-C1, CBV, 10-ethoxy-9-hydroxy-delta-6a-tetrahydrocannabinol, 8,9-dihydroxy- delta-61 -tetrahydrocannabinol, CBT, CBTV, THC, THC-C4, THCA-A, THCA-B, THCA-C4, THC-C1, THCA-C1, THCV, THCVA, OTHC, CBCF, CBF, cannabiglendol, CBR, cannbicitran, DCBF, cis-THC, triOH-THC, OH-iso-HHCV, synthetic cannabinoids, and/or combinations of any of the foregoing. For example, in some embodiments, the nanoparticle composition may comprise CBN, CBD, and CBG. [0119] In several embodiments, the kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts, are isolated from their plant sources. In several embodiments, the kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts, are isolated from their plant sources using solvent extraction. In several embodiments, the kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts, are isolated from their plant sources using acid base titration. In several embodiments, the kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts, are isolated from their plant sources using CO2 (supercritical or nonsupercritical), In several embodiments, the kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts, are isolated from their plant sources using cyrogenic ethanol. In several embodiments, the kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts, are isolated from their plant sources using other forms of extraction. In several embodiments, the extract is an alkaloid (e.g., a kratom alkaloid), as disclosed elsewhere herein.
[0120] In several embodiments, the kratom is provided as a kratom plant powder. In several embodiments, the kanna is provided as a kanna plant powder. In several embodiments, the kava is provided as a kava plant powder. In several embodiments, the mushroom is provided as a mushroom powder. In several embodiments, the Cannabis is provided as a Cannabis plant powder.
[0121] In several embodiments, a kratom active (e.g., alkaloid), a kanna active, a kava active, a mushroom active, a Cannabis active may be provided in a salt form. In several embodiments, salt is a pharmaceutically acceptable salt. In several embodiments, the salt is the acetate or citrate salt. In several embodiments, the composition may comprise mixtures of salt forms.
[0122] In several embodiments, when formulated, the dry weight % of one or more active agents (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, etc.) present in the nanoparticle compositions is equal to or at least about: 0.5%, 1%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 25%, 50%, or ranges including and/or spanning the aforementioned values. In several embodiments, the active agents are provided in an aqueous composition. In several embodiments, the wet weight % of one or more active agents (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, etc.) present in the composition (with water included) is equal to or at least about: 0.5%, 1%, 2%, 3%, 4%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, or ranges including and/or spanning the aforementioned values. In several embodiments, the one or more active agents (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, etc.) may be provided in the wet composition at a concentration of greater than or equal to about: 1 mg/mL, 5 mg/mL, 20 mg/mL, 30 mg/mL, 50 mg/mL, 100 mg/mL, or ranges including and/or spanning the aforementioned values.
[0123] In several embodiments, the active agents, collectively or individually, are present in the aqueous nanoparticle composition at a concentration of less than or equal to about: 150 mg/mL, 100 mg/mL, 75 mg/mL, 50 mg/mL, 25 mg/mL, 20 mg/mL, 10 mg/mL, 5 mg/mL, 2.5 mg/mL or ranges including and/or spanning the aforementioned values. In several embodiments, the one or more active agents, collectively or individually, are present in the aqueous composition at a concentration of greater than or equal to about: 150 mg/mL, 100 mg/mL, 75 mg/mL, 50 mg/mL, 25 mg/mL, 20 mg/mL, 10 mg/mL, 5 mg/mL, or ranges including and/or spanning the aforementioned values. In several embodiments, the one or more active agents, collectively or individually, are present in the composition at a dry wt. % of equal to or at least about: 0.5%, 1%, 5%, 7.5%, 10%, 15%, 20%, 25%, or ranges including and/or spanning the aforementioned values. In several embodiments, the one or more active agents, collectively or individually, are present in the composition at a wet wt. % of equal to or at least about: 0.1%, 0.25%, 0.5%, 1%, 2%, 3%, 4%, 5%, 7.5%, 10%, or ranges including and/or spanning the aforementioned values. In several embodiments, as disclosed elsewhere herein, the composition is aqueous, while in others it has been dried into a powder (that is free of or substantially free of water). In several embodiments, where the composition has been dried, it comprises a water content of less than or equal to 20%, 15%, 10%, 7.5%, 5%, 2.5%, 1%, or ranges including and/or spanning the aforementioned values.
[0124] In several embodiments, as disclosed elsewhere herein, the nanoparticle (or compositions comprising the nanoparticle) may be used to deliver combination extracts (e.g., combinations of one or more kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts), additional actives, terpenes, and/or combinations thereof (as disclosed elsewhere herein). As disclosed elsewhere herein, in some embodiments, the nanoparticle composition may include one or more active agents (e.g., a single active agent or a combination of active agents). In several embodiments, the nanoparticle composition may include a single active agent or a plurality of active agents (e.g., 1, 2, 3, 4, or more). For example, the nanoparticle composition may comprise a kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts, cannabinoids and a different active (e.g., a pharmaceutical, nutraceutical, cosmetic, pigment, flavoring, a kratom extract, and/or a terpene). In several embodiments, the nanoparticle may comprise one or more therapeutic plant extracts and one or more non-plant based therapeutic agent. Other combinations of therapeutics selected from kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts, and other therapeutics are also envisioned.
[0125] In several embodiments, the composition comprises combinations of active compounds of varying ratios. For example, a first active compound (e.g., a kratom extract, a kanna extract, a kava extract, a mushroom extract, or a Cannabis extract) to a second active compound (e.g., a different a kratom extract, a kanna extract, a kava extract, a mushroom extract, or a Cannabis extract) present in the composition may be about: 10: 1, 5: 1, 4: 1, 3: 1 2: 1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, or ratios including and/or spanning the aforementioned ratios.
[0126] In several embodiments, as disclosed elsewhere herein, the one or more non- kratom/non-kanna/non-kava active/non-mushroom active/non-Cannabis active agent(s), collectively or individually, are present in the aqueous composition at a concentration of greater than or equal to about: 100 mg/mL, 75 mg/mL, 50 mg/mL, 25 mg/mL, 20 mg/mL, 10 mg/mL, 5 mg/mL, or ranges including and/or spanning the aforementioned values. In several embodiments, the one or more non-kratom/non-kanna/non-kava active/non-mushroom active/non-Cannabis active agent(s) (collectively or individually) are present in the composition at a dry wt. % of equal to or at least about: 0.5%, 1%, 5%, 7.5%, 10%, 15%, 20%, 25%, or ranges including and/or spanning the aforementioned values. In several embodiments, the one or more non-kratom/non-kanna/non-kava active/non-mushroom active/non-Cannabis active agent(s) (collectively or individually) are present in the composition at a wet wt. % of equal to or at least about: 0.1%, 0.25%, 0.5%, 1%, 2%, 3%, 4%, 5%, 7.5%, 10%, 15%, or ranges including and/or spanning the aforementioned values.
[0127] In several embodiments, as disclosed elsewhere herein, the composition is aqueous (e.g., contains water) while in other embodiments, the composition is dry (lacks water or substantially lacks water). In several embodiments, the composition has been dried (e.g., has been subjected to a process to remove most or substantially all water). In several embodiments, the composition comprises nanoparticles in water (e.g., as a solution, suspension, or emulsion). In other embodiments, the composition is provided as a powder (e.g., that may be constituted or reconstituted in water). In several embodiments, as disclosed elsewhere herein, the water content (in wt. %) of the composition is less than or equal to about: 30%, 20%, 10%, 5%, 2.5%, 1%, 0.5%, 0.1%, 0%, or ranges including and/or spanning the aforementioned values. In several embodiments, as disclosed elsewhere herein, the water content (in wt. %) of the composition is greater than or equal to about: 50%, 60%, 70%, 80%, 85%, 90%, 92.5%, 95%, 97.5%, or ranges including and/or spanning the aforementioned values. In several embodiments, the water is nanopure, deionized, USP grade, WFI, and/or combinations of the foregoing. In some aspects, the composition is a dried composition comprising a nanoparticle having weight ratios of a first therapeutic active agent: a lipid source: and optionally a surfactant of 1 to 50:1 to 50:0 to 17.5.
[0128] In several embodiments, as disclosed elsewhere herein, the nanoparticle composition provides an oil-in-water emulsion (e.g., a nanoemulsion), water-in-oil emulsion, a water-in-oil-in-water emulsion, an oil-in-water-in-oil emulsion, a liposome (and variants including multi-lamellar, double liposome preparations, etc.), micelle, and/or solid lipid particles. Any one of these structures may be provided as a nanoparticle or microparticle.
[0129] As disclosed elsewhere herein, in some embodiments, the nanoparticle composition comprises a lipid source. In several embodiments, the lipid source comprises a charged lipid, which can impart a charge to the nanoparticle. In several embodiments, the lipid source comprises a neutral lipid. In several embodiments, the lipid source comprises one or more phospholipids. In several embodiments, the one or more phospholipids comprises one or more of phosphatidic acid, phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylinositol phosphate, phosphatidylinositol bisphosphate, phosphatidylinositol trisphosphate, lipoid H 100-3, phospholipon 90H, phospholipon 80H, lipoid 100-3, lipoid P75-3, or any combination of the foregoing. In several embodiments, the lipid source is a phosphatidylcholine. In several embodiments, the only lipid present is a phosphatidylcholine (e.g., the lipid source lacks phospholipids other than phosphatidylcholine or is substantially free of other phospholipids). In several embodiments, the one or more lipid source lipid(s) (collectively or individually) are present in the composition at a dry wt. % of equal to or less than about: 0%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, or ranges including and/or spanning the aforementioned values. In several embodiments, the one or more lipid source lipid(s) (collectively or individually) are present in the composition at a wet wt. % of equal to or less than about: 0%, 0.1%, 0.5%, 1.0%, 2.5%, 4%, 5%, 6%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or ranges including and/or spanning the aforementioned values. In several embodiments, the one or more lipid source lipid(s) (collectively or individually) are present in the composition at a wet w/v of equal to or less than about: 0 mg/mL, 0.1 mg/mL, 0.5 mg/mL, 1.0 mg/mL, 2.5 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7.5 mg/mL, 10 mg/mL, 12.5 mg/mL, 15 mg/mL, 17.5 mg/mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 45 mg/mL, 50 mg/mL, or ranges including and/or spanning the aforementioned values. In several embodiments, as disclosed elsewhere herein, the composition is aqueous, while in others it has been dried into a powder. For instance, as disclosed elsewhere herein, in several embodiments, the composition is aqueous (wet), while in others it has been dried into a powder (dry). In several embodiments, the one or more lipid(s) of the lipid source are synthetic, derived from sunflower, soy, egg, or mixtures thereof. In several embodiments, the one or more lipids of the lipid source can be hydrogenated or nonhydrogenated. In several embodiments, the lipid source exceeds requirements of the United States Pharmacopeia (is USP grade) and/or is National Formulary (NF) grade.
[0130] In several embodiments, the lipid source (e.g., phosphatidylcholine, including hydrogenated soybean phosphatidylcholine) may be of high purity. For example, in some embodiments, the phosphatidylcholine is H100-3 grade (from Lipoid) and includes over 96.3% phosphatidylcholine (hydrogenated) or over 99% phosphatidylcholine (hydrogenated). In several embodiments, the one or more lipids of the lipid source has a purity of greater than or equal to about: 92.5%, 95%, 96%, 96.3%, 98%, 99%, 100%, or ranges including and/or spanning the aforementioned values. In several embodiments, the one or more lipids of the lipid source has a total % impurity content by weight of less than or equal to about: 8.5%, 5%, 4%, 3.7%, 2%, 1%, 0%, or ranges including and/or spanning the aforementioned values. In several embodiments, the one or more lipids of the lipid source comprises less than or equal to about 8.5%, 5%, 4%, 3.7%, 2%, 1%, or 0.1% (or ranges including and/or spanning the aforementioned values) of any one or more of saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids (C 18), arachidonic acid (ARA) (C 20:4), docosahexaenoic acid DHA (C 22:6), phosphatidic acid, phosphatidylethanolamine, and/or lysophosphatidylcholine by weight. In several embodiments, the one or more lipids of the lipid source has less than about 1.1% lysophosphatidylcholine and less than about 2.0% triglycerides by weight.
[0131] In some embodiments, the lipid source (e.g., phosphatidylcholine, including hydrogenated soybean phosphatidylcholine) may be 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% pure, or ranges including and/or spanning the aforementioned values.
[0132] As disclosed elsewhere herein, in some embodiments, the nanoparticle composition comprises a surfactant. In some embodiments, the nanoparticle composition does not comprises a surfactant. In several embodiments, the surfactant is a pharmaceutically acceptable surfactant. In several embodiments, the surfactant is a food surfactant. In several embodiments, the surfactant comprises one or more of a polyoxyethylene sorbitan esters (e.g., polysorbates/tweens, including polysorbate 80, polysorbate 20, etc.), cremophor (e.g., a nonionic solubilizer and emulsifier that is made by reacting ethylene oxide with castor oil), propylene oxide-modified polymethylsiloxane, dodecyl betaine, lauramidopropyl betaine, cocoamido-2-hydroxypropyl sulfobetaine, sodium stearate (or other stearate salts), polyoxyethylene alcohol, lecithins, mono- and diglycerides of fatty acids (MDG), acetic acid esters of MDG, lactic acid esters of MDG, citric acid esters of MDG, mono- and diacetyl tartaric acid esters of MDG, sucrose esters of fatty acids, polyglycerol esters of fatty acids (e.g., polyglycerol esters), polyglycerol polyricinoleate, propane- 1,2-diol esters of fatty acids, propylene glycol esters, sodium stearoyl-2-lactylate, calcium stearoyl-2-lactylate, sorbitan fatty acid esters, quillaja extract surfactant, yucca extract surfactant, saponins, silicone emulsifiers, sorbitan trioleate, soya lecithin, dioctyl sodium sulfosuccinate, dioctyl sodium sulfonate, polyoxyethylene, hydrogenated castor oil, sucrose fatty acid ester, or combinations of any of the foregoing. Natural or synthetic surfactants can be used, including polyethylene glycol and dextrans, such as cyclodextran. In several embodiments, the one or more surfactants are present in the nanoparticle composition (collectively or individually) at a dry wt. % of equal to or less than about: 0%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, or ranges including and/or spanning the aforementioned values. Surfactants can include cationic, anionic, nonionic, and zwitterionic surfactants. In several embodiments, the one or more surfactants (collectively or individually) are present in the composition at a wet wt. % of equal to or less than about: 0%, 0.1%, 0.5%, 1.0%, 2.5%, 4%, 5%, 6%, 7.5%, 10%, 12.5%, 15%, 17.5%, or ranges including and/or spanning the aforementioned values. In several embodiments, the one or more surfactants (collectively or individually) are present in the composition at a wet w/v of equal to or less than about: 0 mg/mL, 0.1 mg/mL, 0.5 mg/mL, 1.0 mg/mL, 2.5 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7.5 mg/mL, 10 mg/mL, 12.5 mg/mL, 15 mg/mL, 17.5 mg/mL, or ranges including and/or spanning the aforementioned values. In several embodiments, the surfactant exceeds requirements of the United States Pharmacopeia (is USP grade) and/or is National Formulary (NF) grade.
[0133] In several embodiments, one or more co-emulsifiers are used. In several embodiments, the co-emulsifier is a pharmaceutically acceptable co-emulsifier. In several embodiments, the co-emulsifier is selected from the group consisting of oleic acid, miglyol 812N (all versions), triglycerides, conjugated linoleic acid (CLA), cetearyl olivate, isoprpyle myristate, glyceryl stearate (e.g., glycerol monostearate), celluloses and polysaccharides (e.g., methylcellulose, propylmethylcellulose, hydroxypropyl methylcellulose, xanthan gum, etc.) and/or combinations of any of the foregoing. In several embodiments, the one or more coemulsifiers are present in the nanoparticle composition (collectively or individually) at a dry wt. % of equal to or less than about: 0%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, or ranges including and/or spanning the aforementioned values. In several embodiments, the one or more co-emulsifiers (collectively or individually) are present in the composition at a wet wt. % of equal to or less than about: 0%, 0.1%, 0.5%, 1.0%, 2.5%, 4%, 5%, 6%, 7.5%, 10%, 12.5%, 15%, 17.5%, or ranges including and/or spanning the aforementioned values. In several embodiments, the one or more co-emulsifiers (collectively or individually) are present in the composition at a wet w/v of equal to or less than about: 0 mg/mL, 0.1 mg/mL, 0.5 mg/mL, 1.0 mg/mL, 2.5 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7.5 mg/mL, 10 mg/mL, 12.5 mg/mL, 15 mg/mL, 17.5 mg/mL, or ranges including and/or spanning the aforementioned values. In several embodiments, the co-emulsifiers exceeds requirements of the United States Pharmacopeia (is USP grade) and/or is National Formulary (NF) grade. In some embodiments, the co-emulsifier component comprises a medium chain triglyceride (MCT) or a MCT- substitute. In some embodiments, the medium chain triglyceride comprises a fatty acid selected from one or more of caprioc acid, octanoic acid, capric acid, caprylic acid, and/or lauric acid (e.g., is formed from). In some embodiments, the medium chain triglyceride comprises a fatty acid 6-12 carbons in length (e.g., 6, 7, 8, 9, 10, 11, or 12). In some embodiments, the coemulsifier component comprises a long chain triglyceride (LCT). In some embodiments, the long chain triglyceride comprises a fatty acid greater than 12 carbons in length (e.g., greater than or equal to 13, 14, 15, 16, 17, 18, 19, or 20 carbons in length, or ranges including and/or spanning the aforementioned values). In some embodiments, the co-emulsifier component is a single lipid. In some embodiments, the co-emulsifier component is MCT. In some embodiments, the MCT is highly pure. In some embodiments, the MCT has a purity by weight % of equal to or greater than about: 90%, 95%, 97%, 98%, 99%, 100%, or ranges including and/or spanning the aforementioned values. In some embodiments, the MCT (or LCT) is present in the nanoparticle composition at dry weight % of equal to or greater than about: 10%, 20%, 30%, 35%, 40%, 45%, 50%, or ranges including and/or spanning the aforementioned values. In some embodiments, the MCT-substitute lipid (e.g., the non-phospholipid lipid) is selected from one or more of oleic acid, capric acid, caprylic acid, and triglycerides of such (Captex 8000, Captex GTO, Captex 1000), glycerol monooleate, glycerol monostearate (Geleol™ Mono and Diglyceride NF), omega-3 fatty acids (a-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), Tonalin, Pronova Pure® 46:38, free fatty acid Tonalin FFA 80), conjugated linoleic acid, alpha glycerylphosphorylcholine (alpha GPC), palmitoylethanolamide (PEA), cetyl alcohol, or emulsifying wax. In some embodiments, the one or more MCT-substitute(s) are present in the nanoparticle composition (collectively or individually) at a dry wt. % of equal to or less than about: 0.5%, 1.0%, 2.5%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 80% or ranges including and/or spanning the aforementioned values. In some embodiments, the one or more MCT-substitute(s) (collectively or individually) are present in the composition at a wet wt. % of equal to or less than about: 0.5%, 1.0% 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 30%, 40%, 60% or ranges including and/or spanning the aforementioned values. In some embodiments, the MCT-substitute has a purity of greater than or equal to about: 70%, 80%, 85%, 92.5%, 95%, 96%, 98%, 99%, 99.9%, 100%, or ranges including and/or spanning the aforementioned values. In some embodiments, the MCT-substitute has a total % impurity content by weight of less than or equal to about: 8.5%, 5%, 4%, 3.7%, 2%, 1%, 0%, or ranges including and/or spanning the aforementioned values
[0134] In some embodiments, the nanoparticle composition comprises one or more sterols. In some embodiments, the one or more sterols comprises one or more cholesterols, ergosterols, hopanoids, hydroxysteroids, phytosterols (e.g., vegapure), ecdysteroids, and/or steroids. In some embodiments the sterol comprises a cholesterol. In some embodiments, the sterol component is a single sterol. In some embodiments, the sterol component is cholesterol. In some embodiments, the cholesterol (or other sterol) is highly pure. In some embodiments, the one or more sterol(s) (e.g., cholesterol, and/or other sterols), collectively or individually, are present in the aqueous composition at a concentration of less than or equal to about: 50 mg/mL, 40 mg/mL, 20 mg/mL, 10 mg/mL, 5 mg/mL, or ranges including and/or spanning the aforementioned values. In some embodiments, the one or more sterol(s) are present in the composition at a dry wt. % of equal to or less than about: 0.25%, 0.5%, 1%, 5%, 7.5%, 10%, 15%, 20%, 25%, or ranges including and/or spanning the aforementioned values. In some embodiments, the one or more sterol(s) (collectively or individually) are present in the composition at a wet wt. % of equal to or less than about: 0.1%, 0.25%, 0.5%, 1%, 2%, 3%, 4%, 5%, 7.5%, 10%, or ranges including and/or spanning the aforementioned values. In some embodiments, the cholesterol used in the composition comprises cholesterol from one or more of sheep’s wool, synthetic cholesterol, or semisynthetic cholesterol from plant origin. In some embodiments, the sterol has a purity of greater than or equal to about: 92.5%, 95%, 96%, 98%, 99%, 99.9%, 100.0%, or ranges including and/or spanning the aforementioned values. In some embodiments, the sterol has a total % impurity content by weight of less than or equal to about: 8.5%, 5%, 4%, 3.7%, 2%, 1%, 0%, or ranges including and/or spanning the aforementioned values. In some embodiments, the sterol is cholesterol. In some embodiments, the sterol is not cholesterol. In some embodiments, the sterol is phytosterol.
[0135] In several embodiments, the nanoparticle composition comprises a preservative. In several embodiments, the preservative includes one or more benzoates (such as sodium benzoate or potassium benzoate), nitrites (such as sodium nitrite), sulfites (such as sulfur dioxide, sodium or potassium sulphite, bisulphite or metabisulphite), sorbates (such as sodium sorbate, potassium sorbate), ethylenediaminetetraacetic acid (EDTA) (and/or the disodium salt thereof), polyphosphates, organic acids (e.g., citric, succinic, malic, tartaric, benzoic, lactic and propionic acids), and/or antioxidants (e.g., vitamins such as vitamin E and/or vitamin C, butylated hydroxy toluene). In several embodiments, sorbates and benzoates may be used in acidic pH formulations. In several embodiments, the one or more preservatives (collectively or individually) are present in the composition at a dry wt. % of equal to or at less than about: 0.01%, 0.1%, 0.25%, 0.5%, 1%, 5%, 7.5%, 10%, 15%, 20%, 25%, or ranges including and/or spanning the aforementioned values. In several embodiments, the one or more preservatives (collectively or individually) are present in the composition at a wet wt. % of equal to or less than about: 0.001%, 0.01%, 0.025%, 0.05%, 0.1%, 0.5%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 5%, or ranges including and/or spanning the aforementioned values. In several embodiments, the one or more surfactants (collectively or individually) are present in the composition at a wet w/v of equal to or less than about: 0 mg/mL, 0.001 mg/mL, 0.1 mg/mL, 0.5 mg/mL, 1.0 mg/mL, 2.5 mg/mL, 4 mg/mL, 5 mg/mL, or ranges including and/or spanning the aforementioned values. In several embodiments, as disclosed elsewhere herein, the composition is aqueous, while in others it has been dried into a powder. For instance, as disclosed elsewhere herein, in several embodiments, the composition is aqueous (wet), while in others it has been dried into a powder (dry). In several embodiments, the preservatives inhibit or prevent growth of mold, bacteria, and fungus.
[0136] In several embodiments, the nanoparticle composition comprises one or more flavoring agents. In several embodiments, the one or more flavoring agent(s) comprise an essential oil (or combinations of essential oils). In several embodiments, the one or more flavoring agents of the composition comprise monk fruit extract (e.g., MonkGold50), stevia, glycerin, peppermint oil or flavoring, lemon oil or flavoring, orange oil or flavoring, vanilla, taste makers, bitter blockers, or the like, or combinations thereof. In several embodiments, the one or more flavoring agent(s) (collectively or individually) are present in the composition at a dry wt. % of equal to or less than about: 0.01%, 0.1%, 0.25%, 0.5%, 1%, 5%, 7.5%, 10%, 15%, 20%, 25%, or ranges including and/or spanning the aforementioned values. In several embodiments, the one or more flavoring agents (collectively or individually) are present in the composition at a wet wt. % of equal to or less than about: 0.001%, 0.01%, 0.025%, 0.05%, 0.1%, 0.5%, 0.75%, 1.0%, 1.5%, 2.0%, 2.5%, 5.0%, or ranges including and/or spanning the aforementioned values. In several embodiments, as disclosed elsewhere herein, the composition is aqueous, while in others it has been dried into a powder. For instance, as disclosed elsewhere herein, in several embodiments, the composition is aqueous (wet), while in others it has been dried into a powder (dry).
[0137] In several embodiments, the composition comprises an active agent or combination of actives and a lipid source. In several embodiments, as disclosed elsewhere herein, the nanoparticle composition comprises an active agent or combination of actives and a surfactant. In several embodiments, as disclosed elsewhere herein, the nanoparticle composition comprises an active agent or combination of actives and a co-emulsifier (e.g., oleic acid, miglyol 812N (all versions), triglycerides, conjugated linoleic acid (CLA), cetearyl olivate, isoprpyle myristate, glyceryl stearate, etc.). In several embodiments, the composition further comprises a flavoring agent. In several embodiments, the composition further comprises a preservative.
[0138] In several embodiments, the composition comprises, consists of, or consists essentially of one or more active agents, one or more lipid sources, one or more surfactants, one or more flavoring agents, one or more preservatives, one or more co-emulsifiers, or any combination thereof. In several embodiments, the composition comprises, consists of, or consists essentially of one or more active agents, one or more lipid sources, one or more surfactants, one or more preservatives, and one or more co-emulsifiers. In several embodiments, the composition comprises, consists of, or consists essentially of one or more active agents, one or more lipid sources, one or more surfactants, one or more flavoring agents, and one or more co-emulsifiers. In several embodiments, the composition comprises, consists of, or consists essentially of one or more active agents, one or more surfactants, and one or more co-emulsifiers. In several embodiments, the composition comprises, consists of, or consists essentially of one or more active agents, one or more lipid sources, one or more surfactants, one or more flavoring agents, and one or more preservatives. In several embodiments, the composition comprises, consists of, or consists essentially of one or more active agents, one or more lipid sources, and one or more surfactants. In several embodiments, the composition comprises, consists of, or consists essentially of one or more active agents, one or more lipid sources, one or more surfactants, and one or more preservatives. In several embodiments, the composition comprises, consists of, or consists essentially of one or more active agents, one or more surfactants, one or more flavoring agents, and one or more preservatives. In several embodiments, the compositions above do not comprise a surfactant. [0139] In several embodiments, the nanoparticle composition lacks terpenes (e.g., as impurities or additives). However, in other embodiments, one or more terpenes may be added to prepare the nanoparticle composition. In several embodiments, the one or more terpenes includes one or more of alpha fenchone, alpha terpinene, alpha terpineol, beta caryophyllene, alpha pinene, beta pinene, bisabolene, bisabolol, borneol, eucalyptol, gamma terpinene, guaiacol, humulene, linalool, myrcene, para cymene, phytol, and/or terpinolene. In several embodiments, the one or more terpenes includes one or more of 7,8-dihydro-alpha-ionone, 7,8- dihydro-beta-ionone, Acetanisole, Acetic Acid, Acetyl Cedrene, Anethole, Anisole, Benzaldehyde, Bergamotene (Alpha-cis-Bergamotene) (Alpha-trans-Bergamotene), Bisabolol (Beta-Bisabolol), Alpha Bisabolol, Borneol, Bornyl Acetate, Butanoic/Butyric Acid, Cadinene (Alpha-Cadinene) (Gamma-Cadinene), Cafestol, Caffeic acid, Camphene, Camphor, Capsaicin, Carene (Delta- 3 -Carene), Carotene, Carvacrol, Dextro-Carvone, Laevo-Carvone, Alpha-Caryophyllene, Beta-Caryophyllene, Caryophyllene oxide, Cedrene (Alpha-Cedrene) (Beta-Cedrene), Cedrene Epoxide (Alpha-Cedrene Epoxide), Cedrol, Cembrene, Chlorogenic Acid, Cinnamaldehyde, Alpha-amyl-Cinnamaldehyde, Alpha-hexyl-Cinnamaldehyde, Cinnamic Acid, Cinnamyl Alcohol, Citronellal, Citronellol, Cryptone, Curcumene (Alpha- Curcumene) (Gamma-Curcumene), Decanal, Dehydrovomifoliol, Diallyl Disulfide, Dihydroactinidiolide, Dimethyl Disulfide, Eicosane/Icosane, Elemene (Beta-Elemene), Estragole, Ethyl acetate, Ethyl Cinnamate, Ethyl maltol, Eucalyptol/1,8-Cineole, Eudesmol (Alpha-Eudesmol) (Beta-Eudesmol) (Gamma-Eudesmol), Eugenol, Euphol, Farnesene, Farnesol, Fenchol (Beta-Fenchol), Fenchone, Geraniol, Geranyl acetate, Germacrenes, Germacrene B, Guaia- 1( 10), 11 -diene, Guaiacol, Guaiene (Alpha-Guaiene), Gurjunene (Alpha- Gurjunene), Hemiarin, Hexanaldehyde, Hexanoic Acid, Humulene (Alpha-Humulene) (Beta- Humulene), Ionol (3-oxo-alpha-ionol) (Beta-Ionol), Ionone (Alpha-Ionone) (Beta-Ionone), Ipsdienol, Isoamyl Acetate, Isoamyl Alcohol, Isoamyl Formate, Isoborneol, Isomyrcenol, Isopulegol, Isovaleric Acid, Isoprene, Kahweol, Lavandulol, Limonene, Gamma-Linolenic Acid, Linalool, Longifolene, Alpha- Longipinene, Lycopene, Menthol, Methyl butyrate, 3- Mercapto-2-Methylpentanal, Mercaptan/Thiols, Beta-Mercaptoethanol, Mercaptoacetic Acid, Allyl Mercaptan, Benzyl Mercaptan, Butyl Mercaptan, Ethyl Mercaptan, Methyl Mercaptan, Furfuryl Mercaptan, Ethylene Mercaptan, Propyl Mercaptan, Thenyl Mercaptan, Methyl Salicylate, Methylbutenol, Methyl-2-Methylvalerate, Methyl Thiobutyrate, Myrcene (Beta- Myrcene), Gamma-Muurolene, Nepetalactone, Nerol, Nerolidol, Neryl acetate, Nonanaldehyde, Nonanoic Acid, Ocimene, Octanal, Octanoic Acid, P-Cymene, Pentyl butyrate, Phellandrene, Phenylacetaldehyde, Phenylethanethiol, Phenylacetic Acid, Phytol, Pinene, Beta-Pinene, Propanethiol, Pristimerin, Pulegone, Quercetin, Retinol, Rutin, Sabinene, Sabinene Hydrate, cis-Sabinene Hydrate, trans-Sabinene Hydrate, Safranal, Alpha-Selinene, Alpha-Sinensal, Beta-Sinensal, Beta-Sitosterol, Squalene, Taxadiene, Terpin hydrate, Terpineol, Terpine-4-ol, Alpha-Terpinene, Gamma-Terpinene, Terpinolene, Thiophenol, Thujone, Thymol, Alpha-Tocopherol, Tonka Undecanone, Undecanal, Valeraldehyde/Pentanal, Verdoxan, Alpha- Ylangene, Umbelliferone, or Vanillin.
[0140] In several embodiments, the composition may also comprise one or more terpenes. In several embodiments, the one or more terpenes, collectively or individually, are present in the aqueous composition at a concentration of less than or equal to about: 400 mg/mL, 300 mg/mL, 200 mg/mL, 150 mg/mL, 100 mg/mL, 75 mg/mL, 50 mg/mL, 25 mg/mL, or ranges including and/or spanning the aforementioned values. In several embodiments, the one or more terpenes (collectively or individually) are present in the composition at a dry wt. % of equal to or less than about: 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, or ranges including and/or spanning the aforementioned values. In several embodiments, the one or more terpenes (collectively or individually) are present in the composition at a wet wt. % of equal to or less than about: 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 30%, 40%, or ranges including and/or spanning the aforementioned values.
[0141] In several embodiments, as disclosed elsewhere herein, the mixed nanoparticle composition provides particles in the nano-measurement range. In several embodiments, the nanoparticle is spherical or substantially spherical. In several embodiments, a solid lipid nanoparticle possesses a solid lipid core matrix that can solubilize lipophilic molecules. In several embodiments, the lipid core is stabilized by surfactants and/or emulsifiers as disclosed elsewhere herein, while in other embodiments, surfactants are absent. In several embodiments, the size of the particle is measured as a mean diameter. In several embodiments, the size of the particle is measured by dynamic light scattering. In several embodiments, the size of the particle is measured using a zeta-sizer. In several embodiments, the size of the particle can be measured using Scanning Electron Microscopy (SEM). In several embodiments, the size of the particle is measured using a cyrogenic SEM (cryo-SEM). Where the size of a nanoparticle is disclosed elsewhere herein, any one or more of these instruments or methods may be used to measure such sizes.
[0142] In several embodiments, the nanoparticle composition comprises nanoparticles having an average size of less than or equal to about: 10 nm, 25 nm, 40 nm, 50 nm, 100 nm, 250 nm, 500 nm, 1000 nm, or ranges including and/or spanning the aforementioned values. In several embodiments, the composition comprises nanoparticles having an average size of between about 50 nm and 150 nm or between about 50 and about 250 nm. In several embodiments, the size distribution of the nanoparticles for at least 50%, 75%, 80%, 90% (or ranges including and/or spanning the aforementioned percentages) of the particles present is equal to or less than about: 20 nm, 40 nm, 60 nm, 80 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 160 nm, 180 nm, 200 nm, 300 nm, 400 nm, 500 nm, or ranges including and/or spanning the aforementioned nm values. In several embodiments, the composition comprises nanoparticles having an average size of less than or equal to about: 10 nm, 50 nm, 100 nm, 250 nm, 500 nm, 1000 nm, or ranges including and/or spanning the aforementioned values. In several embodiments, the size distribution of the nanoparticles for at least 90% of the particles present is equal to or less than about: 20 nm, 40 nm, 60 nm, 80 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 160 nm, 180 nm, 200 nm, 300 nm, 400 nm, 500 nm, or ranges including and/or spanning the aforementioned nm values. In several embodiments, the size distribution of the nanoparticles for at least 90% of the particles present is equal to or less than about: 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 160 nm, 180 nm, 200 nm, or ranges including and/or spanning the aforementioned nm values. In several embodiments, the D90 of the particles present is equal to or less than about: 80 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 160 nm, 180 nm, 200 nm, 300 nm, 400 nm, 500 nm, or ranges including and/or spanning the aforementioned values. In several embodiments, the size of the nanoparticle is the diameter of the nanoparticle as measured using any of the techniques as disclosed elsewhere herein. For instance, in some embodiments, the size of the nanoparticle is the measured using dynamic light scattering. In several embodiments, the size of the nanoparticle is the measured using a zeta sizer. In several embodiments, consistency in size over time, or within a sample, allows predictable stability for the active agent encapsulated therein.
[0143] In several embodiments, over 50%, 75%, 95% (or ranges spanning and or including the aforementioned values) of the nanoparticles prepared by the methods disclosed herein have a particle size of between about 20 to about 500 nm (as measured by zeta sizing (e.g., refractive index). In several embodiments, over 50%, 75%, 95% (or ranges spanning and or including the aforementioned values) of the nanoparticles prepared by the methods disclosed herein have a particle size of between about 50 nm to about 200 nm (as measured by zeta sizing (e.g., refractive index). In several embodiments, over 50%, 75%, 95% (or ranges spanning and or including the aforementioned values) of the nanoparticles prepared by the methods disclosed herein have a particle size of between about 90 nm to about 150 nm (as measured by zeta sizing (e.g., refractive index). In several embodiments, this consistency in size allows predictable delivery to subjects. In several embodiments, the D90 particle size measurement varies between 150 and 500 nm.
[0144] In several embodiments, as disclosed elsewhere herein, the nanoparticle composition is an oil-in-water emulsion, water-in-oil emulsion, water-in-oil-in-water emulsion, oil-in-water-in-oil emulsion, liposome, solid lipid particles formulation, etc. For brevity, these may just be referred to as the composition. In several embodiments, the nanoparticle composition can be processed to comprises one or more of solid lipid nanoparticles, liposomes (and variants including multi-lamellar, double liposome preparations, etc.), niosomes, ethosomes, electrostatic particulates, microemulsions, nanoemulsions, microsuspensions, nanosuspensions, or combinations thereof. In several embodiments, polymeric nanoparticles may be formed. In several embodiments, cyclodextrin is added.
[0145] In several embodiments, a solid lipid nanoparticle compositions comprises a lipid core matrix. In several embodiments, the lipid core matrix is solid. In several embodiments, the solid lipid comprises one or more ingredients as disclosed elsewhere herein. In several embodiments, the core of the solid lipid comprises one or more lipids, surfactants, active ingredients, etc. In several embodiments, the surfactant acts as an emulsifier. In several embodiments, emulsifiers can be used to stabilize the lipid dispersion (with respect to charge and molecular weight). In several embodiments, the core ingredients (e.g., the components of the core) are present in the composition (collectively or individually) at a dry wt. % of equal to or less than about: 0.5%, 1.0%, 2.5%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 80% or ranges including and/or spanning the aforementioned values. In several embodiments, the core ingredients and/or the emulsifiers (collectively or individually) are present in the composition at a wet wt. % of equal to or less than about: 0.5%, 1.0% 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 30%, 40%, 60% or ranges including and/or spanning the aforementioned values.
[0146] In several embodiments, the nanoparticle composition (e.g., when in water or dried) comprises multilamellar nanoparticle vesicles, unilamellar nanoparticle vesicles, multivesicular nanoparticles, emulsion particles, irregular particles with lamellar structures and bridges, partial emulsion particles, combined lamellar and emulsion particles, and/or combinations thereof. In several embodiments, the composition is characterized by having multiple types of particles (e.g., lamellar, emulsion, irregular, etc.). In other embodiments, a majority of the particles present are emulsion particles. In several embodiments, a majority of the particles present are lamellar (multilamellar and/or unilamellar). In other embodiments, a majority of the particles present are irregular particles. In still other embodiments, a minority of the particles present are emulsion particles. In several embodiments, a minority of the particles present are lamellar (multilamellar and/or unilamellar). In other embodiments, a minority of the particles present are irregular particles.
[0147] In several embodiments, at ambient temperature an aqueous nanoparticle composition as disclosed herein has a viscosity (in centipoise (cP)) of equal to or less than about: 1.0, 1.05, 1.1, 1.2, 1.5, 2.0, 5.0, 10.0, 20, 30, 50, 100, or ranges including and/or spanning the aforementioned values. In several embodiments, at about 25°C or 26°C and a concentration of 20 mg/mL active agent (e.g., CBD) in water (e.g., the total nanoparticle composition may have a concentration of 50 to 250 mg/mL), the nanoparticle composition has a viscosity (in centipoise (cP)) of equal to or less than about: 1.0, 1.05, 1.1, 1.2, 1.5, 2.0, 5.0, 10.0, 20, 30, 50, 100, or ranges including and/or spanning the aforementioned values. In several embodiments, at about 25°C and a concentration of 50 mg/mL, 100 mg/mL, 200 mg/mL, or 250 mg/mL, the nanoparticle composition has a viscosity (in cP) of equal to or less than about: 1.0, 1.05, 1.1, 1.2, 1.5, 2.0, 5.0, 10.0, 20, 30, 50, 100, or ranges including and/or spanning the aforementioned values. In several embodiments, the viscosity of the CBD lipid nanoparticle aqueous solution is equal to or less than 5.0 Cp.
[0148] In several embodiments, the nanoparticle delivery system described herein offers protection to active compounds against degradation in an aqueous environment for long-term storage. In several embodiments, the composition is well characterized to ensure a consistent product from batch to batch and with long-term stability. In several embodiments, the product stability is routinely tested for appearance, particle size and distribution, zeta potential, residual solvents, heavy metals, active compound concentration, and microbial testing and the values measured using these test methods varies (over a period of at least about 1 month or about 6 months at 25°C with 60% relative humidity) by less than or equal to about: 1%, 5%, 10%, 20%, 30%, or ranges including and/or spanning the aforementioned values. In several embodiments, the particle size and/or PDI varies over a period of at least about 1 month or about 6 months (at 25°C with 60% relative humidity) by less than or equal to about: 1%, 5%, 10%, 20%, 30%, or ranges including and/or spanning the aforementioned values. As noted elsewhere herein, PDI and size can be measured using conventional techniques disclosed herein. In several embodiments, the active agent (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like) concentration varies over a period of at least about 1 month or about 6 months (at 25°C with 60% relative humidity) by less than or equal to about: 1%, 5%, 10%, 15%, or ranges including and/or spanning the aforementioned values. As noted elsewhere herein, PDI and size can be measured using conventional techniques disclosed herein.
[0149] In several embodiments, the formulations and/or compositions disclosed herein are stable during sterilization. In several embodiments, the sterilization may include one or more of ozonation, UV treatment, and/or heat treatment. In several embodiments, the particle size and/or PDI after sterilization (e.g., exposure to techniques that allow sterilization of the composition) varies by less than or equal to about: 1%, 5%, 10%, 20%, 30%, or ranges including and/or spanning the aforementioned values. In several embodiments, the active agent (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like) concentration after sterilization (e.g., exposure to techniques that allow sterilization of the composition) varies (e.g., drops) by less than or equal to about: 1%, 5%, 10%, 15%, or ranges including and/or spanning the aforementioned values.
[0150] In several embodiments, the nanoparticle compositions (including after stabilization) disclosed herein have a shelf life of equal to or greater than 6 months, 12 months, 14 months, 16 months, 18 months, 19 months, or ranges including and/or spanning the aforementioned values. The shelf-life can be determined as the period of time in which there is 95% confidence that at least 50% of the response (active agent(s) concentration or particle size) is within the specification limit. This refers to a 95% confidence interval and when linear regression predicts that at least 50% of the response is within the set specification limit.
[0151] In several embodiments, the composition contains preservatives to protect against bacteria, mold, and fungal growth. The product specification is no more than 100 cfu/gram. In several embodiments, over a period of about 1 month, about 6 months, or about 12 months the composition has equal to or not more than: 50 cfu/gram, 10 cfu/gram, 5 cfu/gram, 1 cfu/gram, 0.1 cfu/gram, or ranges including and/or spanning the aforementioned values. In several embodiments, 1 week at 20°C-25°C after a 105-107 CFU/mL challenge with any one of Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida albicans, and Aspergillus brasiliensis the composition has equal to or not more than: 100 cfu/gram, 50 cfu/gram, 25 cfu/gram, 10 cfu/gram, 5 cfu/gram, 1 cfu/gram, 0.1 cfu/gram, or ranges including and/or spanning the aforementioned values. In several embodiments, 1 week at 20°C-25°C after a 105-107 CFU/mL challenge with any one of Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida albicans, and Aspergillus brasiliensis the composition has a log reduction for the bacteria of equal to or greater than: 1, 2, 3, 4, 5, 10, or ranges including and/or spanning the aforementioned values.
[0152] The shelf-life can be determined as the period of time in which there is 95% confidence that at least 50% of the response (active agent(s) concentration or particle size) is within a specification limit. A specification limit is a range of measured values in which a quality parameter should be within in order for products to be considered of the same quality when it was initially released. For example, where the CBD target concentration is 20 mg/mL, a specification limit may be defined as 18 to 22 mg/mL. At a time during a stability study, the CBD concentration may fall below 18 mg/mL due to chemical instability, at that time the product may be considered out of specification.
[0153] In several embodiments, the shelf life determined as a time where the concentration of the active ingredient has changed (e.g., lessened) by less than or equal to 15%, 10%, 5%, 2.5%, or ranges including and or spanning the aforementioned ranges.
[0154] In some embodiments, the density of the composition is purposefully modified. In some embodiments, the density is approximately 0.7 g/mL, 0.75 g/mL, 0.8 g/mL, 0.85 g/mL, 0.9 g/mL, 0.95 g/mL, 1.0 g/mL, 1.05 g/mL, 1.1 g/mL, 1.15 g/mL, 1.2 g/mL, 1.25 g/mL, 1/.3 g/mL, or ranges including and or spanning the aforementioned ranges. In some embodiments, the density of the composition is modified to approximately equal the density of an aqueous solution, a gel, a liquid, a cream, or a lotion. In some embodiments, the density is modified by adjust the ratio of different nanoparticle types (e.g., liposomes, solid lipid nanoparticles, etc.). In some embodiments, the density is modified by adjusting the ratio between a first lipid and second lipid. In some embodiments, the density is modified by adjusting the ratio between a first set of lipids and a second set of lipids. In some embodiments, concentrations of lipids with different chain lengths (e.g. 8 carbon, 10 carbon, 18 carbon lipids) are adjusted to modify the density. Such modifications described for modifying density may also influence API solubility (z.e., encapsulation), physical stability, chemical stability, particle composition
[0155] In some embodiments, the composition comprises 6-7% active agent, 13-14% HSPC, 12-13% MCT, 0-1 % vitamin E, 1-2% cholesterol and/or plant sterol(s), and 66-67% trehalose. In some embodiments, the composition comprises 6-7% active agent, 27-28% lipid carrier, and 66-67% carbohydrate.
A. Nanoparticles
[0156] In several embodiments, the particle comprises a lipid source, a surfactant, a coemulsifier, or combinations of the foregoing. In several embodiments, the particle is a nanoscale particle (e.g., a nanoparticle). In several embodiments, the particle is a microscale particle (e.g., a microparticle).
[0157] In several embodiments, advantageously, the individual particles within the disclosed nanoparticle compositions may not settle or sediment appreciably. In several embodiments, an appreciable amount of the composition (e.g., as viewed by the naked eye) does not settle and/or separate from an aqueous liquid upon standing. In several embodiments, the composition does not appreciably settle or separate from an aqueous liquid upon standing for equal to or at least about 1 day, at least about 1 month, about 3 months, about 6 months, about 9 months, about 1 year, or ranges including and/or spanning the aforementioned values. In several embodiments, upon standing, the composition remains dispersed in an aqueous liquid for at least about 1 day, at least about 1 month, about 3 months, about 6 months, about 9 months, about 1 year, or ranges including and/or spanning the aforementioned values. In several embodiments, the homogeneity of the disclosed compositions changes by equal to or less than about: 0.5%, 1%, 5%, 7.5%, 10%, or 15% (or ranges including and/or spanning the aforementioned values) after a period of one week or one month. In this case, homogeneity is observed through images by SEM or cyro-SEM (e.g., the average size of the particles and/or the particle types). In several embodiments, the composition remains dispersed in an aqueous liquid and does not appreciably settle or separate from an aqueous liquid after at least about: 1 minute, 5 minutes, 30 minutes, or an hour in a centrifuge at a centripetal acceleration of at least about 100 m/s, at least about 1000 m/s, or at least about 10,000 m/s. In several embodiments, the composition remains dispersed in an aqueous liquid and does not appreciably settle or separate from an aqueous liquid after at least about: 1 minute, 5 minutes, 30 minutes, or an hour in a centrifuge at a centrifuge speed of 5000 RPM, 10,000 RPM, or 15,000 RPM.
[0158] In several embodiments, the average size of the nanoparticles of a composition as disclosed herein is substantially constant and/or does not change significantly over time (e.g., it is a stable nanoparticle). In several embodiments, after formulation and storage for a period of at least about 1 month (30 days), about 3 months (90 days), or about 6 months (180 days) (e.g., at ambient conditions, at 25°C with 60% relative humidity, or under the other testing conditions disclosed elsewhere herein), the average size of nanoparticles comprising the composition changes less than or equal to about: 1%, 5%, 10%, 20%, or ranges including and/or spanning the aforementioned values.
[0159] In several embodiments, the polydispersity index (PDI) of the nanoparticles of a composition as disclosed herein is less than or equal to about: 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, or ranges including and/or spanning the aforementioned values. In several embodiments, the size distribution of the nanoparticles is highly monodisperse with a polydispersity index of less than or equal to about: 0.05, 0.10, 0.15, 0.20, 0.25, or ranges including and/or spanning the aforementioned values.
[0160] In several embodiments, the zeta potential of the nanoparticles of a composition as disclosed herein is less than or equal to about: 1 mV, 3 mV, 4 mV, 5 mV, 6 mV, 7 mV, 8 mV, 10 mV, 20 mV, or ranges including and/or spanning the aforementioned values. In several embodiments, the zeta potential of the nanoparticles is greater than or equal to about: -3 mV, -
1 mV, 0 mV, 1 mV, 3 mV, 4 mV, 5 mV, 6 mV, 7 mV, 8 mV, 4 mV, 10 mV, 20 mV, or ranges including and/or spanning the aforementioned values. In several embodiments, the zeta potential and/or diameter of the particles (e.g., measured using dynamic light scattering) is acquired using a zetasizer (e.g., a Malvern ZS90 or similar instrument).
[0161] In several embodiments, the nanoparticle composition has a pH of less than or equal to about: 2, 3, 4, 5, 6, 6.5, 7, 8, 9, or ranges including and/or spanning the aforementioned values. In several embodiments, the composition has a pH of greater than or equal to about: 2, 3, 4, 5, 6, 6.5, 7, 8, 9, or ranges including and/or spanning the aforementioned values. For example, in several embodiments, the composition has a pH ranging from 2 to 4, 4 to 6, 6 to 8,
2 to 9, 2 to 5, 3 to 7, 4 to 8, 5 to 9, etc.
[0162] In several embodiments, multilamellar nanoparticles comprise equal to or at least about 5%, 8%, 9%, 10%, 15%, 25%, 50%, 75%, 85%, 95%, or 100% (or ranges spanning and/or including the aforementioned values), of the particles present in the composition (e.g., the aqueous composition) For example, in some embodiments, between about 5% and about 10% of the particles present are multilamellar. In several embodiments, about 8.6% of the particles present are multilamellar.
[0163] In several embodiments, unilamellar nanoparticles comprise equal to or at least about 5%, 8%, 9%, 10%, 15%, 20%, 25%, 50%, 75%, 85%, 95%, or 100% (or ranges spanning and/or including the aforementioned values) of the particles present in the composition (e.g., the aqueous composition). For example, in some embodiments, between about 10% and about 15% of the particles present are unilamellar. In several embodiments, about 12.88% of the particles present are unilamellar.
[0164] In several embodiments, emulsion particles comprise equal to or at least about 5%, 8%, 9%, 10%, 15%, 25%, 50%, 60%, 65%, 70%, 75%, 85%, 95%, or 100% (or ranges spanning and/or including the aforementioned values) of the particles present in the composition (e.g., the aqueous composition). For example, in some embodiments, between about 60% to about 75% of the particles present are emulsion particles. In several embodiments, about 69.7% of the particles present are emulsion particles.
[0165] In several embodiments, micelle particles comprise equal to or at least about 5%, 8%, 9%, 10%, 15%, 25%, 50%, 60%, 65%, 70%, 75%, 85%, 95%, or 100% (or ranges spanning and/or including the aforementioned values) of the particles present in the composition (e.g., the aqueous composition). [0166] In several embodiments, liposomes comprise equal to or at least about 5%, 8%, 9%, 10%, 15%, 25%, 50%, 60%, 65%, 70%, 75%, 85%, 95%, or 100% (or ranges spanning and/or including the aforementioned values) of the particles present in the composition (e.g., the aqueous composition).
[0167] In several embodiments, irregular particles (including particles with lamellar structures and/or bridges) comprise equal to or at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 25%, 50%, 75%, 85%, 95%, or 100% (or ranges spanning and/or including the aforementioned values) of the particles present in the composition (e.g., the aqueous composition). For example, in some embodiments, between about 1% to about 5% of the particles present are irregular particles. In several embodiments, 2.73% are irregular particles. [0168] In several embodiments, combined lamellar and emulsion particles comprise equal to or at least about 5%, 6%, 7%, 8%, 9%, 10%, 15%, 25%, 50%, 75%, 85%, 95%, or 100% (or ranges spanning and/or including the aforementioned values) of the particles present in the composition (e.g., the aqueous composition). For example, in some embodiments, between about 5% to about 6% of the particles present are combined lamellar and emulsion particles. In several embodiments, 6.06% of the particles are combined lamellar and emulsion particles. [0169] In several embodiments, mixed-micelle particles comprise equal to or at least about 5%, 6%, 7%, 8%, 9%, 10%, 15%, 25%, 50%, 75%, 85%, 95%, or 100% (or ranges spanning and/or including the aforementioned values) of the particles present in the composition (e.g., the aqueous composition).
[0170] The nanoparticle compositions can comprise combinations of multilamellar nanoparticles, unilamellar nanoparticles, emulsion nanoparticles, micelle nanoparticles, irregular particles, and/or liposomes.
[0171] The percentages and/or concentrations of particles present in the composition may be purposefully modified. In some embodiments, the percentage and/or concentration of the particles present in the composition are tailored to the active compound and/or the liquid comprising the particles. Such tailoring may lead to more homogenization and/or dispersion in the liquid. The tailoring may stabilize dispersion in the liquid. Such tailoring may also tailor to specific densities of the compositions. The densities of the compositions can be matched or different from a liquid that the compositions are contacted by or contained within.
[0172] In some embodiments, the composition is biased towards one type of nanoparticle, such as solid nanoparticles or liposomes. The composition may be biased by increasing or decreasing the ratio in the composition of lipids that are solid at room temperature to lipids that are liquid at room temperature. Lipids that are liquid at room temperature may comprise MCT (a mixture of capric and caprylic triglycerides, which may have a ratio of c8:cl0 carbon chains of 45:55), captex 1000 (a triglyceride of capric acid). Lipids that are solid at room temperature may comprise solubilizers and/or emollients. Lipids that are solid at room temperature may comprise phosphatidylcholine (such as HSPC) phosphatidylethanolamine, sphingomyelin, triglycerides of oleic acid, and/or triglycerol monooleate. In some embodiments, the concentration of an oil is adjusted, such as the concentration of a triglyceride, a fatty acid, a diglyceride, or a monoglyceride. In some embodiments, the concentration of a sterol, such as cholesterol or a plant sterol, is adjusted. In some embodiments, the composition is biased towards liposomes by increasing the concentration of lipids that are liquid at room temperature. Biasing the composition may alter characteristics of the composition including density, particle composition, solubility, pharmacokinetic properties, or other characteristics described herein. [0173] Decreasing the concentration of a co-emulsifier that is a liquid at room temperature can bias the outcome of the particles more towards liposomes while increasing the concentration of a co-emulsifier that is a liquid at room temperature can bias the outcome of the particles more towards solid lipid nanoparticles. Also, increasing the concentration of a lipid that is solid at room temperature can bias the outcome of particles more towards liposomes. As non-limiting examples, decreasing concentrations of the co-emulsifier MCT and/or increasing the concentration of HSPC will bias the outcome of the particles more towards liposomes. As a non-limiting example, substituting MCT with a lipid that is a liquid at room temperature and/or increasing the concentration ratio of HSPC to MCT will bias the outcome of the particles more towards liposomes. As another non-limiting example, substituting HSPC with a lipid that is a solid at room temperature will bias the outcome of the particles more towards solid lipid nanoparticles.
[0174] In some embodiments, the composition comprises high purity triglycerides, such as oleic acid and/or conjugated linoleics. The composition may be formulated, such as by changing the composition or concentration of lipids, for specific delivery or specific metabolism. For example, the composition may comprise medium chain triglycerides to bias the composition towards phase 1 liver metabolism. In some embodiments, the composition is formulated for a specific absorption mechanism, such as lymphatic absorption or liver first pass.
[0175] Some embodiments pertain to a lipid-based particle composition, comprising: a nanoparticle comprising an active compound that is of sufficient purity that it exists in a solid and/or powdered state prior to formulation in the nanoparticle composition at a weight percent in the composition ranging from 1% to 10%; a phosphatidylcholine at a weight percent in the composition ranging from 2.5% to 15%; a sterol at a weight percent in the composition ranging from 0.5% to 5%; and a medium chain triglyceride at a weight percent in the composition ranging from 2.5% to 15%. In some embodiments, the composition comprises water at a weight percent in the composition ranging from 60% to about 80%. In some embodiments, the nanoparticles have an average size ranging from about 75 nm to about 175 nm. In some embodiments, upon storage for a period of one month, the average size of the nanoparticles changes by less than about 20%.
[0176] In some embodiments, the nanoparticle composition is in the form of liposomes and/or an oil-in-water nano-emulsion. In some embodiments, an appreciable amount of the nanoparticle composition does not settle and/or separate from the water upon standing for a period of at least about 12 hours, 24 hours, 3 days, 5 days, a week, 2 weeks, 3 weeks, 5 weeks, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months. In some embodiments, the composition is configured such that when concentrated to dryness to afford a powder formulation of nanoparticles, the nanoparticle powder can be reconstituted to provide the nanoparticle composition. In some embodiments, the composition has a Tmax for CBD of less than 4.5 hours. In some embodiments, upon storage for a period of one month, two months, three months, 6 months, 12 months, 18 months, or 24 months the average size of the nanoparticles changes by less than about 20%. In some embodiments, the polydispersity of the nanoparticles in the composition is less than or equal to 0.15. In some embodiments, upon 90 days of storage at 25°C and 60% relative humidity, the polydispersity of the nanoparticles changes by less than or equal to 10%. In some embodiments, upon 90 days of storage at 25°C and 60% relative humidity, the polydispersity of the nanoparticles changes by less than or equal to 0.1. In some embodiments, the composition has a shelf life of greater than 18 months at 25°C and 60% relative humidity. In some embodiments, upon 90 days of storage at 25°C and 60% relative humidity, the D90 of the nanoparticles changes less than or equal to 10%. In some embodiments, the composition has a concentration max (Cmax) of 80 ng/ml after an oral dose of 15 mg/kg.
[0177] In some embodiments, as disclosed elsewhere herein, the nanoparticle composition is in the form and/or comprises one or more of liposomes, an oil-in-water nano-emulsion (and/or microparticle emulsion), and/or solid lipid particles. In some embodiments, when suspended in water, an appreciable amount of the particles in the composition do not settle and/or do not separate (e.g., upon visual inspection) from the water upon standing for a period of at least about 12 hours. In some embodiments, when suspended in water, the particles remain substantially homogenously distributed in the water upon standing for a period of at least about 12 hours, 24 hours, 3 days, 5 days, a week, 2 weeks, 3 weeks, 5 weeks, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months. In some embodiments, the nanoparticles have an average size ranging from about 10 nm to about 500 nm. In some embodiments, the composition comprises nanoparticles having an average size of less than or equal to about: 10 nm, 50 nm, 100 nm, 250 nm, 500 nm, 1000 nm, or ranges including and/or spanning the aforementioned values. In some embodiments, the composition comprises microparticles having an average size of less than or equal to about: 1000 nm, 1.5 pm, 2 pm, 3 pm, 5 pm, 10 pm or ranges including and/or spanning the aforementioned values. In some embodiments, the dried powder composition comprises microparticles that form nanoparticles (as disclosed herein) when reconstituted. In some embodiments, these dried powder compositions comprise particles having an average size of less than or equal to about: 250 nm, 500 nm, 1000 nm, 1.5 pm, 2 pm, 3 pm, 5 pm, 10 pm, 50 pm, or ranges including and/or spanning the aforementioned values. In some embodiments, upon storage for a period of one month, the average size of the nanoparticles (or microparticles) increases by less than about 10%.
[0178] In some embodiments, the nanoparticle composition is configured such that when concentrated to dryness to afford dry particles (e.g., from any one of the oil-in-water emulsion (e.g., a nanoemulsion or microemulsion), liposome solution, and/or solid lipid particle) as a powder, the dry nanoparticles can be reconstituted to provide a reconstituted particle based solution (e.g., the nanoparticle composition). In some embodiments, when reconstituted, the average size of the nanoparticles increases or decreases by less than about 15% and/or by less than about 100%. In some embodiments, to form powders, excipients (and/or additives as disclosed elsewhere herein) may be added to the liposomes, oil-in-water nano-emulsions (and/or microparticle emulsions), and/or a solid lipid particle. In some embodiments, the excipient comprises trehalose.
B. Active Compounds
[0179] Certain embodiments herein concern active compounds. The active compounds may be encapsulated in one or more of the nanoparticles described herein. The active compounds may be pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like.
[0180] In some embodiments, the active compound comprises a therapeutic. The therapeutic may be an analgesic, an anesthetic, an antibacterial agent, an anticonvulsant, an antidementia agent, an antidepressant, an antidote, a deterrent, a toxicologic agent, an antiemetic, an antifungal, an antigout agent, an anti-inflammatory agent, an antimigraine agent, an antimyasthenic agent, an antineoplastic agent, an antiparasitic agent, an antiparkinson agent, an antipsychotic, an antipasticity agent, an antiviral, an anxiolytic, a bipolar agent, a blood glucose regulator, a blood product, a blood modifier, a blood volume expander, a cardiovascular agent, a central nervous system agent, a dental agent, an oral agent, a dermatological agent, an enzyme replacement agent, an enzyme modifying agent, a gastrointestinal agent, a genitourinary agent, a hormonal agent, a hormone stimulant, a hormone replacement, a hormone modifying agent, a hormone suppressant, an immunological agent, an inflammatory bowel disease agent, a metabolic bone disease agent, an ophthalmic agent, an otic agent, a respiratory tract agent, a sedative, a hypnotic, a skeletal muscle relaxant, a therapeutic nutrient, a therapeutic mineral, and/or a therapeutic electrolyte. The hormonal agent, a hormone stimulant, a hormone replacement, a hormone modifying agent, and/or hormone surpressant may act on the adrenal system, the pituitary system, the prostaglandin system, sex hormone, the thyroid, and/or the parathyroid.
[0181] The active compound may comprise a small molecule. The active compound may comprise a biologic. The active compound may comprise a biomolecule. The active compound may comprise a macromolecule. In some embodiments, the active compound comprises a nucleic acid, a protein, a lipid, a carbohydrate, or a combination thereof. In some embodiments, the active compound comprises a cell or a derivative of a cell. In some embodiments, the active compound comprises antisense RNA. In some embodiments, the active compound comprises an siRNA, a miRNA, a IncRNA, or a combination thereof. In some embodiments, the active compound comprises a nucleic acid vector.
[0182] In some embodiments, the active compound is selected from the group consisting of Cannabidiol, Cannabigerol, Cannabinol, Cannabichromene, Tetrahydrocannabivarin, Tetrahydrocannabinol, Full extracts of hemp, Specific ratios of isolated cannabinoids, Cannabigerolic acid, Cannabidolic acid, Mitragynine, Payantheine, Mitraphylline, Speciociliantine, Speciogynine, Cholecalciferol, Ergocalciferol, D,L-Alpha-Tocopherol, Menaquinone, Ascorbyl palmitate, Retinyl palmitate, Beta-Sitosterol, Plant Sterol Rich Extracts, Cholesterol, Ubiquinone, Phosphatidylcholine, Phosphatidylserine, Eicosapentaenoic/Docosahexaenoic Acid Mixtures, Oleic Acid, Conjugated Linoleic Acid, Capric Triglycerides, Caprylic Triglycerides, Capric and Caprylic Triglyceride mixtures, Peppermint, Orange, Lemon Oils, Lutein, Kavain, Methysticin, Yangonin, Dihydromethysticin, and a combination thereof. [0183] In some embodiments, the active compound comprises kratom extracts, kanna extracts, kava extracts, mushroom extracts (e.g., Psilocybe cuhensisy Cannabis extracts, cannabinoids, other therapeutic agents, phytocannabinoids, fish oils, vitamin D, other vitamins, and/or combinations of any of the foregoing. The active compounds may be prepared using the thoroughness and diligence of pharmaceutical drug development to consumer products.
[0184] In several embodiments, the one or more therapeutic agents include one or more kratom extracts. In several embodiments, the one or more therapeutic agents include one or more plant extracts or fungus extracts (e.g., mushroom extracts). In several embodiments, the one or more therapeutic agents may comprise, consist of, or consist essentially of kratom extracts, kanna extracts, kava extracts, mushroom extracts (e.g., Psilocybe cubensisy Cannabis extracts, cannabinoids, and/or combinations of any of the foregoing.
[0185] Kratom, or Mitragyna speciosa, is a tropical evergreen tree in the coffee family. This tree is native to Southeast Asia and is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea. Extracts from this tree have been used in herbal medicine. For example, leaves of the kratom tree may be consumed as a tea or chewed directly and are purported to induce stimulant and opioid-like analgesic effects in the user in a dose- and timedependent manner. Kratom also has been used in ameliorating withdrawal symptoms following cessation of drug use (e.g., opioid use). However, delivery of these kratom extracts using traditional methods and current formulations is highly inefficient, highly uncontrolled, with low reliability, and/or high variability batch-to-batch. Such problems persist in other active compounds disclosed herein. Several embodiments of the nanoparticles and/or compositions disclosed herein solve one or more of these problems or others.
[0186] Kratom strains may be selected from the group consisting of Maeng da, Indo, Bali/red vein, Green Malay, Super Green Malaysian, Red Kali Kratom, Green Vein Kali, White Vein Kali, Red Indo Kratom, Green Indo Kratom, White Vein Indo Kratom, White Vein Thai Kratom, Gold Reserve Kratom Extract, Ultra Enhanced Indo Extract, ISOL-8 Extract, Natural Enhanced True Thai, Natural Enhanced White Sumatra, other kratoms, or combinations of any of the foregoing. In several embodiments, nanoparticles (or compositions comprising the nanoparticles) are composed of and/or comprise one or more kratom extracts. In several embodiments, nanoparticles (or compositions comprising the nanoparticles) are composed of and/or comprise kratom powders and/or one or more kratom active ingredients. In several embodiments, the kratom active ingredients include, but are not limited to, alkaloids, mitaphylline, 7-OH-mitragynine, paynantheine, speciogynine, mitragynine, other kratom active agents, and/or combinations of any of the foregoing. In several embodiments, a kratom extract may be an alkaloid from kratom. In several embodiments, the kratom extract is an alkaloid selected from the group consisting of Ajmalicine or Raubasine (a cerebrocirculant, antiaggregant, anti-adrenergic (at alpha- 1), sedative, anticonvulsant, smooth muscle relaxer), akuammigine, ciliaphylline (antitussive, analgesic), corynantheidine (p-opioid antagonist, also found in yohimbe), corynoxeine (calcium channel blocker), corynoxine A and/or B (dopamine mediating anti-locomotives, epicatechin (antioxidant, antiaggregant, antibacterial, antidiabetic, antihepatitic, anti-inflammatory, anti-leukemic, antimutagenic, antiperoxidant, antiviral, potential cancer preventative, alpha-amylase inhibitor), 9-hydroxycorynantheidine (partial opioid agonist), 7-hydroxymitragynine (analgesic, antitussive, antidiarrheal), isomitraphylline (immunostimulant, anti-leukemic), isomitrafoline, isopteropodine (immunostimulant), isorhynchophylline (immuno stimulant), isospeciofoline, mitraciliatine, mitragynine (indole alkaloid, analgesic, antitussive, antidiarrheal, adrenergic, antimalarial, possible psychedelic (5- HT2A) antagonist), mitragynine oxindole B, mitrafoline, mitraphylline (oxindole alkaloid, vasodilator, antihypertensive, muscle relaxer, diuretic, anti-amnesic, anti-leukemic, possible immuno stimulant), mitraversine, paynantheine (smooth muscle relaxer), rhynchophylline, (vasodilator, antihypertensive, calcium channel blocker, antiaggregant, anti-inflammatory, antipyretic, anti- arrhythmic, antithelmintic), speciociliatine, speciofoline, speciogynine (smooth muscle relaxer), speciophylline (anti-leukemic), stipulatine, tetrahydroalstonine (hypoglycemic, anti- adrenergic (at alpha-2), or the kratom extract includes combinations of any of the foregoing kratom actives. In several embodiments, the kratom extracts are extracted from kratom (e.g., are natural extracts). In other embodiments, the kratom extracts may be produced synthetically (e.g., in a laboratory). In several embodiments, the synthetic extract may share a structure with an extract that is naturally occurring. In several embodiments, the kratom extracts are analogs of natural extracts of kratom (e.g., produced synthetically).
[0187] In several embodiments, the kratom extract is an alkaloid extracted from kratom (e.g., is a natural extract). In other embodiments, the kratom extract is a kratom alkaloid produced synthetically (e.g., in a laboratory). In several embodiments, the synthetic extract may share a structure with an extract that is naturally occurring. In several embodiments, the kratom alkaloid is an analogs of natural extracts of kratom (e.g., produced synthetically).
[0188] Sceletium tortuosum is a succulent plant commonly found in South Africa, which is also known as Kanna, Channa, Kougoed. There are eight generally recognized Sceletium species, including S. crassicaule, S. emarcidum, S. exalatum, S. expansum, S. rigidum, S. strictum, S. tortuosum and S. various. In several embodiments, the one or more kanna extracts may be from any one or more of these kanna plants. The kanna plant has been used by South African pastoralists and hunter-gatherers as a mood-altering substance. Traditionally, dried Sceletium was chewed and the saliva swallowed. It has also been made into gel caps, teas and tinctures. It has also been used as a snuff and smoked. However, delivery of these kanna extracts using traditional methods and current formulations is highly inefficient, highly uncontrolled, with low reliability, and/or high variability batch-to-batch. Several embodiments of the nanoparticle compositions disclosed herein solve one or more of these problems or others.
[0189] In several embodiments, as disclosed elsewhere herein, the nanoparticle compositions comprise one or more kanna extracts. In several embodiments, the kanna extracts are from one or more Sceletium species. In several embodiments, the one or more species are selected from the Tortuosum family (Sceletium tortuosum; Sceletium crassicaule; Sceletium strictum; Sceletium expansum, Sceletium varians, etc.) or the Emarcidum family (Sceletium emarcidum; Sceletium exalatum, Sceletium rigidum, etc.). In several embodiments, extracts from combinations of Sceletium species are used, other Sceletium species, or combinations of any of the foregoing. In several embodiments, the nanoparticle (or a composition comprising the nanoparticle) comprises or is composed of Sceletium extracts. In several embodiments, the nanoparticle (or a composition comprising the nanoparticle) comprises or is composed of Sceletium powders and/or one or more Sceletium active ingredients (e.g., including but not limited to alkaloids). In several embodiments, the kanna extract is an alkaloid (or a combination thereof). In several embodiments, the kanna extract is an alkaloid selected from the group consisting of joubertiamine dehydrojoubertiamine dihydrojoubertiamine joubertinamine, O-methyldehydrojoubertiamine, O-methyljouberiamine, O- methyldihydrojoubertiamine, 3’-methoxy-4’-o-methyl joubertiamine, 4-(3,4- dimehoxyphenyl)-4-[2-acetylmethylamino)ethyl]cyclohexanone, 4-(3-methoxy-4-hydroxy- phenyl)-4-[2-(aceylmethylamino)ethyl]cyclohexadienone, sceletium alkaloid A4, touruosamine, N-formyltortuosamine, N-acetyltortuosamine, or combinations of any of the foregoing. In several embodiments, the alkaloid is a 3a-aryl-cis-octahydroindole class (e.g. mesembrine), C-seco mesembrine alkaloids (e.g. joubertiamine), an alkaloid containing a 2,3- disubstituted pyridine moiety and 2 nitrogen atoms (e.g. sceletium A4), a ring C-seco Sceletium alkaloid A4 group (e.g. tortuosamine), or combinations of the foregoing. In several embodiments, the kanna (e.g., Sceletium) extracts are extracted from Sceletium (e.g., are natural extracts). In other embodiments, the Sceletium extracts may be produced synthetically (e.g., in a laboratory). In several embodiments, the synthetic extract may share a structure with an extract that is naturally occurring. In several embodiments, the Sceletium extracts are analogs of natural extracts of Sceletium (e.g., produced synthetically).
[0190] In several embodiments, solutions of lipid particles are composed and or comprise kava extracts. Kava Piper methysticum) is a plant found in the south Pacific. The root of the plant can be used to produce a drink with sedative, anesthetic, and euphoriant properties. Kava has a number of active kavalactones ingredients. Consumption of kava extracts produced with excessive amounts of poor-quality kava products, may be linked to an increased risk of adverse health outcomes, including potential liver injury. Thus, delivery of these kava extracts using traditional methods and current formulations is highly inefficient, highly uncontrolled, has potential side-effects, and may suffer from with low reliability, and/or high variability batch- to-batch. Several embodiments of the nanoparticle compositions disclosed herein solve one or more of these problems or others.
[0191] In several embodiments, the mushroom extracts are from a mushroom species that produces psilocybin (e.g., a psilocybin mushroom). In several embodiments, the mushroom species is selected from the group consisting of Mitragyna speciosa, Psilocybe azurescens, Psilocybe semilanceata, Psilocybe cyanescens, or combinations thereof. In several embodiments, the mushroom extract is an alkaloid. In several embodiments, the alkaloid is psilocin (3-[2 (dimethylamino)ethyl]-4-indolol), psilocybin ([3-(2-dimethylaminoethyl)-l H- indol-4-yl] dihydrogen phosphate), baeocystin, norbaeocystin, bufotenin, aeruginascin, or combinations of any of the foregoing. In several embodiments, the mushroom extracts are extracted from mushrooms (e.g., are natural extracts). In other embodiments, the mushroom extracts may be produced synthetically (e.g., in a laboratory). In several embodiments, the synthetic extract may share a structure with an extract that is naturally occurring. In several embodiments, the mushroom extracts are analogs of natural extracts of mushrooms (e.g., produced synthetically).
[0192] In several embodiments, the cannabinoids are highly pure isolates derived from hemp or marijuana plant. Cannabinoids may also be from other sources, for example, ones derived from terpenes and natural sources that do not include hemp. Examples include “citrus CBD” “terpene CBD” and pharmaceutical “synthetic” CBD. In several embodiments, the cannabinoids are derived from broad spectrum hemp and/or cannabis oil, full spectrum hemp and/or cannabis oil, distillates from hemp and/or cannabis oil and combinations thereof.
[0193] In several embodiments, as shown in the Examples, the active agent may comprise or may be a full spectrum or broad spectrum plant extract (e.g., from kratom, kanna, kava, mushroom, Cannabis). In several embodiments, the active agent comprises rosin. In several embodiments, the rosin is extract that is produced after pressing cannabis or hemp flower using a high-pressure press. In several embodiments, the rosin is a broad spectrum extract. In several embodiments, as shown in the Examples, the active agent may comprise full spectrum extract, broad spectrum extract, crude, distillates, oils, and isolates, and combinations thereof.
[0194] In several embodiments, the composition is a non-THC containing composition. In several embodiments, for non-THC containing compositions (e.g., including cannabinoids without delta-9-tetrahydrocannabinols), the total potential THC does not to exceed 0.3 weight % of the phytocannabinoid, where the total potential THC is defined as THCa x 0.877 + 9- THC + 8-THC. In several embodiments, for non-THC compositions (e.g., including cannabinoids without THC), the total potential THC does not to exceed 0.3 weight % of the phytocannabinoid, where the total potential THC is defined as THCa + 9-THC.
[0195] In several embodiments, as disclosed elsewhere herein, in addition to kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts, the nanoparticle composition may comprise other active agent (e.g., agents that are not a kratom active, a kanna active, a kava active, a mushroom active, or a Cannabis active). In several embodiments, the non-kratom/non-kanna/non-kava active/non-mushroom active/non-Cannabis active agent is one or more of a vitamin, a nutrient, a different plant extract, a nutraceutical, a pharmaceutical, or another beneficial agent. In several embodiments, the non-kratom/non-kanna/non-kava active/non-mushroom active/non-Cannabis active agent is hydrophilic. In several embodiments, the non-kratom/non-kanna/non-kava active/non-mushroom active/non- Cannabis active agent is hydrophobic. In several embodiments, the non-kratom/non- kanna/non-kava active/non-mushroom active/non-Cannabis active agent is amphiphilic.
[0196] In several embodiments, the non-kratom/non-kanna/non-kava active/non- mushroom active/non-Cannabis active agent is selected from the group consisting of Noopept (N-phenylacetyl-L-prolyglygice ethyl ester), melatonin, glutathione, gamma-glutamylcysteine (GGC), gamma-aminobutyric acid (GABA), valerian root, magnesium, theanine, 5-HTP, tyrosine, taurine, zinc, alpha fenchone, alpha terpinene, alpha terpineol, beta caryophyllene, alpha pinene, beta pinene, bisabolene, bisabolol, borneol, eucalyptol, gamma terpinene, guaiacol, humulene, linalool, myrcene, para cymene, phytol, terpinolene, limonene, others, and/or combinations thereof. In several embodiments, as disclosed elsewhere herein, these non-kratom/non-kanna/non-kava active/non-mushroom active/non-Cannabis active agent may be provided in combination with actives at the concentrations disclosed herein. In several embodiments, when a hydrophilic composition is used, it is mixed with the aqueous soluble ingredients before mixing with the lipid ingredients. [0197] In some embodiments, the active compound comprises at least one cosmetic ingredient. The CTFA International Cosmetic Ingredient Dictionary and Handbook (2004 and 2008) describes a wide variety of non-limiting cosmetic ingredients that can be used in the context of the present disclosure, including as active compounds. In some embodiments, the active compound comprises a fragrance, flavor, dye, etc. Examples of these ingredient classes include: fragrance agents (artificial and natural; e.g., gluconic acid, phenoxyethanol, and triethanolamine), dyes and color ingredients (e.g., Blue 1, Blue 1 Lake, Red 40, titanium dioxide, D&C blue no. 4, D&C green no. 5, D&C orange no. 4, D&C red no. 17, D&C red no. 33, D&C violet no. 2, D&C yellow no. 10, and D&C yellow no. 11), flavoring agents / aroma agents (e.g., Stevia rebaudiana (sweetleaf) extract, and menthol), adsorbents, lubricants, solvents, moisturizers (including, e.g., emollients, humectants, film formers, occlusive agents, and agents that affect the natural moisturization mechanisms of the skin), water-repellants, UV absorbers (physical and chemical absorbers such as para-aminobenzoic acid (“PABA”) and corresponding PABA derivatives, titanium dioxide, zinc oxide, etc.), essential oils, vitamins (e.g., A, B, C, D, E, and K), trace metals (e.g., zinc, calcium and selenium), anti-irritants (e.g., steroids and non-steroidal anti-inflammatories), botanical extracts (e.g., Aloe vera, chamomile, cucumber extract, Ginkgo biloba, ginseng, and rosemary), anti-microbial agents, antioxidants (e.g., BHT and tocopherol), chelating agents (e.g., disodium EDTA and tetrasodium EDTA), preservatives (e.g., methylparaben and propylparaben), pH adjusters (e.g., sodium hydroxide and citric acid), absorbents (e.g., aluminum starch octenylsuccinate, kaolin, corn starch, oat starch, cyclodextrin, talc, and zeolite), skin bleaching and lightening agents (e.g., hydroquinone and niacinamide lactate), humectants (e.g., sorbitol, urea, methyl gluceth-20, saccharide isomerate, and mannitol), exfoliants, waterproofing agents (e.g., magnesium/aluminum hydroxide stearate), skin conditioning agents (e.g., aloe extracts, allantoin, bisabolol, ceramides, dimethicone, hyaluronic acid, biosaccharide gum-1, ethylhexylglycerin, pentylene glycol, hydrogenated poly decene, octyldodecyl oleate, and dipotassium glycyrrhizate).
[0198] In some embodiments, the active compound includes at least one UV absorption and/or reflecting agent. UV absorption and/or reflecting agents that can be used in combination with the compositions of the present disclosure include chemical and physical sunblocks. Nonlimiting examples of chemical sunblocks that can be used include para-aminobenzoic acid (PABA), PABA esters (glyceryl PABA, amyldimethyl PABA and octyldimethyl PABA), butyl PABA, ethyl PABA, ethyl dihydroxypropyl PABA, benzophenones (oxybenzone, sulisobenzone, benzophenone, and benzophenone- 1 through 12), cinnamates (octyl methoxycinnamate (octinoxate), isoamyl p-methoxycinnamate, octylmethoxy cinnamate, cinoxate, diisopropyl methyl cinnamate, DEA-methoxycinnamate, ethyl diisopropylcinnamate, glyceryl octanoate dimetho xycinnamate and ethyl methoxy cinnamate), cinnamate esters, salicylates (homomethyl salicylate, benzyl salicylate, glycol salicylate, isopropylbenzyl salicylate, etc.), anthranilates, ethyl urocanate, homosalate, octisalate, dibenzoylmethane derivatives (e.g., avobenzone), octocrylene, octyl triazone, digalloyl trioleate, glyceryl aminobenzoate, lawsone with dihydroxyacetone, ethylhexyl triazone, dioctyl butamido triazone, benzylidene malonate polysiloxane, terephthalylidene dicamphor sulfonic acid, disodium phenyl dibenzimidazole tetrasulfonate, diethylamino hydroxybenzoyl hexyl benzoate, bis diethylamino hydroxybenzoyl benzoate, bis benzoxazoylphenyl ethylhexylimino triazine, drometrizole trisiloxane, methylene bis-benzotriazolyl tetramethylbutylphenol, and bis-ethylhexyloxyphenol methoxyphenyltriazine, 4-methylbenzylidene camphor, and isopentyl 4-methoxycinnamate. Non-limiting examples of physical sunblocks include, kaolin, talc, petrolatum and metal oxides (e.g., titanium dioxide and zinc oxide).
[0199] In some embodiments, the active compound comprises at least one moisturizing agent. Non-limiting examples of moisturizing agents that can be used with the compositions of the present invention include amino acids, chondroitin sulfate, diglycerin, erythritol, fructose, glucose, glycerin, glycerol polymers, glycol, 1,2,6-hexanetriol, honey, hyaluronic acid, hydrogenated honey, hydrogenated starch hydrolysate, inositol, lactitol, maltitol, maltose, mannitol, natural moisturizing factor, PEG- 15 butanediol, polyglyceryl sorbitol, salts of pyrrolidone carboxylic acid, potassium PCA, propylene glycol, saccharide isomerate, sodium glucuronate, sodium PCA, sorbitol, sucrose, trehalose, urea, and xylitol. Other examples include acetylated lanolin, acetylated lanolin alcohol, alanine, algae extract, Aloe barbadensis, Aloe barbadensis extract, Aloe barbadensis gel, Althea officinalis extract, apricot (P imus armeniaca) kernel oil, arginine, arginine aspartate, Arnica montana extract, aspartic acid, avocado (Persea gratissima) oil, barrier sphingolipids, butyl alcohol, beeswax, behenyl alcohol, beta-sitosterol, birch (Betula alba) bark extract, borage (Borago officinalis) extract, butcherbroom (Ruscus aculeatus) extract, butylene glycol, Calendula officinalis extract, Calendula officinalis oil, candelilla (Euphorbia cerifera) wax, canola oil, caprylic/capric triglyceride, cardamom (Elettaria cardamomum) oil, carnauba (Copernicia cerifera) wax, carrot (Daucus carota sativa) oil, castor (Ricinus communis) oil, ceramides, ceresin, ceteareth- 5, ceteareth-12, ceteareth-20, cetearyl octanoate, ceteth-20, ceteth-24, cetyl acetate, cetyl octanoate, cetyl palmitate, chamomile (Anthemis nobilis) oil, cholesterol, cholesterol esters, cholesteryl hydroxystearate, citric acid, clary (Salvia sclarea) oil, cocoa (Theobroma cacao) butter, coco-caprylate/caprate, coconut (Cocos nucifera) oil, collagen, collagen amino acids, com (Zea mays) oil, fatty acids, decyl oleate, dimethicone copolyol, dimethiconol, dioctyl adipate, dioctyl succinate, dipentaerythrityl hexacaprylate/hexacaprate, DNA, erythritol, ethoxydiglycol, ethyl linoleate, Eucalyptus globulus oil, evening primrose (Oenothera biennis) oil, fatty acids, Geranium maculatum oil, glucosamine, glucose glutamate, glutamic acid, glycereth-26, glycerin, glycerol, glyceryl distearate, glyceryl hydroxystearate, glyceryl laurate, glyceryl linoleate, glyceryl myristate, glyceryl oleate, glyceryl stearate, glyceryl stearate SE, glycine, glycol stearate, glycol stearate SE, glycosaminoglycans, grape (Vitis vinifera) seed oil, hazel (Corylus americana) nut oil, hazel (Corylus avellana) nut oil, hexylene glycol, hyaluronic acid, hybrid safflower (Carthamus tinctorius) oil, hydrogenated castor oil, hydrogenated coco-glycerides, hydrogenated coconut oil, hydrogenated lanolin, hydrogenated lecithin, hydrogenated palm glyceride, hydrogenated palm kernel oil, hydrogenated soybean oil, hydrogenated tallow glyceride, hydrogenated vegetable oil, hydrolyzed collagen, hydrolyzed elastin, hydrolyzed glycosaminoglycans, hydrolyzed keratin, hydrolyzed soy protein, hydroxylated lanolin, hydroxyproline, isocetyl stearate, isocetyl stearoyl stearate, isodecyl oleate, isopropyl isostearate, isopropyl lanolate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, isostearamide DEA, isostearic acid, isostearyl lactate, isostearyl neopentanoate, jasmine (Jasminum officinale) oil, jojoba (Buxus chinensis) oil, kelp, kukui (Aleurites moluccana) nut oil, lactamide MEA, laneth-16, laneth-10 acetate, lanolin, lanolin acid, lanolin alcohol, lanolin oil, lanolin wax, lavender (Lavandula angustifolia) oil, lecithin, lemon (Citrus medica limonum) oil, linoleic acid, linolenic acid, Macadamia ternifolia nut oil, maltitol, matricaria (Chamomilla recutita) oil, methyl glucose sesquistearate, methylsilanol PCA, mineral oil, mink oil, mortierella oil, myristyl lactate, myristyl myristate, myristyl propionate, neopentyl glycol dicaprylate/dicaprate, octyldodecanol, octyldodecyl myristate, octyldodecyl stearoyl stearate, octyl hydroxystearate, octyl palmitate, octyl salicylate, octyl stearate, oleic acid, olive (Olea europaea) oil, orange (Citrus aurantium dulcis) oil, palm (Elaeis guineensis) oil, palmitic acid, pantethine, panthenol, panthenyl ethyl ether, paraffin, PCA, peach (Prunus persica) kernel oil, peanut (Arachis hypogaea) oil, PEG-8 C12-18 ester, PEG- 15 cocamine, PEG- 150 distearate, PEG-60 glyceryl isostearate, PEG-5 glyceryl stearate, PEG-30 glyceryl stearate, PEG-7 hydrogenated castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-20 methyl glucose sesquistearate, PEG-40 sorbitan peroleate, PEG-5 soy sterol, PEG- 10 soy sterol, PEG-2 stearate, PEG-8 stearate, PEG-20 stearate, PEG-32 stearate, PEG-40 stearate, PEG-50 stearate, PEG-100 stearate, PEG-150 stearate, pentadecalactone, peppermint (Mentha piperita) oil, petrolatum, phospholipids, plankton extract, polyamino sugar condensate, polyglyceryl-3 diisostearate, polyquatemium- 24, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 85, potassium myristate, potassium palmitate, propylene glycol, propylene glycol dicaprylate/dicaprate, propylene glycol dioctanoate, propylene glycol dipelargonate, propylene glycol laurate, propylene glycol stearate, propylene glycol stearate SE, PVP, pyridoxine dipalmitate, retinol, retinyl palmitate, rice (Oryza sativa) bran oil, RNA, rosemary (Rosmarinus officinalis') oil, rose oil, safflower (Carthamus tinctorius) oil, sage (Salvia officinalis) oil, sandalwood (Santalum album) oil, serine, serum protein, sesame (Sesamum indicum) oil, shea butter (Butyrospermum parkii), silk powder, sodium chondroitin sulfate, sodium hyaluronate, sodium lactate, sodium palmitate, sodium PCA, sodium polyglutamate, soluble collagen, sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan sesquioleate, sorbitan stearate, sorbitol, soybean (Glycine soja) oil, sphingolipids, squalane, squalene, stearamide MEA-stearate, stearic acid, stearoxy dimethicone, stearoxytrimethylsilane, stearyl alcohol, stearyl glycyrrhetinate, stearyl heptanoate, stearyl stearate, sunflower (Helianthus annuus) seed oil, sweet almond (Prunus amygdalus dulcis) oil, synthetic beeswax, tocopherol, tocopheryl acetate, tocopheryl linoleate, tribehenin, tridecyl neopentanoate, tridecyl stearate, triethanolamine, tristearin, urea, vegetable oil, water, waxes, wheat (Triticum vulgare) germ oil, and ylang ylang (Cananga odorata) oil. [0200] In some embodiments, the active compound comprises at least one antioxidant. Non-limiting examples of antioxidants that can be used with the compositions of the present invention include acetyl cysteine, ascorbic acid polypeptide, ascorbyl dipalmitate, ascorbyl methylsilanol pectinate, ascorbyl palmitate, ascorbyl stearate, BHA, BHT, t-butyl hydroquinone, cysteine, cysteine HCI, diamylhydroquinone, di-t-butylhydroquinone, dicetyl thiodipropionate, dioleyl tocopheryl methylsilanol, disodium ascorbyl sulfate, distearyl thiodipropionate, ditridecyl thiodipropionate, dodecyl gallate, erythorbic acid, esters of ascorbic acid, ethyl ferulate, ferulic acid, gallic acid esters, hydroquinone, isooctyl thioglycolate, kojic acid, magnesium ascorbate, magnesium ascorbyl phosphate, methylsilanol ascorbate, natural botanical anti-oxidants such as green tea or grape seed extracts, nordihydroguaiaretic acid, octyl gallate, phenylthioglycolic acid, potassium ascorbyl tocopheryl phosphate, potassium sulfite, propyl gallate, quinones, rosmarinic acid, sodium ascorbate, sodium bisulfite, sodium erythorbate, sodium metabisulfite, sodium sulfite, superoxide dismutase, sodium thioglycolate, sorbityl furfural, thiodiglycol, thiodiglycolamide, thiodiglycolic acid, thioglycolic acid, thiolactic acid, thiosalicylic acid, tocophereth-5, tocophereth-10, tocophereth-12, tocophereth-18, tocophereth-50, tocopherol, tocophersolan, tocopheryl acetate, tocopheryl linoleate, tocopheryl nicotinate, tocopheryl succinate, and tris (nony Ipheny l)pho sphite . [0201] In some embodiments, the active compound comprises at least one essential oil. Essential oils include oils derived from herbs, flowers, trees, and other plants. Such oils are typically present as tiny droplets between the plant’s cells, and can be extracted by several methods known to those of skill in the art (e.g., steam distilled, enfleurage, maceration, solvent extraction, or mechanical pressing). When these types of oils are exposed to air they tend to evaporate. As a result, many essential oils are colorless, but with age they can oxidize and become darker. Essential oils are insoluble in water and are soluble in alcohol, ether, fixed oils (vegetal), and other organic solvents. Typical physical characteristics found in essential oils include boiling points that vary from about 160 to 240°C and densities ranging from about 0.759 to about 1.096.
[0202] Essential oils typically are named by the plant from which the oil is found. For example, rose oil or peppermint oil are derived from rose or peppermint plants, respectively. Non-limiting examples of essential oils that can be used in the context of the present invention include sesame oil, macadamia nut oil, tea tree oil, evening primrose oil, Spanish sage oil, Spanish rosemary oil, coriander oil, thyme oil, pimento berries oil, rose oil, anise oil, balsam oil, bergamot oil, rosewood oil, cedar oil, chamomile oil, sage oil, clary sage oil, clove oil, cypress oil, eucalyptus oil, fennel oil, sea fennel oil, frankincense oil, geranium oil, ginger oil, grapefruit oil, jasmine oil, juniper oil, lavender oil, lemon oil, lemongrass oil, lime oil, mandarin oil, marjoram oil, myrrh oil, neroli oil, orange oil, patchouli oil, pepper oil, black pepper oil, petitgrain oil, pine oil, rose otto oil, rosemary oil, sandalwood oil, spearmint oil, spikenard oil, vetiver oil, wintergreen oil, or ylang ylang. Other essential oils known to those of skill in the art are also contemplated as being useful within the context of the present invention.
[0203] In some embodiments, the active agent comprises an algae extract. The algae extract may comprise ashwagandha and/or astoxantin.
[0204] In some embodiments, the active compound is encapsulated by a nanoparticle at a concentration of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, or ranges including and/or spanning the aforementioned values, per kg of the nanoparticle. C. Pharmacokinetic Properties
[0205] In several embodiments, as disclosed elsewhere herein, the nanoparticle composition aids in absorption, bioavailability, or other pharmacokinetic properties of the active compound when administered to an individual, including by orally ingestion. In several embodiments, the compositions disclosed herein allow the active compound to be delivered to and/or absorbed through the gut. As disclosed elsewhere herein, some embodiments pertain to the use of the nanoparticle based nanodelivery system to protect the active compound from degradation and/or precipitation in a solution comprising the active compound (e.g., in an aqueous composition for administration to a subject). In several embodiments, use of the delivery systems, including the nanoparticles, disclosed herein result in improved bioavailability and/or absorption rate. For instance, in some embodiments, the Cmax of an active compound is increased using a disclosed embodiment, the Tmax of an active compound is decreased using an embodiment as disclosed herein, and/or the AUC of an active compound is increased using a disclosed embodiment.
[0206] In several embodiments, the pharmacokinetic outcomes disclosed elsewhere herein (Cmax, Tmax, AUC, ti/2, etc.) can be achieved using aqueous nanoparticle compositions or powdered nanoparticle compositions (e.g., where the powder is supplied by itself, in a gel capsule, as an additive to food, etc.).
[0207] In several embodiments, the Cmax of the active agent is increased using the disclosed embodiments relative to other delivery vehicles (e.g., after administration to a subject). In several embodiments, the Cmax is increased relative to the active agent (e.g., pharmaceuticals, nutraceuticals, and the like) alone or comparator embodiments (e.g., oil-based products) by equal to or at least about: 15%, 20%, 50%, 100%, 150%, 200%, or ranges including and/or spanning the aforementioned values. In several embodiments, the active agent Cmax is increased (relative to a comparator oil-based product) by equal to or at least about: 5%, 10%, 20%, 30%, 50%, 100%, or ranges including and/or spanning the aforementioned values. In several embodiments, the active agent Cmax is increased (relative to a comparator oil-based product) by equal to or at least about: 10 ng/mL, 20 ng/mL, 30 ng/mL, 40 ng/mL, 50 ng/mL, 60 ng/mL, 70 ng/mL, 80 ng/mL, 90 ng/mL, or ranges including and/or spanning the aforementioned values.
[0208] In several embodiments, after a dose of 15 mg of active agent (e.g., pharmaceuticals, nutraceuticals, and the like) provided in an embodiment as disclosed herein to a subject (e.g., a mini-pig, human, etc.), the Cmax of the active agent is equal to or at least about: 0.5 pg/L, 1 pg/L, 2 pg/L, 3 pg/L, 4 pg/L, 5 pg/L, 6 pg/L, or ranges including and/or spanning the aforementioned values. In several embodiments, after a dose of 15 mg/kg of active agent (e.g., pharmaceuticals, nutraceuticals, and the like) provided in an embodiment as disclosed herein to a subject, the Cmax is equal to or at least about: 40 ng/mL, 50 ng/mL, 60 ng/mL, 70 ng/mL, 80 ng/mL, 90 ng/mL, 100 ng/mL, 150 ng/mL, 200 ng/mL, or ranges including and/or spanning the aforementioned values.
[0209] In several embodiments, the Cmax for a disclosed embodiment is increased relative to an equal dose of an active agent (e.g., pharmaceuticals, nutraceuticals, and the like) in an oil-based comparator vehicle. In several embodiments, the Cmax for a disclosed embodiment is increased relative to an oil-based comparator vehicle by equal to or at least about: 15%, 20%, 50%, 100%, 150%, 200%, or ranges including and/or spanning the aforementioned values. In several embodiments, these pharmacokinetic results can be achieved using aqueous compositions or powdered compositions (where the powder is supplied by itself, in a gel capsule, as an additive to food, etc.). In some instances, the Cmax using a disclosed embodiment is 1.25 times higher than when using a comparator delivery system (e.g., the Cmax of the comparator x 1.25). In some instances, the Cmax using a disclosed embodiment is equal to or at least about 1.25 times higher, 1.5 times higher, 2 times higher, 3 times higher (or ranges including or spanning the aforementioned values) than when using a comparator delivery system.
[0210] In several embodiments, the Tmax for an active agent using a disclosed embodiment is shortened relative to other vehicles. In several embodiments, after a dose of active agent (e.g., pharmaceuticals, nutraceuticals, and the like) provided in an embodiment as disclosed herein to a subject as disclosed herein, the Tmax is equal to or at less than about: 30 minutes, 1 hours, 2 hours, 3 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 8 hours, or ranges including and/or spanning the aforementioned values. In several embodiments, after a dose of 15 mg/kg of active agent provided in an embodiment as disclosed herein to a subject, the Tmax is equal to or at less than about: 30 minutes, 1 hours, 2 hours, 3 hours, 4 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 8 hours, or ranges including and/or spanning the aforementioned values. In several embodiments, after a dose of active agent provided in an embodiment as disclosed herein to a subject, the Tmax is between about 4 hours and about 6.5 hours or between about 3 hours and about 7 hours. In several embodiments, after a dose of 15 mg of active agent provided in an embodiment as disclosed herein to a human patient, the Tmax is equal to or less than about: 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, or ranges including and/or spanning the aforementioned values. [0211] In several embodiments, after of a dose of active agent (e.g., pharmaceuticals, nutraceuticals, and the like) (e.g., a 15 mg/kg dose) provided in an embodiment as disclosed herein to a subject (e.g., a mini-pig, human, etc.), the AUC is equal to or at least about: 50 ng/mL*hr, 100 ng/mL*hr, 200 ng/mL*hr, 300 ng/mL*hr, 400 ng/mL*hr, 450 ng/mL*hr, 500 ng/mL*hr, 550 ng/mL*hr, 600 ng/mL*hr, 650 ng/mL*hr, 700 ng/mL*hr, 800 ng/mL*hr, 1000 ng/mL*hr, or ranges including and/or spanning the aforementioned values.
[0212] In several embodiments, the half-life for an active agent (e.g., pharmaceuticals, nutraceuticals, and the like) (ti/2) in vivo using a disclosed embodiment can be shorter relative to other vehicles. In several embodiments, after a dose of active agent (e.g., pharmaceuticals, nutraceuticals, and the like) provided in an embodiment as disclosed herein to a subject as disclosed herein, the ti/2 of active agent is equal to or at less than about: 4 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, or ranges including and/or spanning the aforementioned values. In several embodiments, after a dose of active agent provided in an embodiment as disclosed herein to a subject, the ti/2 of active agent is between about 4 hours and about 6.5 hours or between about 3 hours and about 7 hours. In several embodiments, the ti/2 for a disclosed embodiment is decreased relative to an active agent alone or an oil-based comparator vehicle by equal to or at least about: 15%, 20%, 50%, 100%, 150%, 200%, or ranges including and/or spanning the aforementioned values. In several embodiments, the ti/2 of active agent for a disclosed embodiment is decreased relative to the active alone or an oil-based comparator vehicle by equal to or at least about: 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, or ranges including and/or spanning the aforementioned values. In some instances, the ti/2 is a fraction of that achieved using a comparator delivery system. In some instances, the time to ti/2 using a disclosed embodiment is 0.5 times, 0.7 times, 0.8 times, 0.9 times, or 0.95 times the ti/2 of a comparator delivery system (or ranges including or spanning the aforementioned values).
[0213] In several embodiments, as disclosed elsewhere herein, the nanoparticle composition is stable. In several embodiments, for example, after formulation (e.g., in water at concentrations disclosed elsewhere herein) and storage for a period of at least about 1 month, 3 months, 6 months, 12 months, 18 months, 24 months, or ranges including or spanning the aforementioned values, the polydispersity of the nanoparticles changes less than or equal to about: 1%, 5%, 10%, 20%, or ranges including and/or spanning the aforementioned values. In several embodiments, after formulation (e.g., in water at concentrations disclosed elsewhere herein) and storage for a period of at least about 1 month, 3 months, 6 months, 12 months, 18 months, 24 months, or ranges including or spanning the aforementioned values, the soluble fraction of active agent (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like) in the formulation changes less than or equal to about: 1%, 5%, 10%, 20%, 30%, or ranges including and/or spanning the aforementioned values. In several embodiments, after formulation and storage for a period of at least about 1 month, 3 months, 6 months, 12 months, 18 months, 24 months, or ranges including or spanning the aforementioned values, (e.g., at ambient conditions, at 25°C with 60% relative humidity, or under the other testing conditions disclosed elsewhere herein), the PDI of nanoparticles comprising the composition changes by less than or equal to about: 1%, 5%, 10%, 20%, or ranges including and/or spanning the aforementioned values. In several embodiments, after formulation and storage for a period of at least about 1 month, 3 months, 6 months, 12 months, 18 months, 24 months, or ranges including or spanning the aforementioned values, (e.g., at ambient conditions, at 25°C with 60% relative humidity, or under the other testing conditions disclosed elsewhere herein), the PDI of nanoparticles comprising the composition changes by less than or equal to about: 0.05, 0.1, 0.2, 0.3, 0.4, or ranges including and/or spanning the aforementioned values.
[0214] In several embodiments, when exposed to simulated gastric fluid (e.g., at a concentration of 20 mg/mL), the particle size of the nanoparticles of a composition as disclosed herein does not change and/or changes less than 5% during a period of greater than or equal to about: 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 10 hours, or ranges including and/or spanning the aforementioned values. In several embodiments, when exposed to simulated intestinal fluid (e.g., at a concentration of 20 mg/mL), the particle size of the nanoparticles disclosed herein does not change and/or changes less than 5% during a period of greater than or equal to about: 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 10 hours, or ranges including and/or spanning the aforementioned values. In several embodiments, after formulation (e.g., at a concentration of 20 mg/mL) and storage in simulated gastric fluid for a period of at least about 1 hour or about 2 hours (e.g., at 37°C, or under the other testing conditions disclosed elsewhere herein), the average particle size of nanoparticles comprising the composition changes by less than or equal to about: 1%, 5%, 10%, 20%, 50%, or ranges including and/or spanning the aforementioned values. In several embodiments, after formulation (e.g., at a concentration of 20 mg/mL) and storage in simulated gastric fluid for a period of at least about 1 hour, about 2 hours, about 3 hours, or about 4 hours (e.g., at 37°C or under the other testing conditions disclosed elsewhere herein), the PDI of nanoparticles comprising the composition changes by less than or equal to about: 1%, 5%, 10%, 20%, or ranges including and/or spanning the aforementioned values. In several embodiments, after formulation (e.g., at a concentration of 20 mg/mL) and storage in simulated gastric fluid for a period of at least about 1 hour or about 2 hours (e.g., at 37°C or under the other testing conditions disclosed elsewhere herein), the PDI of nanoparticles comprising the composition changes by less than or equal to about: 0.01, 0.05, 0.1, 0.2, 0.3, or ranges including and/or spanning the aforementioned values. In several embodiments, after formulation (e.g., at a concentration of 20 mg/mL) and storage in simulated intestinal fluid for a period of at least about 1 hour or about 2 hours (e.g., at 37°C, or under the other testing conditions disclosed elsewhere herein or under the other testing conditions disclosed elsewhere herein), the average particle size of nanoparticles comprising the composition changes by less than or equal to about: 1%, 5%, 10%, 20%, 50%, or ranges including and/or spanning the aforementioned values. In several embodiments, after formulation (e.g., at a concentration of 20 mg/mL) and storage in simulated intestinal fluid for a period of at least about 1 hour, about 2 hours, about 3 hours, or about 4 hours (e.g., at 37°C or under the other testing conditions disclosed elsewhere herein), the PDI of nanoparticles comprising the composition changes by less than or equal to about: 1%, 5%, 10%, 20%, 100%, 150%, or ranges including and/or spanning the aforementioned values. In several embodiments, after formulation (e.g., at a concentration of 20 mg/mL) and storage in simulated intestinal fluid for a period of at least about 1 hour, about 2 hours (e.g., at 37°C or under the other testing conditions disclosed elsewhere herein), the PDI of nanoparticles comprising the composition changes by less than or equal to about: 0.01, 0.05, 0.1, 0.2, 0.3, or ranges including and/or spanning the aforementioned values.
[0215] In several embodiments, the composition particle size remains consistent (a size change of less than or equal to about: 0%, 0.5%, 1%, 2%, 3%, 5%, or ranges including and/or spanning the aforementioned values) for a period of at least about 30 days when stored at room temperature, refrigeration, and up to 40°C. In several embodiments, the active agent (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like) concentration in the composition remains consistent (a loss of less than or equal to about: 0.5%, 1%, 2%, 3%, 5%, or ranges including and/or spanning the aforementioned values) for a period of at least about 30 days, 60 days, 90 days, or 120 days when stored at room temperature, refrigeration, and up to 40°C. In several embodiments, when stored at room temperature, refrigeration, and up to 40°C, the composition is stable (e.g., the particle size or active agent concentration in the nanoparticles remains consistent and/or has a change of less than or equal to about: 0.5%, 1%, 2%, 5%, or ranges including and/or spanning the aforementioned values) for a period of at least about: 2 weeks, 30 days, 2 months, 3 months, 6 months, 9 months, 1 year, or ranges including and/or spanning the aforementioned measures of time.
[0216] In several embodiments, the method of using the nanoparticle composition and/or of treating a subject with the nanoparticle composition includes administering to a subject in need of treatment (e.g., orally, topically, etc.) an effective amount of the composition. In several embodiments, the composition (e.g., delivery system) improves the stability of the active agent (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like) after ingestion where the composition is exposed to the stomach and/or intestines in an aqueous environment with harsh pH conditions. In several embodiments, the bioavailability of the active agent (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like) relative to the initial administered dose is greater than or equal to about: 10%, 20%, 50%, 75%, or ranges including and/or spanning the aforementioned values. In several embodiments, using the disclosed compositions, the oral bioavailability of the active agent (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like ) delivered (as measured using AUC) is higher using an embodiment disclosed herein relative to oral delivery of the active alone. In several embodiments, the oral bioavailability is improved over the active alone by greater than or equal to about: 10%, 50%, 75%, 100%, 200%, or ranges including and/or spanning the aforementioned values.
[0217] In other embodiments, solutions of particles are composed of non-lipid ingredients, such as polymers and/or cyclodextrin. In other embodiments, solutions are cannabinoids, mushrooms, and kratom extracts or powders are prepared without particles.
III. Manufacturing Compositions
[0218] As disclosed elsewhere herein, some embodiments pertain to methods of preparing nanoparticle compositions. In several embodiments, the composition is prepared by adding one or more of an active compound, a lipid source, a surfactant, a co-emulsifier, a preservative, a flavoring agent, or combinations of any of the foregoing to water. In several embodiments, the composition is prepared using high sheer inline mixing (including for example via Silverson). In several embodiments, the composition is prepared using an overhead mixer (such as, for example, a IKA and/or Silverson). In several embodiments, the composition is prepared using high pressure homogenization. In several embodiments, the composition is prepared using microfluidization. In several embodiments, the composition is prepared using sonication. In several embodiments, the composition is prepared using mechanical stirring. In several embodiments, the composition is prepared using coacervation. In several embodiments, the composition is prepared using solvent precipitation. In several embodiments, the composition is prepared using hot melt extrusion (HME) tablet manufacturing. In several embodiments, the composition is prepared using one or more of the techniques or steps described above or elsewhere herein together. In several embodiments, the composition is prepared with methods excluding any one or more of these steps or techniques. [0219] In several embodiments, the nanoparticle compositions herein are lyophilized (e.g., to provide a powder). In several embodiments, where lyophilization is used to prepare a mixed micelle-based powder, one or more lyoprotectant agents may be added. In several embodiments, an individual lyoprotectant agent may be present at a dry wt. % equal to or less than the dry weight of the lipophilic ingredients. In several embodiments, the lyoprotectant agent(s) (collectively or individually) may be present at a dry wt. % equal to or less than about: 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, or ranges including and/or spanning the aforementioned values. In several embodiments, the lyoprotectant agent(s) (collectively or individually) may be present at a wet wt. % of equal to or less than about: 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 30%, or ranges including and/or spanning the aforementioned values. In several embodiments, the lyoprotectant is selected from the group consisting of lactose, dextrose, trehalose, arginine, glycine, histidine, and/or combinations thereof. In several embodiments, the nanoparticle compositions herein are spray dried (e.g., to provide a powder). In several embodiments, the nanoparticle compositions are spray dried and not lyophilized. In some embodiments, the nanoparticle composition is spray dried, fluid bed dried, desiccated, and/or lyophilized.
[0220] In several embodiments, the composition is prepared by forming a lipid-in-oil emulsion. In several embodiments, an oil-in-water emulsion can be prepared without the use of organic solvents as shown in FIG. 1 (e.g., in an organic solvent-free method). In several embodiments, solid ingredients 101 are added and dissolved into liquid ingredients 102. In several embodiments, the lipid (e.g., phosphatidylcholine, including phosphatidylcholine of any purity disclosed herein) can be added with mixing. In several embodiments, when a well dispersed lipid phase is formed after mixing, the addition of water 103 (e.g., having a temperature of equal to or at least about: 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 80°C, or ranges including and/or spanning the aforementioned values) and additional mixing 104 achieves an oil-in-water emulsion 105. In several embodiments, the oil-in-water emulsion is then subject to high-shear mixing to form nanoparticle compositions. In several embodiments, high-shear mixing 106 is performed using a high shear dispersion unit or an in-line mixer can be used to prepare the emulsions. In several embodiments, the particles can be made by solvent evaporation and/or solvent precipitation. In several embodiments, high sheer mixing is not required.
[0221] In several embodiments, as shown in FIG. 2, the lipid-in-oil emulsion is formed by dissolving ingredients 201, such as, one or more of a lipid (e.g., phosphatidylcholine, including phosphatidylcholine or any purity disclosed herein), a surfactant, one or more active compounds, and/or a preservative in a solvent 202. In several embodiments, the solvent can include one or more organic solvents, including but not limited to, ethanol, chloroform, and/or ethyl acetate. In several embodiments, the solvents are class II solvents, class III solvents (e.g., at least class II and/or class III by the ICH Q3C standard), or mixtures thereof. In several embodiments, the solution of ingredients and solvent is dried 203. In several embodiments, after drying, the ingredients are provided as lipids and or liposomes as a thin film. In several embodiments, the solvent is removed from the composition by subjecting the solution to heat under vacuum to promote evaporation. In several embodiments, the film may further be dried under nitrogen gas. In several embodiments, the lipid film is hydrated 205 with warm aqueous solution to form an oil-in-water emulsion. In several embodiments, high-shear mixing is performed 206 using a high shear dispersion unit or an in-line mixer can be used to prepare the emulsions.
[0222] In some embodiments, the dried composition, comprising the nanoparticle, is reconstituted. In some embodiments, the nanoparticle composition, such as the percentage and/or concentration of the types of nanoparticles, may change when dried. In some embodiments, the nanoparticle composition, such as the percentage and/or concentration of the types of nanoparticles, may change when reconstituted. In some embodiments, the nanoparticle composition, such as the percentage and/or concentration of the types of nanoparticles, may not change when dried. In some embodiments, the nanoparticle composition, such as the percentage and/or concentration of the types of nanoparticles, may not change when reconstituted.
[0223] In several embodiments, as disclosed elsewhere herein, the lipid-in-water emulsion is subject to high pressure homogenization using a microfluidizer. In several embodiments, high sheer mixing can be used to reduce the particle size. In several embodiments, the oil-in- water emulsion is processed to a nanoparticle (e.g., about 20 to about 500 nm, etc.) using the microfluidizer or other high sheer processes. In several embodiments, the oil-in-water emulsion is processed to a nanoparticle having a size from about 80 nm to 180 nm in diameter or about 100 run to about 150 nm in diameter. In several embodiments, high sheer mixing is not used.
[0224] In several embodiments, the lipid-in-water emulsion is passed through the microfluidizer a plurality of times (e.g., equal to or at least 1 time, 2 times, 3 times, 4 times, 5 times, 10 times, or ranges including and/or spanning the aforementioned values). In several embodiments, the emulsion is passed through the microfluidizer at a pressure of equal to or less than about: 5,000 PSI, 15,000 PSI, 20,000 PSI, 25,000 PSI, 30,000 PSI, or ranges including and/or spanning the aforementioned values. In several embodiments, the emulsion is passed through the microfluidizer at a temperature of equal to or at least about: 30°C, 40°C, 50°C, 65°C, 80°C, or ranges including and/or spanning the aforementioned values. In several embodiments, the emulsion is passed through the microfluidizer at least about room temperature (e.g., about 20°C or about 25°C) and/or without any heating and/or temperature control. In several embodiments, the emulsion is passed through the microfluidizer at a temperature of equal to or less than about 80°C. In several embodiments, the microfluidizer includes an interaction chamber consisting of 75 pm to 200 pm pore sizes and the emulsion is passed through this chamber. In several embodiments, the pore size of the microfluidizer are less than or equal to about: 75 pm, 100 pm, 150 pm, 200 pm, 250 pm, 300 pm, or ranges including and/or spanning the aforementioned values. In several embodiments, the nanoparticle composition is prepared by high shear mixing, sonication, or extrusion.
[0225] In several embodiments, after preparation, the nanoparticle composition is characterized by an ability to pass through a 0.2 pm filter while preserving the nanoparticle structure (e.g., a change in average nanoparticle size of no greater than 10 nm, 20 nm, or 30 nm). In several embodiments, after passage through a 0.2 pm there is a change in average diameter of the particles of equal to or at less than about: 1%, 5%, 10%, 20%, or ranges including and/or spanning the aforementioned values. In several embodiments, after passage through a 0.2 pm there is a change in PDI of the particles of equal to or at less than about: 1%, 5%, 10%, 20%, or ranges including and/or spanning the aforementioned values.
[0226] In several embodiments, as disclosed elsewhere herein, the active nanoparticle composition imparts solubility to hydrophobic active agents (e.g., kratom, CBD, other phytocannabinoids, etc.) in a delivery system that is easily dispersible in aqueous solutions. For example, CBD oils do not disperse well in aqueous solutions and have poor oral absorption. CBD particle formulations made using methods other than those disclosed herein have inconsistent particle size and may not be stable with storage over time. [0227] Some embodiments, as disclosed elsewhere herein, pertain to a method of manufacturing a lipid-based particle composition. In some embodiments, one or more active compounds (e.g., CBD) is mixed with one or more lipophilic components of the composition to provide a solution. In some embodiments, one or more lipid components (including those that are not phospholipids) are added. In some embodiments, one or more sterols are added. In some embodiments, one or more phospholipids are added. In some embodiments, one or more flavoring and/or preservatives are added. In some embodiments, water is added. In some embodiments, the lipophilic ingredients are combined and the hydrophilic ingredients are combined separately. In some embodiments the lipophilic ingredients are then added to the hydrophilic ingredients. In some embodiments, the solution is passed through a microfluidizer and/or a high sheer homogenizer. In some embodiments, the process affords a particle composition.
[0228] In several embodiments, advantageously, the nanoparticle delivery systems (comprising e.g., a kava extract, kana extract, kratom extract, psilocybin mushroom extract, a cannabinoid, and/or combinations of any of the foregoing) disclosed herein are reproducibly manufacturable.
[0229] In several embodiments, the active compound, including for example kratom, kanna, kava, mushrooms, and/or Cannabis, may be preprocessed. In several embodiments, pre-processing allows greater encapsulation efficiency and stability by precipitating “other” plant material away from extracts. In several embodiments, pre-processing may provide enhanced consumer experience due to less impurity/non-actives in the formulation. In several embodiments, “salt” byproducts are removed directly/indirectly by various extraction techniques. In several embodiments, pre-processing techniques include ethanol and co-solvent precipitation, filtration, activated charcoal soaking + filtration; chromatography, etc. By way of removing solvent such as ethanol, rotary evaporation may be used. Other forms of solvent removal are possible. Other forms of removing active and non-active plant material are disclosed elsewhere herein (including solvent extraction, acid/base titration, CO2 extraction (both supercritical and non), cryogenic ethanol extraction, etc. In several embodiments, preprocessing (prior to use in the composition) allows a formulator to use any kind of kratom extract or biomass regardless of prior extraction techniques. Extract and formulations are incredibly sensitive to presence of salt and pH.
[0230] In several embodiments, the preprocessing includes one or more of the following steps. Kratom raw material extract (e.g., an unenriched extract) is isolated from kratom leaves (e.g., kratom powder). In several embodiments, as extracted, the unenriched kratom extract comprises “salt” byproducts of kratom actives. In several embodiments, free base actives are prepared by adding a base (e.g., a sodium or potassium carbonate, bicarbonate, etc.). Upon preparation of the free bases, remaining salts (and other insoluble) are precipitated by adding solvent. In several embodiments, remaining solids are removed directly /indirectly by filtration (or other various solid removal techniques disclosed herein). In several embodiments, preprocessing techniques include ethanol and co- solvent precipitation, filtration, activated charcoal soaking + filtration; chromatography, etc. By way of removing solvent (such as ethanol), rotary evaporation may be used. Other forms of solvent removal are possible. Other forms of removing active and non-active plant material are disclosed elsewhere herein (including solvent extraction, acid/base titration, CO2 extraction (both supercritical and non), cryogenic ethanol extraction, etc. In several embodiments, pre-processing (prior to use in the composition) allows a formulator to use any kind of kratom extract or biomass regardless of prior extraction techniques. In several embodiments, extract and formulations are incredibly sensitive to presence of salt and pH. Thus preprocessing may lead to higher stability and/or yield of formulations.
[0231] In several embodiments, the preprocessing includes one or more of the following steps. In several embodiments, dissolve (or suspend) kratom extract (and/or leaf powder) in organic nonpolar or polar solvent (e.g., hexane, chloroform, dichloromethane, and ethanol). In several embodiments, perform crystallization or precipitation. In several embodiments, dissolve kratom extract (and/or leaf powder) in organic solvent (e.g., ethanol). In several embodiments, incubate in cold storage (-20C, -80C, or 2-8C) for 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7 or more days. In several embodiments, allow salt (and/or “other” constituents) species to precipitate. In several embodiments, the salt present in the kratom extract is an alkaloid salt. In several embodiments, the alkaloid is alkaloid citrate, alkaloid acetate, alkaloid chloride, alkaloid sodium salt e.g. gluconate, etc. (depending on its extraction technique). In several embodiments, prior to precipitation, the solution comprises one or more of the following salts (e.g., of impurities), the active ingredients (and/or active ingredients of salts), and various other insolubles, etc. In several embodiments, the solution is decanted or filtered to remove solids (e.g., the insoluble including salts). In several embodiments, the mother liquor is suspended and/or the kratom extract is solubilized in buffer such as carbonate or sodium at various pH ranges (titration optional) including 5-6, 6-7, 7-8, 8-9, 9-10, 11-12 (e.g., to convert into free base bioactive ingredients such as alkaloids). In several embodiments, extraction free base with a polar or non-polar solvent like (e.g., hexane, chloroform, dichloromethane, and ethanol). In several embodiments, filtration, decant, and/or isolation technique. In several embodiments, evaporate (e.g., rotary evaporation) to remove precipitation solvent. In several embodiments, the solvent is incubated in cold-chain storage (-20C, -80C, or 2-8C) prior to filtration and solvent evaporation.
[0232] Other appropriate methods of salt separation and/or purification during preprocessing may include one or more of size exclusion, ion exchanger in presence of neutral organic compounds may also be a suitability method of purifications, evaporation and distillation membrane extraction, liquid-liquid extraction, solid phase extraction, immobilized liquid extraction, sorptive extraction, charged resin, and/or gel filtration. In several embodiments, pharmaceutical acceptable applications may also be used such as high purity filter media such as diatomite filter aids. Example may include Celpure®, AW Celite®, Harborlite®, etc. In several embodiments, dialysis methods may also be used. In several embodiments, activated charcoal is used to treat a solution comprising the extract. In several embodiments, acidic conditions may be used for preprocessing. In several embodiments, polar, aprotic solvent like DMSO may also be used to solubilize hydrophobic substances like alkaloids during preprocessing. In several embodiments, DMSO and may be acidified or basified to maximize solubility and stability of alkaloids and other compounds.
[0233] One or more benefits of the preprocessing step may include better formulations, better encapsulation, purer compositions, industrial isolation for raw material, certified reference material/standards, manufacturer of finished intermediate and/or raw materials, or other benefits.
[0234] In several embodiments, the formulation is provided as a suspension type (e.g., to formulate kratom leaf powder formulations). In several embodiments, formulations containing kratom leaf powder will provide greater regulatory certainty if extracts are considered controlled substance and/or drugs. In several embodiments, formulating with leaf powder may create a suspensions. In several embodiments, pre-processing may also be beneficial. However, in not all embodiments is preprocessing used.
IV. Administration of Compositions
[0235] Certain embodiments of the disclosure relate to compositions and methods of administering the compositions.
[0236] The compositions, which may comprise the nanoparticles and active compounds of the disclosure, may be administered via a route of administration. In some embodiments, the composition is administered by more than one route of administration. In some embodiments, the composition is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. The appropriate dosage may be determined based on the type of disease to be treated, severity and course of the disease, the clinical condition of the individual, the individual's clinical history and response to the treatment, and the discretion of the attending physician.
[0237] In some embodiments, the composition is administered at a dose of between 1 mg/kg and 5000 mg/kg. In some embodiments, the composition is administered at a dose of at least, at most, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,
48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,
73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,
98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108, 109, 110, 111, 112, 113, 114, 115, 116,
117, 118, 119, 120, 121, 122, 123, 124, 125, 126 , 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534,
535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553,
554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572,
600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100,
2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, or 5000 mg/kg.
[0238] The quantity to be administered, both according to number of treatments and dose, depends on the treatment effect desired. An effective dose is understood to refer to an amount necessary to achieve a particular effect. In the practice in certain embodiments, it is contemplated that doses in the range from 10 mg/kg to 200 mg/kg can affect the protective capability of these agents. Thus, it is contemplated that doses include doses of about 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, and 200, 300, 400, 500, 1000 pg/kg, mg/kg, pg/day, or mg/day or any range derivable therein. Furthermore, such doses can be administered at multiple times during a day, and/or on multiple days, weeks, or months.
[0239] In certain embodiments, the effective dose of the composition is one which can provide a sample level of the active compound at a concentration of about 1 pM to 150 pM. In another embodiment, the effective dose provides a sample level of about 4 pM to 100 pM.; or about 1 pM to 100 pM; or about 1 pM to 50 pM; or about 1 pM to 40 pM; or about 1 pM to 30 pM; or about 1 pM to 20 pM; or about 1 pM to 10 pM; or about 10 pM to 150 pM; or about 10 pM to 100 pM; or about 10 pM to 50 pM; or about 25 pM to 150 pM; or about 25 pM to 100 pM; or about 25 pM to 50 pM; or about 50 pM to 150 pM; or about 50 pM to 100 pM (or any range derivable therein). In other embodiments, the dose can provide the following sample level of the agent that results from an active agent being administered to a subject: about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,
19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,
44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,
69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93,
94, 95, 96, 97, 98, 99, or 100 pM or any range derivable therein. The sample level may be analyzed from any biological sample, such as a blood sample, urine sample, skin sample, saliva sample, or the like. In certain embodiments, the active agent that is administered to a subject is metabolized in the body to a metabolized active agent, in which case the blood levels may refer to the amount of that agent. Alternatively, to the extent the active agent is not metabolized by a subject, the blood levels discussed herein may refer to the unmetabolized active agent.
[0240] Precise amounts of the active composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting dose include physical and clinical state of the patient, the route of administration, the intended goal of treatment (alleviation of symptoms versus cure) and the potency, stability and toxicity of the particular therapeutic substance or other therapies a subject may be undergoing.
[0241] It will be understood by those skilled in the art and made aware that dosage units of pg/kg or mg/kg of body weight can be converted and expressed in comparable concentration units of pg/mL or mM. It is also understood that uptake is species and organ/tissue dependent. The applicable conversion factors and physiological assumptions to be made concerning uptake and concentration measurement are well-known and would permit those of skill in the art to convert one concentration measurement to another and make reasonable comparisons and conclusions regarding the doses, efficacies and results described herein.
[0242] In certain instances, it will be desirable to have multiple administrations of the composition, e.g., 2, 3, 4, 5, 6 or more administrations. The administrations can be at 1, 2, 3, 4, 5, 6, 7, 8, to 5, 6, 7, 8, 9, 10, 11, or 12 week intervals, including all ranges there between.
[0243] The compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, subcutaneous, or intraperitoneal routes. Typically, such compositions can be prepared as either liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and, the preparations can also be emulsified.
[0244] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including, for example, aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In certain embodiments, the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
[0245] Administration of the compositions will typically be via any common route. This includes, but is not limited to oral, or intravenous administration. Alternatively, administration may be by orthotopic, intradermal, subcutaneous, intramuscular, intraperitoneal, or intranasal administration. Such compositions would normally be administered as pharmaceutically acceptable compositions that include physiologically acceptable carriers, buffers or other excipients.
[0246] Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically or prophylactic ally effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above.
[0247] As disclosed elsewhere herein, some embodiments pertain to methods of treating a subject. In several embodiments, the method of treating comprises selecting patient for treatment. In several embodiments, the method of threating comprises administering to the patient an effective amount of a formulation comprising a nanoparticle composition comprising an active agent (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like).
[0248] In several embodiments, compositions as described herein may be used to induce at least one effect, e.g. therapeutic effect, that may be associated with at least one active agent (e.g., pharmaceuticals, nutraceuticals, and the like), which is capable of inducing, enhancing, arresting or diminishing at least one effect, by way of treatment or prevention of unwanted conditions or diseases in a subject. As disclosed elsewhere herein, the at least one active agent may be selected amongst therapeutic agents, such as agents capable of inducing or modulating a therapeutic effect when administered in a therapeutically effective amount.
[0249] In several embodiments, the compositions disclosed herein (e.g., mixed nanoparticle compositions including a kava extract, kana extract, kratom extract, psilocybin mushroom extract, a cannabinoid, and/or combinations of any of the foregoing) can be used in methods of treatment and can be administered to a subject having a condition to be treated. In several embodiments, the subject is treated by administering an effective amount of a composition as disclosed herein to the subject.
[0250] In several embodiments, the disease or condition to be treated via administration of a composition as disclosed herein may include one or more of opioid withdrawal, pain relief, anxiety relief, depression, insomnia, inflammation, fever, fatigue, muscle aches, etc. In several embodiments, the nanoparticle composition (e.g., those including one or more active agents) is provided for use in treating a condition selected from pain associated disorders (as an analgesic), inflammatory disorders and conditions (as anti-inflammatory), appetite suppression or stimulation (as anoretic or stimulant), symptoms of vomiting and nausea (as antiemetic), intestine and bowl disorders, disorders and conditions associated with anxiety (as anxiolytic), disorders and conditions associated with psychosis (as antipsychotic), disorders and conditions associated with seizures and/or convulsions (as antiepileptic or antispasmodic), sleep disorders and conditions (as anti-insomniac), disorders and conditions which require treatment by immunosuppression, disorders and conditions associated with elevated blood glucose levels (as antidiabetic), disorders and conditions associated with nerve system degradation (as neuroprotectant), inflammatory skin disorders and conditions (such as psoriasis), disorders and conditions associated with artery blockage (as anti-ischemic), disorders and conditions associated with bacterial infections, disorders and conditions associated with fungal infections, proliferative disorders and conditions, disorders and conditions associated with inhibited bone growth, post trauma disorders, and others.
[0251] In several embodiments, the nanoparticle composition (e.g., those comprising cannabinoids, such as CBD, non-cannabinoids, and combinations thereof as disclosed elsewhere herein) is provided for use in a method of treating a subject suffering from a condition selected from pain associated disorders, inflammatory disorders and conditions, symptoms of vomiting and nausea, intestine and bowl disorders, disorders and conditions associated with anxiety, disorders and conditions associated with psychosis, disorders and conditions associated with seizures and/or convulsions, sleep disorders and conditions, disorders and conditions which require treatment by immunosuppression, disorders and conditions associated with elevated blood glucose levels, disorders and conditions associated with nerve system degradation, inflammatory skin disorders and conditions, disorders and conditions associated with artery blockage, disorders and conditions associated with bacterial infections, disorders and conditions associated with fungal infections, proliferative disorders and conditions, and disorders and conditions associated with inhibited bone growth, post trauma disorders and others, a patient in need of appetite suppression or stimulation. In several embodiments, the method comprises administering to the subject an effective amount of a composition of this disclosure.
[0252] In several embodiments, the nanoparticle compositions (e.g., those including a kava extract, kana extract, kratom extract, psilocybin mushroom extract, a cannabinoid, and/or combinations of any of the foregoing) described herein may be used for inducing, enhancing, arresting or diminishing at least one effect, by way of treatment or prevention of unwanted conditions or diseases in a subject. The active agent (substance, molecule, element, compound, entity, or a combination thereof) may be selected amongst therapeutic agents, such as agents capable of inducing or modulating a therapeutic effect when administered in a therapeutically effective amount, and non-therapeutic agents, such as agents which by themselves do not induce or modulate a therapeutic effect but which may endow the pharmaceutical composition with a selected desired characteristic.
[0253] In several embodiments, a nanoparticle compositions as disclosed herein (e.g., a pharmaceutical composition comprising a kava extract, kana extract, kratom extract, psilocybin mushroom extract, a cannabinoid, and/or combinations of any of the foregoing) may be selected to treat, prevent or ameliorate any pathology or condition. In several embodiments, administering of a therapeutic amount of the composition or system described herein, whether in a concentrate form or in a diluted formulation form, is effective to ameliorate undesired symptoms associated with a disease, to prevent the manifestation of such symptoms before they occur, to slow down the progression of the disease, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the disease, to delay the onset of said progressive stage, to lessen the severity or cure the disease, to improve survival rate or more rapid recovery, or to prevent the disease from occurring or a combination of two or more of the above.
[0254] In several embodiments, as mentioned elsewhere herein, the compositions disclosed herein, may be provided in a number of different forms for administration and/or ingestion. In several embodiments, including when provided in a ready-to-drink beverage, the compositions are stable during ozonation sterilization, UV sterilization, heat sterilization, filtration sterilization, and/or gamma irradiation during beverage preparation and packaging. In several embodiments, the particle size and/or PDI after sterilization (e.g., exposure to techniques that allow sterilization of the composition) varies by less than or equal to about: 1%, 5%, 10%, 20%, 30%, or ranges including and/or spanning the aforementioned values. In several embodiments, the active agent (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like) concentration after sterilization (e.g., exposure to techniques that allow sterilization of the composition) drops by less than or equal to about: 1%, 5%, 10%, 15%, or ranges including and/or spanning the aforementioned values. In several embodiments, including after stabilization, the beverages comprising nanoparticle compositions have a shelf life of equal to or greater than 6 months, 12 months, 14 months, 16 months, 18 months, 19 months, 24 months, or ranges including and/or spanning the aforementioned values.
[0255] In several embodiments, the compositions are provided in a sterilized beverage. In several embodiments, the sterilized beverage may be a cold beverage (e.g., juices, sports drinks, energy drinks, protein drinks, nutritional drinks, sodas, etc.). In several embodiments, the cold beverage may be a carbonated beverage. In several embodiments, the cold beverage may be an alcoholic beverage. In several embodiments, the compositions may be provided in hot beverages (e.g., coffee, tea, etc.). In several embodiments, after a 30 minute period in a hot beverage, the particle size and/or PDI varies by less than or equal to about: 1%, 5%, 10%, 20%, 30%, or ranges including and/or spanning the aforementioned values. In several embodiments, after a 30 minute period in a hot beverage, the active agent (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like) concentration drops by less than or equal to about: 1%, 5%, 10%, 15%, or ranges including and/or spanning the aforementioned values.
[0256] Several embodiments also encompass methods for administering the disclosed compositions. Multiple techniques of administering the nanoparticle compositions as disclosed herein exist including, but not limited to, oral, sublingual, buccal, rectal, topical, vaginal, aerosol, injection and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injections. In several embodiments, administration is performed through oral pathways, which administration includes administration in an emulsion, capsule, tablet, film, chewing gum, suppository, granule, pellet, spray, syrup, or other such forms. As further examples of such modes of administration and as further disclosure of modes of administration, disclosed herein are various methods for administration of the disclosed compositions including modes of administration through intraocular, intranasal, and intraauricular pathways. In several embodiments, oral formulations may comprise of DMSO and NMP.
[0257] In several embodiments, the nanoparticles (or compositions comprising them) may be used to deliver extracts, combination extracts (e.g., combinations of one or more kratom extracts, kanna extracts, kava extracts, mushroom extracts, Cannabis extracts), additional actives, terpenes, and/or combinations thereof (as disclosed elsewhere herein) to a biomass. Thus, the biomass may be fortified with extracts additional terpenes, and/or combinations thereof (as disclosed elsewhere herein). For example, a kratom biomass may be supplemented with a kratom extract. A hemp biomass may be supplemented with other cannabinoids, noncannabinoid therapeutics (including kratom extracts, kanna extracts, etc.), and/or combinations of any one of the foregoing. In several embodiments, the fortification is accomplished by spraying a liquid solution onto the biomass (or other consumer product). In several embodiments, by drying to completeness, a product that is fortified with an active is provided. In several embodiments, these fortifying therapeutic agents can be used to enhance health benefits of the consumer product (e.g., biomass), to change the flavor profile of the consumer product (e.g., biomass), to change the physiological effects of the consumer product (e.g., biomass), and/or to provide other benefits. [0258] In several embodiments, where a topical is provided, the topical formulation may include SLM2026 (skin lipid matrix including Aqua (Water), Caprylic/Capric Triglyceride, Hydrogenated Phosphatidylcholine, Pentylene Glycol, Glycerin, Butyrospermum Parkii (Shea) Butter, Squalane, Ceramide NP), SLM2038 (skin lipid matrix including Aqua (and) Caprylic/Capric Triglyceride (and) Hydrogenated Phosphatidylcholine (and) Pentylene Glycol (and) Glycerin (and) Butyrospermum Parkii Butter (and) Squalane), or other formulated emulsion systems. In several embodiments, where a topical is provided, topical permeation enhancers may be included and may be selected from, but not inclusive of, the following: dimethyl sulfoxide, dimethyl sulfone, ethanol, propylene glycol, dimethyl isosorbide, polyvinyl alcohol, CapryolTM 90, Labrafil Ml 944 CS, Labrasol, Labrasol ALF, LauroglycolT M90, Transcutol HP, Capmul S12L, Campul PG-23 EP/NF, Campul PG-8 NF. The topical may include one or more of Lipoid’s Skin Lipid Matrix 2026 technology, lipid/oil based ingredients or oil soluble ingredients, and includes Captex 170 EP as a skin permeation enhancer, argan oil, menthol, arnica oil, camphor, grapefruit seed oil, For example, dimethyl sulfoxide, dimethyl isosorbide, topical analgesics such as lidocaine, wintergreen oil, and terpenes such as guaiacol. In several embodiments, any one or more of these ingredients is present in the topical composition at a dry wt. % of equal to or less than about: 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, or ranges including and/or spanning the aforementioned values. In several embodiments, any one or more of these ingredients is present in the topical at a wet wt. % of equal to or at least about: 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 30%, or ranges including and/or spanning the aforementioned values.
[0259] In several embodiments, the nanoparticle compositions disclosed herein can be in admixture with a suitable carrier, diluent, or excipient such as sterile water, physiological saline, glucose, or the like, and can contain auxiliary substances such as wetting or emulsifying agents, pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired. See, e.g., “Remington: The Science and Practice of Pharmacy”, Lippincott Williams & Wilkins; 20th edition (June 1, 2003) and “Remington’s Pharmaceutical Sciences,” Mack Pub. Co.; 18th and 19th editions (December 1985, and June 1990, respectively). In several embodiments, these additional agents are not added. Such preparations can include liposomes, microemulsions, micelles, and/or unilamellar or multilamellar vesicles.
[0260] In several embodiments, the nanoparticle composition is configured for oral ingestion. In several embodiments, the nanoparticle formulation is provided as a drinkable solution, such as a beverage, elixir, tonic, or the like. In several embodiments, the nanoparticle formulation is provided as a powder that can be constituted in a liquid (e.g., water, juice, coffee) and ingested orally.
[0261] For administration (e.g., oral), the nanoparticle compositions can be provided as a tablet, capsule, pressed tablet, aqueous or oil suspension, dispersible powder or granule (as a food additive, drink additive, etc.), emulsion, hard or soft capsule, syrup or elixir. Compositions intended for oral use can include one or more of the following agents: sweeteners, flavoring agents, coloring agents and preservatives. In several embodiments, the compositions are provided in ready-to-drink formulations, such as protein drinks, energy drinks, sodas, juices, coffees, etc.
[0262] Formulations for oral use can also be provided as gelatin capsules. In several embodiments, a powder composition as disclosed herein is added to the gelatin capsule. In several embodiments, the active ingredient(s) in the nanoparticle compositions disclosed herein are mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as water. Stabilizers and microspheres formulated for oral administration can also be used. Capsules can include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
[0263] In capsule formulations, trehalose can be added. In several embodiments, trehalose is present in the nanoparticle composition at a dry wt. % of equal to or less than about: 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, or ranges including and/or spanning the aforementioned values. In several embodiments, the trehalose is present in the composition at a wet wt. % of equal to or at least about: 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 30%, or ranges including and/or spanning the aforementioned values.
[0264] Dry powder formulations or liquid embodiments may also be used in a variety of consumer products. For example, in some embodiments, dry powders can be added (e.g., scooped, from a packet, squirted from a dispenser, etc.) into any consumer product (e.g., a hot or cold beverage).
[0265] In several embodiments, liquid solutions or powdered nanoparticle formulations can be coated onto and/or added into a consumer product (e.g., sprayed and/or squirted from a dispenser, through dipping, soaking, rolling, dusting, etc.). In several embodiments, the consumer product is a food product (e.g., candies, lollipops, edibles, food, ingestible, buccal adhesives, or others). In several embodiments, the consumer product is a biomass. In several embodiments, the biomass is a hemp biomass (e.g., the buds and/or nugs of the hemp plant), a marijuana biomass (e.g., the buds and/or nugs of the marijuana plant), a mushroom biomass (plant or powdered plant, cordyceps, lion mane, reishi, chaga gano, psilocybin, or combinations thereof), and/or kratom biomass (plant or powdered plant, Maeng da, Indo, Bali/red vien, Green Malay, or combinations thereof). In several embodiments, the biomass is a moonrock (e.g., a marijuana nug dipped in or sprayed with concentrate (e.g., solvent extracted marijuana) and/or hash oil; a moon rock may be further rolled in and/or coated with kief). In several embodiments, the biomass is a rosin. In several embodiments, the biomass is hash. In several embodiments, the biomass is bubble hash. Bubble hash is a cannabis concentrate comprising trichomes, or resinous glands, that have been separated from the plant (e.g., using ice water, agitation, and a sieve).
[0266] In several embodiments, the nanoparticles (e.g., of the compositions disclosed herein) supplement and/or fortify the consumer product (e.g., biomass) with an active agent from the nanoparticles. In several embodiments, the active agent is delivered to the user in a greater quantity than would be achieved using (e.g., consuming) the biomass alone.
[0267] In several embodiments, the nanoparticle compositions may be used to improve a condition. In several embodiments, an improvement in a condition can be a reduction in disease symptoms or manifestations (e.g., opioid withdrawal symptoms, pain, anxiety & stress, mood disorders (e.g., depression), seizures, malaise, inflammation, insomnia, etc.). Actual dosage levels of active ingredients in an active composition of the presently disclosed subject matter can be varied so as to administer an amount of the active compound(s) that is effective to achieve the desired response for a particular subject and/or application. The selected dosage level will depend upon a variety of factors including, but not limited to, the activity of the composition, composition, route of administration, combination with other drugs or treatments, severity of the condition being treated, and the physical condition and prior medical history of the subject being treated. In several embodiments, a minimal dose is administered, and dose is escalated in the absence of dose-limiting toxicity to a minimally effective amount. Determination and adjustment of an effective dose, as well as evaluation of when and how to make such adjustments, are contemplated herein.
[0268] In several embodiments, surprisingly, an aqueous nanoparticle composition comprising an active agent (e.g., pharmaceuticals, nutraceuticals, cosmetics, pigments, flavorings, and the like) as disclosed herein may be administered using an atomizer. In several embodiments, an atomizer nozzles are used in oral spray, such as the binaca spray. In several embodiments, an atomizer nozzle is used in a nasal spray. This result is surprising, as the extracts disclosed herein would be typically be understood to clog atomizer nozzles. [0269] In several embodiments, as disclosed elsewhere herein, the nanoparticles or compositions may be used as coatings. In several embodiments, coating is performed with an aqueous or solvent solution of the nanoparticles. For example, the solution may be sprayed (e.g., via a spray nozzle, atomizer, etc.) or otherwise coated (e.g., dip-coated, etc.) onto the biomass hemp biomass, marijuana biomass, mushroom biomass, kratom biomass, kava biomass, kanna biomass, or combinations thereof. In several embodiments, pharmaceutical coating equipment (e.g., that used to coat tablets, beads, drug layered/coated films) is used to coat the biomass. In several embodiments, fluid bed technology, film bed technology, dry powder laying technology, and/or combinations thereof are used to coat the biomass. In several embodiments, film coating is used.
[0270] In several embodiments, prior to coating with a liquid solution of nanoparticles, the biomass is dried completely. Then, after coating, the fortified biomass is dried. In other implementations, freshly harvested biomass is solution coated (e.g., prior to drying). After coating and/or spraying with the lipid particles, the biomass can then be dried together with the nanoparticles to provide a fortified biomass.
[0271] In several embodiments, as disclosed elsewhere herein, a powder can be used to coat the biomass. In several embodiments, a powder nanoparticle formulation is dusted or coated onto either dried or freshly harvested biomass. Additional drying may be performed to afford a consumable fortified product. In several embodiments, where the biomass is dried prior to coating with a powder nanoparticle, an additional drying step may optionally be performed (though it may not be required). In several embodiments, the dried fortified biomass is suitable for use by a user. In several embodiments, the powdered biomass of one plant may be used to coat the biomass of another plant (e.g., kanna on a kratom biomass, kratom on hemp biomass, kratom on kanna biomass, etc.).
[0272] In several embodiments, the fortified biomass is further processed prior to use (e.g., in dried or undried form). In several embodiments, milling is used to reduce the size of the coated biomass particles. In several embodiments, the milling is a two stage process with a first course milling and then a fine milling. In some embodiment, after milling (dry or wet) the average particle size of the fortified biomass is such that greater than 50% pass through screen having a mesh size of less than or equal to 100, 150, 200, or ranges spanning and/or including the aforementioned values. In some embodiment, after milling (dry or wet) the average particle size of the fortified biomass is less than or equal to about: 1000 pm, 500 pm, 200 pm, or ranges including and/or spanning the aforementioned values. In several embodiments, after drying and/or milling, the fortified biomass is suitable for delivery to a user. [0273] In several embodiments, the biomass is smoked or vaporized and inhaled where active agents from the biomass (including the fortifying agents) are delivered as smoke or vapor to the lungs. In several embodiments, the fortified biomass is suitable for delivery to a user via the gastrointestinal tract (e.g., as an edible, a food ingredient, a gummy, a coated candy, etc.). In several embodiments, as disclosed elsewhere herein, coatings can be applied to candies, lollipops, edibles, food, ingestible, buccal adhesives, or others.
[0274] In several embodiments, the lipid particle formulation, can be remote loaded with active agents (kratom extracts, cannabinoids, non-cannabinoid therapeutics, terpenes, etc.). In several embodiments, a liquid formulation of lipid particles is adding to an active agent. In several embodiments, the active agent incorporates into the particles by hydrophobic/hydrophilic interactions, electrostatic interactions, etc. In several embodiments, a remote loaded product could be coated onto biomass (as disclosed above), dried, and/or milled to provide a fortified, finished product. In several embodiments, the lipid particle can be provided with or without an active agent inside prior to remote loading. Then, other active agents (cannabinoids, non-cannabinoid actives, etc.) can be loaded into that particle through remote loading. In several embodiments, the remote loaded active is THC. Advantageously, this allows the lipid particles to be transported (e.g., across state lines or through territories) even through jurisdictions where some cannabinoids (e.g., d9-THC) are not legal. Once the lipid particle reaches a state where the therapeutic agent is legal, the therapeutic agent can be remote loaded and used to, for example, fortify biomass (or otherwise be delivered to a user). [0275] For oral administration, the pharmaceutical lipid-based particle compositions can be provided as a tablet, aqueous or oil suspension, dispersible powder or granule (as a food additive, drink additive, etc.), emulsion, hard or soft capsule, syrup or elixir. Compositions intended for oral use can include one or more of the following agents: sweeteners, flavoring agents, coloring agents and preservatives. Formulations for oral use can also be provided as gelatin capsules. In some embodiments, a powder composition as disclosed herein is added to the gelatin capsule. In some embodiments, the active ingredient(s) in the nanoparticle compositions disclosed herein are mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as water. Stabilizers and microspheres formulated for oral administration can also be used. Capsules can include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. [0276] In several embodiments, liquid formulations can be added measured and poured into any consumer product. In several embodiments, the consumer product can include one or more alcoholic beverages, milks (dairy, but also nuts “milks” such as almond juice, etc.), coffee, sodas, tea, fermented beverages, wines, nutritional supplements, smoothies, simple water, sports drinks, sparkling water, or the like. In several embodiments, the consumer product can include one or more eye drops, mouth wash, lotions/creams/serums, lip balms, hair care products, deodorant, nasal solutions, enema solutions, liquid soaps, solid soaps, or the like. In several embodiments, the consumer product can include one or more food products. In several embodiments, the consumer product can include desserts. In several embodiments, the consumer product can include single serving products of multi-serving products (e.g., family size). In several embodiments, the consumer product can include one or more dried products (e.g., flour, coffee creamer, protein shakes, nutritional supplements, etc.). In several embodiments, these dried products can be configured to be reconstituted for use. In several embodiments, the consumer product can include one or more the dried product can be added to other dietary supplements (e.g., multivitamins, gummies, etc.).
[0277] Some embodiments also encompass methods for making (as disclosed elsewhere herein) and for administering the disclosed compositions. Multiple techniques of administering the lipid-based particle compositions as disclosed herein exist including, but not limited to, oral, rectal, topical, aerosol, injection and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. In some embodiments, administration is performed through oral pathways, which administration includes administration in an emulsion, capsule, tablet, film, chewing gum, suppository, granule, pellet, spray, syrup, or other such forms. As further examples of such modes of administration and as further disclosure of modes of administration, disclosed herein are various methods for administration of the disclosed compositions including modes of administration through intraocular, intranasal, and intraauricular pathways. In some embodiments, where a topical is provided, topical permeation enhancers may be included and may be selected from, but not inclusive of, the following: dimethyl sulfoxide, dimethyl sulfone, ethanol, propylene glycol, dimethyl isosorbide, polyvinyl alcohol, CapryolTM 90, Labrafil Ml 944 CS, Labrasol, Labrasol ALF, LauroglycolT M90, Transcutol HP, Capmul S12L, Campul PG-23 EP/NF, Campul PG-8 NF. The topical may include one or more of Lipoid’s Skin Lipid Matrix 2026 technology, lipid/oil based ingredients or oil soluble ingredients, and includes Captex 170 EP as a skin permeation enhancer, argan oil, menthol, arnica oil, camphor, grapefruit seed oil, dimethyl sulfoxide, dimethyl isosorbide, topical analgesics such as lidocaine, wintergreen oil, and terpenes such as guaiacol. In some embodiments, any one or more of these ingredients is present in the topical composition at a dry wt. % of equal to or less than about: 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, or ranges including and/or spanning the aforementioned values. In some embodiments, any one or more of these ingredients is present in the topical at a wet wt. % of equal to or at least about: 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 30%, or ranges including and/or spanning the aforementioned values.
[0278] Several illustrative embodiments of compositions and methods have been disclosed. Although this disclosure has been described in terms of certain illustrative embodiments and uses, other embodiments and other uses, including embodiments and uses which do not provide all of the features and advantages set forth herein, are also within the scope of this disclosure. Components, elements, features, acts, or steps can be arranged or performed differently than described and components, elements, features, acts, or steps can be combined, merged, added, or left out in various embodiments. All possible combinations and subcombinations of elements and components described herein are intended to be included in this disclosure. No single feature or group of features is necessary or indispensable.
[0279] Certain features that are described in this disclosure in the context of separate implementations can also be implemented in combination in a single implementation. Conversely, various features that are described in the context of a single implementation also can be implemented in multiple implementations separately or in any suitable subcombination. Moreover, although features may be described above as acting in certain combinations, one or more features from a claimed combination can in some cases be excised from the combination, and the combination may be claimed as a subcombination or variation of a subcombination.
[0280] The agents in some aspects of the disclosure may be formulated into preparations for local delivery (such as to a specific location of the body, such as a specific tissue or cell type) or systemic delivery, in solid, semi-solid, gel, liquid or gaseous forms such as tablets, capsules, powders, granules, ointments, solutions, depositories, inhalants and injections allowing for oral, parenteral or surgical administration. Certain aspects of the disclosure also contemplate local administration of the compositions by coating medical devices and the like. [0281] Suitable carriers for parenteral delivery via injectable, infusion or irrigation and topical delivery include distilled water, physiological phosphate-buffered saline, normal or lactated Ringer's solutions, dextrose solution, Hank's solution, or propanediol. In addition, sterile, fixed oils may be employed as a solvent or suspending medium. For this purpose any biocompatible oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The carrier and agent may be compounded as a liquid, suspension, polymerizable or non-polymerizable gel, paste or salve.
[0282] In certain aspects, the actual dosage amount of a composition administered to a patient or subject can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject.
[0283] In certain aspects, the pharmaceutical compositions are administered in the form of injectable compositions either as liquid solutions or suspensions; solid forms suitable or solution in, or suspension in, liquid prior to injection may also be prepared. These preparations also may be emulsified. In some embodiments, the composition comprises a pharmaceutically acceptable carrier. For instance, the composition may contain 10 mg or less, 25 mg, 50 mg or up to about 100 mg of human serum albumin per milliliter of phosphate buffered saline. Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like.
[0284] Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oil and injectable organic esters such as ethyloleate. Aqueous carriers include water, alcoholic/aqueous solutions, saline solutions, parenteral vehicles such as sodium chloride, Ringer's dextrose, etc. Intravenous vehicles include fluid and nutrient replenishers. Preservatives include antimicrobial agents, antgifungal agents, anti-oxidants, chelating agents and inert gases. The pH and exact concentration of the various components the pharmaceutical composition are adjusted according to well-known parameters.
[0285] Additional formulations are suitable for oral administration. Oral formulations include such typical excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. The compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders. In further aspects, the pharmaceutical compositions may include classic pharmaceutical preparations.
[0286] Administration of compositions according to certain aspects may be via any common route so long as the target tissue is available via that route. This may include oral, nasal, buccal, rectal, vaginal or topical administration. Alternatively, administration may be by orthotopic, intradermal, subcutaneous, intramuscular, intraperitoneal or intravenous injection. Such compositions would normally be administered as pharmaceutically acceptable compositions that include physiologically acceptable carriers, buffers or other excipients. For treatment of conditions of the lungs, aerosol delivery can be used. Volume of the aerosol may be between about 0.01 ml and 0.5 ml, for example.
[0287] Precise amounts of the pharmaceutical composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting the dose include the physical and clinical state of the patient, the route of administration, the intended goal of treatment (e.g., alleviation of symptoms versus cure) and the potency, stability and toxicity of the particular active substance. It is contemplated that other agents may be used in combination with certain aspects of the present embodiments to improve the therapeutic efficacy of treatment.
[0288] Any portion of any of the steps, processes, and/or compositions disclosed or illustrated in one embodiment, flowchart, or example in this disclosure can be combined or used with (or instead of) any other portion of any of the steps, processes, and/or compositions disclosed or illustrated in a different embodiment, flowchart, or example. The embodiments and examples described herein are not intended to be discrete and separate from each other. Combinations, variations, and other implementations of the disclosed features are within the scope of this disclosure.
Examples
[0289] The following examples are included to demonstrate preferred embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.
I. Example 1: Composition
[0290] The following provides an example formulation for certain embodiments:
Ingredient Percent of Composition
Water 20-99.9%
Propylene Glycol 0-20% Surfactant 0-12%
Xanthan gum 0-2%
Methylcellulose 0-2%
Kratom Powder 0-50%
Preservatives 0-3%
Flavoring 0-5%
Antioxidants 0-0.5%
Sweetener 0-5%
II. Example 2: Method of Treating Opioid Withdrawal
[0291] Based on the inventor’s experience, the following prophetic results are projected using controlled studies.
[0292] Three groups of patients of age between 45 and 55 are admitted to treatment after entering a treatment facility for opiate addition. The first group is treated with a kratom extract containing mixed nanoparticle composition as disclosed herein (orally). The second group of patients is treated orally with a kratom extract oil based comparator composition orally. The third group of patients is treated with a placebo orally. The first group of patients experiences milder withdrawal symptoms than the second group as measured by a self-evaluation and evaluation from a doctor. The patients in the first group report less feelings of nervousness, less feelings of restlessness, less feelings of impending danger, panic or doom, less trouble concentrating, and less trouble sleeping. After oral ingestion, the patients in the first group have lower heart rates and less trembling than those in the second group. The results show statistically significant improvements in the first group relative to either the second group or the third group.
[0293] The patients in the second group show statistically significant improvement over the placebo, but not to the degree achieved reported by the first group. The patients in the second group have statistically higher reports of side effects associated with treatment than either the first or the third group.
III. Example 3: Method of Treating Pain
[0294] Based on the inventor’s experience, the following prophetic results are projected using controlled studies. [0295] Three groups of female and male patients of age between 25 and 40 are admitted to treatment after having had been diagnosed with pain due to exercise related injuries. The first group is treated with a kratom extract containing mixed nanoparticle composition as disclosed herein topically. The second group of patients is treated topically with a competitor liposomal kratom extract based composition made with kratom extract oil. The third group of patients is treated with a placebo topically. The first group of patients experiences recovery from pain faster than the second group and to a higher degree as measured by a self-evaluation. The results show statistically significant improvements in the first group relative to either the second group or the third group.
[0296] The patients in the second group show statistically significant improvement over the placebo, but not to the degree achieved reported by the first group. The patients in the second group have statistically higher reports of side effects associated with treatment than either the first or the third group.
IV. Example 4: Method of Treating Anxiety
Based on the inventor’s experience, the following prophetic results are projected using controlled studies.
Three groups of patients of age between 45 and 55 are admitted to treatment after having had been diagnosed with anxiety. The first group is treated with a kratom extract containing mixed nanoparticle composition as disclosed herein orally. The second group of patients is treated orally with a kratom based comparator composition orally. The third group of patients is treated with a placebo orally. The first group of patients experiences recovery from each of the symptoms of anxiety faster than the second group and to a higher degree as measured by a self-evaluation. The patients in the first group report less feelings of nervousness, less feelings of restlessness, less feelings of impending danger, panic or doom, less trouble concentrating, less trouble sleeping. After oral ingestion, the patients in the first group have lower heart rates and less trembling than those in the second group. The results show statistically significant improvements in the first group relative to either the second group or the third group.
[0297] The patients in the second group show statistically significant improvement over the placebo, but not to the degree achieved reported by the first group. The patients in the second group have statistically higher reports of side effects associated with treatment than either the first or the second group. V. Example 5: Cannabidiol LNP Metabolite Analysis in Swine Plasma Using High Resolution Mass Spectrometry
[0298] The pharmacokinetic of liquid and powder (in gelatin capsules) lipid nanoparticle formulations of CBD were determined in male Gottingen mini-pigs at a dose of 15 mg/kg. Mini-pigs (20-24 kg) were orally administered the product into the stomach by oral gavage tube. Blood samples were collected via an accessible vein into blood collection tubes. Blood samples were collected at 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 14, and 16 or 24 hours. CBD concentration was measured in blood plasma by HPLC. Pharmacokinetic parameters were determined from the plasma concentrations using PK Slover, a Microsoft Excel plug-in, or by hand using the linear trapezoid rule. For comparison, commercially available, oil-based CBD products were also envaulted after oral administration. Data was normalized to 15 mg/kg for comparison.
[0299] Experiments and the results provided identify peaks observed in swine plasma pharmacokinetic (PK) study consisting of the same MRM transition as Cannabidiol (CBD) using reference standards for CBD and 7-OH CBD and unknowns by Full Scan mass spectrometry (MS)-High Resolution Mass Spectrometry (HRMS) and tandem mass spectrometry (MS/MS). Swine plasma samples were analyzed at 4, 5, and 6 hr after dosing for animals that were dosed with spray dried cannabidiol (CBD) LNP (6.63% CBD, 13.26% HSPC, 12.33% MCT, 0.13% Vitamin E, 1.33% Cholesterol, 66.31% Trehalose), as described herein, powder formulations. The standards analyzed with samples include 100 ng/mL each of CBD and 7-OH-CBD. Peaks observed in swine plasma have been identified as a glucuronide conjugates of CBD and 7-OH CBD. The exact mass and fragmentation is consistent with the structure of CBD-glucuronide (CBD-gluc) and 7-OH-CBD glucuronide (7-OH-CBD-gluc). Neutral loss fragments of 176 for CBD-gluc and 194 for 7-OH-CBD-gluc, confirm the presence of glucuronides. Additional metabolites were detected in the samples. A peak at 5.6min has a molecular weight of 344.2 (CBD + 30) consistent with oxidation to a carboxylic acid. A large peak at 7.4min has a molecular weight of 360.2 (CBD + 46) consistent with further oxidation of the carboxylic acid. These results suggest that the LNP can effectively deliver hydrophobic active agents to the blood stream by oral administration in either liquid or powdered form.
[0300] Samples were prepared by pooling aliquots from plasma samples from swing that received spray dried cannabidiol LNP powder at 4, 5, and 6 hr time points. Total volume of pooled plasma sample was 150 pL and was precipitated with 1:3 volume of acetonitrile, vortexed and centrifuged at 5,000 rpm for 5 min. After centrifugation, 300 pL of supernatant was removed and dried under a gentle stream of nitrogen. Dried samples were then reconstituted in 100 pL water/acetonitrile (50/50). Samples were injected on Agilent QTOF 6550 mass spectrometer equipped with Agilent 1260 HPLC. Data were acquired using HRMS and auto MS/MS to evaluate fragments and propose structures. Data analysis was performed by SeventhWave Laboratories (BASi).
[0301] The LC/MS conditions were as follows: HPLC: Agilent 1260 Infinity; Mobile Phases: lOmM ammonium formate in water and acetonitrile; Column: Waters Atlantis C18 3pM, 2.1x150 mm (PN: 186001299); Injection volume: 10 pL; Flow Rate: 300 pL/min; Gradient: 0-0.5 min - 25% B (in some embodiments B comprises acetonitrile), 0.5-8 min - 25- 90% B, 8-11 min - 90% B, 11-11.5 min - 25% B, 11.5-15 min - 25% B; Mass Spectrometer: Agilent 6550 ifunnel QTOF.
VI. Example 6: Forced Degradation of Cannabidiol and Empty LNPs
[0302] Forced degradation of cannabidiol LNPs and empty LNPs under various conditions, including acidic, basic, oxidative conditions, and high temperature/high humidity were performed. The degradations evaluated analytical method for the utility to detect degradants and impurities found in Cannabidiol and Empty LNPs. The results were to determine if Cannabidiol LNP converts to D9-THC under acidic conditions or if degradation occurs under basic, oxidative conditions, and high temperature/high humidity. Cannabidiol and empty LNPs were stressed according to the following separate conditions: 0.01 M hydrochloric acid, 0.01 M sodium hydroxide, 0.1% hydrogen peroxide. Cannabidiol and empty LNPs were stressed either at room temperature (25C/60% relative humidity) or an accelerated temperature (40C/75% relative humidity). Lipid encapsulated nanoparticles (without cannabidiol) were stressed under similar conditions. Cannabidiol solubilized in 200-Proof USP ethanol was also stressed with 0.01M hydrochloric acid at 25C/60% RH and 40C/75% RH as a positive control. Test articles were analyzed by Ultra Performance Liquid Chromatography (UPLC) using the cannabinoids method described herein. Cannabidiol LNPs were prepared using manufacturing described herein at an R&D scale. Ingredients include: cannabidiol API (2.0%), sunflower phosphatidylcholine (10.0%), capric and caprylic triglycerides (9.3%), cholesterol (1.0%), vitamin E (0.1%), potassium sorbate (0.1%), sodium benzoate (0.1%), citric acid (0.1%), and water for injection (77.3%). APLgrade, crystalline, synthetic cannabidiol was purchased from Benuvia Manufacturing (Round Rock, Texas) Catalog Number: ITI-GMP-002, Lot Number: RM19084. The Cannabidiol LNP Characteristics were white, free of sedimenting particulates with a pH of 4.406, a density of 0.998 g/mL, a Z-average of 86.51 nm, and a PDI of 0.181. [0303] 0.01M hydrochloric acid samples were prepared by adding 5 mL of lipid encapsulated cannabidiol to 4.9 mL of water for injection. 0.1 mL of IM hydrochloric acid (JT Baker) was added to achieve a final concentration of 0.01M hydrochloric acid. The 10 mL of sample was divided into 2 x 5 mL samples in amber vials and crimp sealed. A sample was stored at either 25C/60% RH or 40C/75% RH.
[0304] 0.01M sodium hydroxide samples were prepared by adding 5 mL of lipid encapsulated cannabidiol to 4.9 mL of water for injection. 0.1 mL of IM sodium hydroxide (JT Baker) was added to achieve a final concentration of 0.01M sodium hydroxide. The 10 mL of sample was divided into 2 x 5 mL samples in amber vials and crimp sealed. A sample was stored at either 25C/60% RH or 40C/75% RH.
[0305] 0.1% hydrogen peroxide samples were prepared by adding 5 mL of lipid encapsulated cannabidiol to 4.967 mL of water for injection. 0.033 mL of 30% hydrogen peroxide (JT Baker) was added to achieve a final concentration of 0.1% hydrogen peroxide. The 10 mL of sample was divided into 2 x 5 mL samples in amber vials and crimp sealed. A sample was stored at either 25C/60% RH or 40C/75% RH.
[0306] A control sample was prepared by adding 5 mL of lipid encapsulated cannabidiol to 5.0 mL of water for injection. The 10 mL sample was divided into 2 x 5 mL samples and stored at either 25C/60% RH or 40C/75% RH.
[0307] Lipid encapsulated nanoparticles without cannabidiol were prepared and stressed under identical conditions.
[0308] Cannabinoid reference standards were fully separated by Reverse Phase UPLC (Thermo Vanquish Horizon). Cannabidiol (Crystalline) was formulated as LNPs or Ethanol solutions and subjected to degradation by the acid, base, oxidative, or high temperature/high humidity conditions previously described. Degradants and/or impurities that eluted or eluted near cannabinoid reference standards were evaluated by ultra-performance liquid chromatography method with diode array detection (UPLC-DAD), Spectra, Retention Time, and NMR analysis.
[0309] The results from the forced degradation of empty and cannabidiol LNPs when stored in water for injection for 24 hrs at 40C/75% RH are as follows: under neat conditions (WFI) conditions, an unknown peak eluting at 3.817 minutes was observed in empty LNP control. This unknown peak was not observed in previous blank injection and only present in Empty LNPs, therefore likely an artifact that has been incorporated during use. Unknown impurities observed in extraction diluent and trended with increasing concentration regardless of sample type. No other degradants or impurities were observed in Cannabidiol and empty LNPs.
[0310] The results from the forced degradation of empty and cannabidiol LNPs when stored in 0.01M NaOH for 24 hrs at 40C/75% RH are as follows: under basic conditions (0.01M NaOH) conditions, a degradation product eluted near Exo-THC (6.503 vs. 6.526 minutes). Spectral matching software was able to differentiate Exo-THC from the unknown degradant due to differences in lambda max values. As a result, this peak eluting at 6.526 minutes was determined to be unknown rather than Exo-THC. Basic conditions cause Cannabidiol LNPs to transition into "purple/violet" color that is characteristic to cannabinoid formulations that experienced oxidative degradation into its cannabidiol hydroxy quinone. Empty LNPs when stored under basic conditions generated unknown impurity and eluted at 3.818 minutes. This unknown peak was not observed in previous blank injection and only present in Empty LNPs. As previously mentioned this unknown could be an impurity from use. Unknown impurities observed in extraction diluent and trended with increasing concentration regardless of sample type.
[0311] The results from the investigation of degradant eluting at 6.503 minutes in cannabidiol LNPs when stored in 0.1M NaOH for 24 hrs at 40C/75% RH are as follows: cannabidiol has been shown to undergo oxidative degradation into its hydroxylated form as "cannabidiol hydroxy quinone" (referred as HU-331 in literature). Since the 6.503-minute degradant was unique to Cannabidiol LNPs when exposed to basic conditions (0.01M NaOH), the cannabidiol hydroxyquinone reference material was injected and compared to support its identification. Based on retention time and spectra analysis, the degradant at 6.503-minute degradant was tentatively identified as cannabidiol hydroxy quinone. Given the reactivity of quinone compounds, investigations will monitor any chemical changes to cannabidiol LNPs from a manufacturing standpoint, embodiments herein implement process controls to eliminate exposure to pharmaceutical and/or food detergents that contain oxidizing agents. The presence of degradants and impurities in HU-331 standard are likely additional oxidative degradants and/or synthesis byproducts.
[0312] The results from the forced degradation of empty and cannabidiol LNPs when stored in 0.01M HC1 for 24 hrs at 40C/75% RH are as follows: Under acidic conditions (0.01M HC1) conditions, no degradation products related to cannabidiol LNPs were observed. It's well published that CBD may experience significant degradation when exposed to acidic and oxygenated conditions including pharmaceutical compositions and in vivo. Acid catalyzed cyclization of CBD to d9-THC was not observed in cannabidiol LNPs when exposed to forced degradation conditions. Unknown impurities observed in extraction diluent and trended with increasing concentration regardless of sample type. It has been proposed that cannabidiol would convert to d9-THC under acidic conditions when formulated in LNPs, similar to what commonly occurs in alcohol-based compositions. However, use of the LNPs did not show degradation to d9-THC under acidic conditions.
[0313] To compare the utility of LNPs with cannabidiol solubilized in ethanol a forced degradation study using identical acidic conditions were performed. Under acidic conditions (0.01M HC1), at least 13 degradation products were observed in cannabidiol solubilized in ethanol. A degradation product closely eluted near CBG (3.070 vs. 3.132 minutes). At first, spectral matching software was not able to differentiate the unknown degradant with spectra for CBG (208.64 vs 206.01 nm). Due to difference in lambda max values, this peak eluting at 3.070 minutes was determined to be unknown rather than CBG. Additional degradation products were observed and eluted at 3.475, 5.506, 6.774, 7.120, 8.729, 9.599, and 10.706 minutes. Degradants that eluted at 6.774 and 7.210 minutes corresponded to reference standard retention times for Delta-8 THC and Delta-9-THC. Using a combination of spectra analysis (lambda max: 208.99 vs. 208.98 nm), retention time, mass comparisons (m/z), and NMR, these peaks can be separated and identifiable as Delta-8 and Delta-9 THC. It is well understood that CBD can be converted to Delta-9 THC and Delta- 8 THC under acidic conditions. Another degradant was observed to elute near CBN at 5.510 minutes compared to 5.318 minutes (reference material). CBN is a common oxidative byproduct of Delta-9 THC although spectra and retention time analysis for this particular sample was not supportive of this conclusion. Accordingly, use of the LNPs containing cannabidiol provided significant protection of the cannabidiol under acidic conditions.
[0314] The results from the forced degradation of empty and cannabidiol LNPs when stored in 0.1% hydrogen peroxide for 24 hrs at 40C/75% RH are as follows: in comparison to Empty LNPs, oxidative conditions (0.1% Hydrogen Peroxide) did not generate degradation products that eluted at peaks of interest. A small unknown peak eluted at 9.5 minutes that has a spectra that does not correlate to cannabinoids and also present in Empty LNP control, therefore likely an impurity in hydrogen peroxide. UV absorbances at 208, 210, 224, or 280 did not provide additional perspective on other degradants. Empty LNPs when stored under oxidative conditions generated an unknown impurity that eluted at 3.8 minutes. Unknown impurities observed in extraction diluent and trended with increasing concentration regardless of sample type. [0315] The forced degradation studies show UPLC-DAD cannabinoids assay is a reliable method to separate impurities, degradants, and naturally occurring cannabinoids, including Delta-8, Delta-9, and Exo-THC stereoisomers. In addition to impurities and degradants, at least 17 cannabinoids can be resolved and quantitated. The formation of Delta-9 THC and Delta-8 THC was only observed in cannabinoid compositions containing 200 proof ethanol under acidic conditions. At least 13 degradants were observed in ethanol solutions compared to zero when loaded in LNPs when stored for 24 hours at accelerated conditions. Basic (0.01M NaOH) conditions was the only condition that caused Cannabidiol LNPs to change colors compared to Empty LNPs. The color change was expected and determined to be a result of presence of HU- 331.
[0316] Using conventional analytical separation techniques, sterochemical separation and purity analysis is difficult to perform. The quality control method using UPLC has been shown to provide excellent separation between THC stereo isomeric forms. Previously, embodiments herein performed targeted mass spectroscopy studies to confirm the separation and quantitation of THC isomers that includes Delta-8 and Delta-9 THC. Proton and Carbon NMR (1H and 13C) was performed for identification purposes.
VII. Example 7: Stability of LNPs after two years
[0317] Embodiments herein provide a stable good manufacturing practice (GMP) material that has been stored for 24 month at room temperature and analyzed using the analytical method disclosed herein. The GMP material is characterized as follows: Days since manufacture (DOM): 745 days, Storage: 25C/60% RH, Appearance: White, free of sedimenting particulates, pH: 4.801, Density: 0.996 grams/mL, Z-average: 130.6 nm, PDI: 0.119, Cannabidiol Source: Plant Extract (Isolate), Target Assay: 20 mg/g Cannabidiol.
[0318] After long-term storage of Cannabidiol LNPs (cannabidiol API (2.0%), sunflower phosphatidylcholine (10.0%), capric and caprylic triglycerides (9.3%), cholesterol (1.0%), vitamin E (0.1%), potassium sorbate (0.1%), sodium benzoate (0.1%), citric acid (0.1%), and water for injection (77.3%)) at 25C/60% RH for over 2 years, Cannabidiol and particle size was within specifications, as shown in FIG. 4. The formation of Delta-9-THC was not observed after long-term storage at room temperature as shown in FIG. 5. Up to 8 degradants were observed all of which have similar UV spectras as cannabinoids. A degradant was observed closely eluting near THCV (3.826 vs 3.621 minutes) with lambda maxes of 203.87 vs. 208.84 nm. 3.826 minute degradant was determined to be cannabidiol hydroxy quinone although in very small amounts. A degradation product also eluted 6.282 minutes near Delta-8-THC compared to 6.518 minutes for reference. A peak eluting at 6.503 minutes was determined to be unknown rather than Delta-8 THC. A degradation product eluting at 3.066 minutes before cannabidiol (3.286 minutes) was identified as "unknown" although the retention time was similar to CBG. The lambda max of the unknown degradant was 208.70 nm compared to 205.99 nm for reference material. Unknown impurities observed in extraction diluent and trended with increasing concentration regardless of sample type. Impurities eluting at 1.887 and 1.973 minutes are artifacts of the extraction solvent. The lack of D9-THC and the maintenance of particle size for over 2 years of storage at 25C/60% RH demonstrates that the LNPs provide significant protection of the active agent encapsulated therein.
VIII. Example 8: Formulations of Compositions
[0319] Embodiments including nutraceutical, consumer friendly compositions: for the lipid nanoparticles, the typical base formulation composition includes phosphatidylcholine source (typically sunflower), sterol source (typically plant sterols or cholesterol), triglyceride source (medium or long chain from coconut, seeds, PUFA, etc.), and purified water. Ratios of excipients (lipids, sterols, and fatty acids) including additional inactive ingredients are added on a case by case basis depending on the intended use or application. The ratio and type of excipients can be selected based on the type of active ingredient to be encapsulated. Ingredients may include the use of reducing agents, antioxidants, acidifiers, flavoring agents, and antimicrobial preservatives (natural or synthetic). The mixed nanoparticle formulations may contain phosphatidylcholine, surfactant, and various inactive and functional ingredients.
[0320] Embodiments including pharmaceutical compositions: for drug delivery applications, all excipients including lipids, cholesterol and triglycerides are sourced from pharmaceutical suppliers that provide GMP, USP, NF, and/or Multi-Compendial graded material. Water for injection (USP/EP) is the aqueous diluent and amenable to USP purified variants as well. Antimicrobial preservatives common to drug products for most routes of administration including parabens, phenols, acids, and alcohols can be used in platform technologies at acceptable levels. All excipients can be GRAS and found in FDA’s inactive list of excipients.
[0321] Certain ingredients used in the compositions (Phosphatidylcholine, cholesterol, Medium Chain Triglycerides, water) can be found on the FDA’s IID list. Examples include: 12 drug products (intravenous, topicals, vaginal) that contain cholesterol; 5 drug products (intravenous) that contain some form of phosphatidylcholine; 2 drug products (sublingual and topical) that containing forms of caprylic/capric triglycerides; 21 drug products (oral, injection, sublingual, topical) that contain Medium Chain Triglycerides.
[0322] The absence or presence of precipitation/sedimentation was used to determine loading capacity, along with cannabidiol remaining in solution by UPLC. Cannabidiol has a logP >5 therefore there are limited sink conditions that can be used in traditional dialysis methods to determine ‘free’ active. Filtration by 0.2 um was also used to demonstrate no change in cannabidiol concentration. From a concentration standpoint, 20 mg/g to 40 mg/g of cannabidiol is routinely encapsulated and used to assay over time. Encapsulation of up to 120 mg/g of cannabidiol has been done for the LNPs herein. The LNPs herein have shown stability for compositions containing 20 mg/g cannabidiol at 18 months when stored at 25C/60% RH.
[0323] Lipid-based cannabidiol formulations were placed in a traditional dialysis setup, where the pore size of the membrane was small enough to contain the particles whereas ‘free drug’ can freely diffuse through non-reactive pores, and the dialysis tube was placed in an aqueous diluent at 37°C with agitation. Cannabidiol was measured at predefined time points to evaluate release media over time. Cannabidiol was not detected in the release media. Sample and separate method was also performed using centrifugation.
[0324] The particle size and dissolution of lipid-based cannabidiol formulations was compared to other marketed “nano” products, as shown in FIGs. 6A-6B. Results showed that the size of cannabidiol loaded particles was consistent from batch to batch whereas marketed products were highly variable in size (too small or too large), highly polydispersed, and/or exhibited phase separation. This was exacerbated when the formula was added to aqueous medias.
IX. Example 9: Stability of LNPs with Various Active Agents
[0325] Nanoparticle compositions (active agent (2.0%), sunflower phosphatidylcholine (10.0%), capric and caprylic triglycerides (9.3%), cholesterol (1.0%), vitamin E (0.1%), potassium sorbate (0.1%), sodium benzoate (0.1%), citric acid (0.1%), and water for injection (77.3%)) comprising the following active agents were evaluated for stability by monitoring particle size distribution and polydispersity over time when stored at controlled room temperature (25°C/60% relative humidity or accelerated conditions (40°C/60% relative humidity). Active ingredients: Cannabidiol, Cannabigerol, Cannabinol, Cannabichromene, Tetrahydrocannabivarin, Tetrahydrocannabinol, Full extracts of hemp, Specific ratios of isolated cannabinoids, Cannabigerolic acid, Cannabidolic acid, Mitragynine, Payantheine, Mitraphylline, Speciociliantine, Speciogynine, Cholecalciferol, Ergocalciferol, D,L-Alpha- Tocopherol, Menaquinone, Ascorbyl palmitate, Retinyl palmitate, Beta-Sitosterol, Plant Sterol Rich Extracts, Cholesterol, Ubiquinone, Phosphatidylcholine, Phosphatidylserine, Eicosapentaenoic/Docosahexaenoic Acid Mixtures, Oleic Acid, Conjugated Linoleic Acid, Capric Triglycerides, Caprylic Triglycerides, Capric and Caprylic Triglyceride mixtures, Peppermint, Orange, Lemon Oils, Lutein, Kavain, Methysticin, Yangonin, Dihydromethysticin. The physical characteristics of the particle (Z-average particle size and poly dispersity index) have been predictive of stability for encapsulated actives. This is especially true for poorly water soluble compounds like cannabinoids. No phase separation occurred for nanoparticles encapsulating the actives provided above. Further, the measured particle size for each of the encapsulated actives was within acceptable limits. The consistency in size over time, or within a sample even at the time of manufacture, is predictive of stability over time for the active agent encapsulated therein.
X. Example 10: Surfactants and Concentrations of Surfactants
[0326] Mixed micelle formulations containing Mitragyna speciosa extract and varying amounts of polysorbate 80 and polysorbate 20 were prepared using a solvent-free manufacturing process, as shown in Table 1. To prepare the mixed micelle composition, water was heated to 75°C before adding additional ingredients. Malic acid was added to adjust the pH. The required amounts of polysorbate 80 and polysorbate 20 were dispersed in the aqueous solution at a fixed ratio of 49:1, followed by the addition of the lipid components. The liquid was high shear mixed until a transparent solution resulted. After the formulation was cooled, the Mitragyna speciosa extract was added with high shear mixing to a final mitragynine alkaloid concentration of 10 mg/mL. When the formulation was optically clear, it was passed through a 0.45 pm PES filter.
Table 1
Figure imgf000095_0001
[0327] The particle size and poly dispersity index for each formulation in Table 1 are shown in Table 2. With an increase in total surfactant concentration (increasing from formulation 1 to formulation 3) the Z-average particle size decreases from 187.0 nm to 67.6 nm. The change in polydispersity index measured for each formulation did not correlate to increasing total surfactant concentration.
Table 2
Figure imgf000096_0001
[0328] Mixed micelle formulations containing Mitragyna speciosa (Kratom) extract and varying amounts of phosphatidylcholine lipid were prepared using a solvent-free manufacturing process, as shown in Table 3. Lipophilic components (lipid, polysorbate 20, polysorbate 80, and Mitragyna speciosa extract) were combined and mixed with surfactant (polysorbate 80 and polysorbate 20) until a homogeneous slurry was formed. Water-soluble components (malic acid) were dissolved in water and added to the slurry. High shear mixing was applied at 65 C until a stable suspension was formed. The resulting solution was filtered with a 1 -micron polypropylene filter. The table below summarizes the formulations made in this example. Lecithin was purchased from Spectrum Chemicals and H20, H50, H90, and Hl 00-3 were purchased from American Lecithin Company (ALC).
Table 3
Figure imgf000096_0002
Figure imgf000097_0001
[0329] The particle size, poly dispersity index, and Mitragynine concentration for each formulation in Table 3 is shown in Table 4 (NA = not available). Increasing lipid concentration generally results in an smaller of Z-average particle size for phosphatidylcholine grades H20 and H90. This observation was not true for lecithin or phosphatidylcholine H100-3. The polydispersity index decreased with increasing lipid concentration for phosphatidylcholine grades H20, H90, and lecithin, indicating lipid concentration plays a role in the homogeneity of the particle size distribution. Viscosity increased as lipid concentration increased as seen in FIG. 7. Viscosity increases steadily with increasing lipid concentration until a sharp rise begins to be seen at high concentrations. A formulation at 300 g/L of lipids was found to be too viscous during compounding. Formulations 8 and 10 did not decrease in mitragynine concentration when stored for 5 months at controlled room temperature (25°C/60% relative humidity), indicating the formulations were chemically stable. Flavor of the mitragynine speciosa extract formulations improves as lipid concentration increases. The high bitterness of Mitragynine speciosa extracts was masked with high lipid content.
Table 4
Figure imgf000097_0002
XI. Example 11: pH
[0330] To evaluate the impact of pH, mixed micelle formulations containing Mitragyna speciosa extract and varying amounts of acids or bases were prepared using a solvent-free manufacturing process, as shown in Table 5. Lipophilic components were combined and mixed with surfactant (polysorbate 80 and polysorbate 20) until a homogeneous slurry was formed. Water-soluble components, including the acid or base, were dissolved in water and added to the slurry. High shear mixing was applied with heat until a stable suspension was formed. The resulting solution was filtered with a 1 -micron polypropylene filter. The table below summarizes the formulations made in this example.
Table 5
Figure imgf000098_0001
[0331] Formulations provided in Table 5 were evaluated for particle size and poly dispersity index as shown in Table 6. From Table 6, a Z-Average particle size minima can be seen with formulations of pH < 4.0. Comparatively more basic formulations tend to have decreased physical stability, which is evidenced by an increased particle size even at relatively low lipid concentrations (formulations 6 and 7). Formulations with less acid have a higher tendency to gel over time. The inclusion of acids and bases has a strong impact on flavor. Bitterness reducers such as acetate and malic acid improve the flavor of the formulation, but acetate imparts instability while malic acid does not. This would suggest an ideal pH range of between 3 and 4. Table 6
Figure imgf000099_0001
XII. Example 12: Temperature
[0332] To determine the impact of processing temperature on the resulting formulation, mixed micelles containing Mitragyna speciosa extract were prepared at various processing temperatures using a solvent-free manufacturing process with high-shear mixing, as shown in Table 7. Lipophilic components were combined and mixed with surfactant (polysorbate 80 and polysorbate 20) until a homogeneous slurry was formed. Water-soluble components were dissolved in water and added to the slurry. High shear mixing was applied at either 45°C, 55°C, or 65°C until a stable suspension was formed. The resulting solution was filtered with a 1- micron polypropylene filter. The table below summarizes the formulations made in this example. Formulations were evaluated for taste and impact. Formulations were monitored for stability by optical clarity over the course of several weeks at room temperature.
Table 7
Figure imgf000099_0002
[0333] Formulations provided in Table 7 were evaluated for particle size and poly dispersity index as shown in Table 8. Incorporation temperatures at 45 °C and 55 °C have large Z- Average particle sizes than formulations prepared at 65 °C. This is also evidenced by reduced physical stability at higher temperatures resulting in increased optical opacity and increased tendency to gel over time (data not shown). Incorporation temperatures of 70°C and higher were attempted, but high optical opacity and low recovered mitragynine concentrations were observed.
Table 8
Figure imgf000100_0001
XIII. Example 13: Flavor Oils
[0334] Mixed micelle formulations containing Mitragyna speciosa extract and varying flavoring oils were prepared using a solvent-free manufacturing process with high shear mixing, as shown in Table 9. Lipophilic components were combined and mixed with surfactant (polysorbate 80 and polysorbate 20) until a homogeneous slurry was formed. Water-soluble components were dissolved in water and added to the slurry. High shear mixing was applied at 65°C until a stable suspension was formed. The resulting solution was filtered with a 1 -micron polypropylene filter.
Table 9
Figure imgf000100_0002
[0335] Formulations were evaluated for particle size, mitragynine concentration initially and after 5 months of storage at controlled room temperature, and taste. Flavor oil was found to not impact Z- Average particle size or poly dispersity index. Both parameters remained fairly consistent between all flavors tested. After storage at controlled room temperature for 5 months, mitragynine concentration was comparable to that measured at stability set down (TO), indicating the formulations, irrespective of flavor oil type, were stable. The particle size, poly dispersity index, and Mitragynine concentration for each formulation in Table 9 is shown in Table 10.
Table 10
Figure imgf000101_0001
XIV. Example 14: Purity of Plant Extracts
[0336] Mixed micelle formulations containing varying input materials of varying purities were prepared using a solvent-free manufacturing process with high shear mixing, as shown in Table 11. Lipophilic components, including the input material outlined in the table below, were combined and mixed with surfactant (polysorbate 80 and polysorbate 20) until a homogeneous slurry was formed. Water-soluble components were dissolved in water and added to the slurry. High shear mixing was applied at 65°C until a stable suspension was formed. The resulting solution was filtered with a 1 -micron polypropylene filter.
Table 11
Figure imgf000101_0002
[0337] Formulations provided in Table 11 were evaluated for particle size and poly dispersity index as shown in Table 12. The Z-average particle size and poly dispersity index data demonstrate comparable particle characteristics are achievable with different encapsulated ingredients.
Table 12
Figure imgf000102_0001
XV. Example 15: Dried Powders of Nanoparticle Compositions
[0338] Nanoparticle formulations containing ribose alone, ribose and niacinamide, or niacinamide alone were formed into spray dried powders. Formulations containing either ribose alone, niacinamide alone, or both ribose and niacinamide with varying amounts of various lipids and other excipients were prepared using a solvent- free manufacturing process. Water-soluble components were dissolved in water at 65°C with magnetic stirring. High shear mixing was applied at 65°C and lipids and excipients were added. High shear mixing was maintained until a stable suspension was formed. The suspension was then microfluidized for 5 passes using an MP110 microfluidizer at 30,000 psi. Following microfluidization, formulations were diluted with an equal volume containing the excipient type such that the excipient is at the stated final concentration. Up to 25% ethanol (e.g., 10%, 15%, 20%, 25%) was added to the formulation and mixed to a homogenous solution prior to spray drying. Formulations were spray dried on a Buchi B290 benchtop spray dryer. The inlet temperature was set at 125 °C, the aspirator set to 100%, the pump rate set to 10%, and nitrogen flow set to 60 mmHg. Powder was collected was measured for residual moisture and recovered yield was calculated. Table 13 shows formulation conditions evaluated. Table 13
Figure imgf000103_0001
[0339] The resulting suspension (spray drying intermediate) was spray dried into a powder under varying conditions. Powder consistency, color, and yield were logged. Table 14 summarizes the formulations and powders made in this example. Moisture content of the powders ranges from 2-5% depending largely on the chemical composition of the spray drying intermediate. Product yield was most directly correlated with excipient content, excipient type, and optimization of spray drying parameters. Higher yields are typically observed at high excipient content, higher spray drying temperatures, and fibrous water-soluble excipients. Table 14
Figure imgf000103_0002
XVII. Example 16: Preparation of CBN Nanoparticle and Stability Study
[0340] CBN isolate containing nanoparticles were prepared using the solvent free manufacturing process described in Example 1. A 15-liter batch containing 2.0% CBN isolate was prepared and 15 grams was filled into 20 mL dropper cap bottles for stability testing, samples were stored at controlled room temperature (25°C/60% relative humidity) for 365 days and at accelerated conditions (40°C/75% relative humidity) for 90 days. Shown in Table 15 are the CBN concentrations for each storage condition at the start and end of the stability study.
Table 15
Figure imgf000104_0001
[0341] When stored at controlled room temperature for 365 days, the CBN concentration increased from 20.0 mg/gram to 22.5 mg/gram, a change of +12%. When stored at accelerated conditions for 90 days the CBN concentration increased from 20.0 mg/gram to 21.3 mg/gram, a change of +6.5%. The increase in concentration during the storage time is likely the result of analytical variability. The concentration of CBN did not decrease during this time at either temperature. Storage at 40°C/75% is generally understood to increase degradation kinetics by a factor of 4 compared to controlled room temperature based on the Arrhenius equation. Therefore, 90 days at accelerated storage indicates that the chemical stability of CBN at room temperature is at least 360 days, which is further confirmed by 365-day stability data at 25°C/60% relative humidity.
XVIII. Example 17: Preparation of CBG Nanoparticle and Stability Study
[0342] CBG isolate containing nanoparticles were prepared using the solvent free manufacturing process described in Example 1. A 15-liter batch containing 2.0% CBG isolate was prepared and 15 grams was filled into 20 mL dropper cap bottles for stability testing. Samples were stored at controlled room temperature (25°C/60% relative humidity) for 365 days. Shown in FIGs. 8 and 9 are the change in CBG concentration and Z-average particle size over the 365-day storage period.
[0343] Over the 365 days of storage at controlled room temperature the CBG concentration changed from 19.9 mg/gram to 22.2 mg/gram, a change of approximately +12%. The apparent increase in CBG concentration is attributed to analytical variability. During the same period of time, the nanoparticle Z-average changed from 131.8 nm to 178.5 nm, a change of +35%. PDI of the mixture increased from 0.068 to 0.153. Chemical stability measurements of the CBG containing nanoparticle over the 365 days of storage have shown no signs of degradation of CBG. Physical stability measurements remain within product specifications of Z-average particle size less than 300 nm and PDI less than 0.3 after 365 days. Therefore, the composition is believed to be stable over this timeframe.
XIX. Example 18: Preparation of BSD Nanoparticle and Stability Study
[0344] BSD (Broad Spectrum Hemp Distillate) containing nanoparticles were prepared using the solvent free manufacturing process described in Example 1. A 15-liter batch containing 2.0% Broad Spectrum Hemp Distillate was prepared and 15 grams was filled into 20 mF dropper cap bottles for stability testing. Prior to preparing the batch the BSD was found to contain CBD as a major cannabinoid and CBG, CBN, and CBC as minor cannabinoids. Samples were stored at controlled room temperature (25°C/60% relative humidity) for 365 days and at accelerated conditions (40°C/75% relative humidity) for 180 days. Shown in FIGs. 10 - 13 are changes in CBD, CBG, CBN, and CBC, respectively, over 365 days of storage at controlled room temperature. Shown in Table 16 are the changes in cannabinoids over 180 days of storage at accelerated temperature. Shown in FIG. 14 is the change in Z-average particle size over 12 months of storage for a 50-liter batch of encapsulated BSD nanoparticles at controlled room temperature.
Table 16
Figure imgf000105_0001
[0345] When the BSD containing nanoparticles were stored at controlled room temperature for 365 days, the CBD concentration varied from 19.8 mg/gram to 22.9 mg/gram (FIG. 10). The overall change in CBD concentration at the end of the 365 days was +16%. The minor cannabinoids (CBG, CBN, and CBC) varied in concentration from 0.74 mg/gram to 0.973 mg/gram. Overall, the change in the CBG concentration was +12%, the CBN concentration was +15% and the CBC concentration was +15% over the 365 days of controlled room temperature storage (FIGs. 11 - 13).
[0346] When stored at accelerated conditions for 180 days the percent change in the CBD, CBG, CBN, and CBC was 11.0%, 8.0%, 13.0%, and 17.0%, respectively (Table 16). Storage at 40°C/75% is generally understood to increase degradation kinetics by a factor of 4 compared to controlled room temperature based on the Arrhenius equation. Therefore, 180 days at accelerated storage indicates that the chemical stability of CBD, CBG, CBN, and CBC at room temperature is at least 720 days. This agrees well with observed stability at 25°C/60% relative humidity over 12 months shown in FIGs. 10-13.
[0347] Taken together, the cannabinoids concentration did not decrease during storage at controlled room temperature or accelerated temperatures, indicating no degradation. The particle size of the formulation did not increase, indicating the composition was physically stable.
XX. Example 19: Preparation of FSD and THCv Nanoparticle and Stability Study
[0348] FSD (Full Spectrum Hemp Distillate) and THCv (tetrahydrocannabivarinand) isolate containing nanoparticles were prepared using the solvent free manufacturing process described in Example 1. A 50-liter batch containing 2.0% Full Spectrum Hemp Distillate and 0.32% THCv isolate was prepared and 30 grams was filled into 30 mL dropper cap bottles for stability testing. Prior to preparing the batch the FSD was found to contain CBD as a major cannabinoid, and CBG, CBN, and CBC as minor cannabinoids. Delta-9 THC was detectable in the FSD raw material at or below the LOQ (limit of quantitation) in the encapsulated FSD nanoparticles. Delta-9 THC is not reported in the data below. Samples were stored at controlled room temperature (25°C/60% relative humidity) for 12 months and at accelerated conditions (40°C/75% relative humidity) for 6 months. Shown in Tables 17 and 18 are changes in CBD, CBN, CBG, CBC, and THCv over 12 months when stored at controlled room temperature and 6 months when stored at accelerated temperature. Shown in FIGs. 15 and 16 are the changes in Z-average particle size and Polydispersity Index (PDI) over the same period of time for each storage condition. Table 17
Figure imgf000107_0001
[0349] When the FSD and THCv isolate containing nanoparticles were stored at controlled room temperature for 12 months the CBD, CBG, CBN, and CBC concentration changed by +10.7%, +7.0%, +11.0%, and +8.3%, respectively. The THCv concentration decreased by 7.1 % after 6 months, by 12.3% after 9 months, and by 14.1% after 12 months (Table 17). Shown in FIG 15 is the change in Z-average particle size and polydispersity index (PDI) over the 12 months of storage at controlled room temperature. The Z-average particle size increased from 115.5 nm 11 to 154.1 nm during this time, while the PDI decreased from 0.212 to 0.134.
Table 18
Figure imgf000107_0002
[0350] When the FSD and THCv isolate containing nanoparticles were stored at accelerated temperature for 6 months the CBD, CBG, CBN, and CBC concentration changed by +0.0%, +0.9%, +4.8%, and +1.4%, respectively. The THCv concentration decreased by 11.2% by 3 months and 25.7% by 6 months (Table 18). Shown in FIG 16 is the change in Z- average particle size and polydispersity index (PDI) over the 6 months of storage at accelerated temperature. The Z-average particle size increased from 115.5 run to 136.5 run during this time, while the PDI decreased from 0.212 to 0.136.
[0351] The cannabinoids, Z-average particle size, and PDI were considered stable when stored for 12 months at room temperature and 6 months stored at accelerated temperature. THCv cannabinoid concentration decreased by 11.2% by 3 months storage at accelerated temperature and by 25.7% by 6 months of storage. Storage at 40°C/75% is generally understood to increase degradation kinetics by a factor of 4 compared to controlled room temperature based on the Arrhenius equation. Therefore, THCv stability is expected to be between 1 and 2 years of storage at controlled room temperature. This agrees well with observed stability at 25°C/60% relative humidity showing 14.1% degradation after 12 months.
* * *
[0352] All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this disclosure have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the disclosure. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the disclosure as defined by the appended claims.

Claims

WHAT IS CLAIMED IS:
1. A nanoparticle composition comprising at least one nanoparticle, the composition comprising at least one active agent, at a weight percent in the composition ranging from 1% to 50%, at least one lipid at a weight percent in the composition ranging from 1% to 50%, optionally at least one surfactant at a weight percent in the composition ranging from 0% to 17.5%, and water at a weight percent in the composition ranging from 50% to about 97.5%.
2. The nanoparticle composition of claim 1, wherein the active agent comprises one or more pharmaceutical, nutraceutical, cosmetic, pigment, or flavoring.
3. The nanoparticle composition of claim 1, wherein the active agent comprises a plant extract.
4. The nanoparticle composition of claim 1, wherein the active agent comprises a cannabis extract, a kanna extract, a kratom extract, an algae extract, and/or a mushroom extract.
5. The nanoparticle composition of claim 1, wherein the active agent comprises a small molecule.
6. The nanoparticle composition of claim 1, wherein the active agent comprises a biologic.
7. The nanoparticle composition of claim 1, wherein the active agent comprises a flavoring agent.
8. The nanoparticle composition of claim 1, wherein the active agent comprises a cosmetic.
9. The nanoparticle composition of claim 1, wherein the lipid comprises phosphatidylcholine and/or phosphatidylserine.
10. The nanoparticle composition of claim 9, wherein a source of the phophatidylcholine is 20% pure, 50%, pure, or 90% pure.
11. The nanoparticle composition of claim 9, wherein the phosphatidylcholine comprises hydrogenated soybean phosphatidylcholine (HSPC) and/or sunflower pho sphatidy Icholine .
12. The nanoparticle composition of claim 1, wherein the surfactant comprises an emulsifier.
13. The nanoparticle composition of claim 1, wherein the at least one nanoparticle does not comprise a surfactant.
14. The nanoparticle composition of claim 1, wherein the composition comprises a mixture of nanoparticles selected from at least two of a multilamellar nanoparticle vesicles, unilamellar nanoparticle vesicles, multivesicular nanoparticles, emulsion particles, irregular particles with lamellar structures and bridges, partial emulsion particles, combined lamellar and emulsion particles, micelles, and/or combinations thereof.
15. The nanoparticle composition of claim 1, comprised in a liquid formulation.
16. The nanoparticle composition of claim 15, wherein the density of the nanoparticle composition is within 10 % of the density of the liquid formulation.
17. The nanoparticle composition of claim 1, further comprising at least one coemulsifier and/or at least one preservative.
18. The nanoparticle composition of claim 1, wherein the at least one nanoparticle comprises phosphatidylcholine, capric and caprylic triglycerides, one or more sterols, vitamin E, potassium sorbate, sodium benzoate, citric acid, and optionally polysorbate 80 and/or polysorbate 20.
19. A method of manufacturing a nanoparticle composition of claim 1, the method comprising the steps of:
(a) adding one or more active agents, one or more lipids, and optionally one or more surfactants to water;
(b) mixing the ingredients of step (a) creating a mixture;
(c) homogenizing the mixture creating a homogenized mixture;
(d) performing microfluidization on the homogenized mixture creating a microfluid;
(e) sonicating the microfluid creating a sonicated microfluid;
(f) stirring the sonicated microfluid creating a stirred microfluid;
(g) creating a coacervation from the stirred microfluid; and
(h) precipitating the coacervation.
20. The method of claim 19, wherein the mixing of step (b) comprises high sheer mixing.
21. The method of claim 19, wherein the homogenizing of step (c) comprises high pressure homogenization.
22. The method of claim 19, wherein the stirring of step (f) comprises mechanical stirring.
23. The method of claim 19, wherein the precipitating of step (h) comprises solvent precipitation.
24. The method of claim 19, further comprising extruding the composition using hot melt extrusion.
25. The method of claim 19, further comprising drying the nanoparticle composition.
26. The method of claim 25, wherein the drying comprises lyophilizing, spray drying, fluid bed drying, and/or desiccating the nanoparticle composition.
27. A nanoparticle composition comprising at least one nanoparticle, the composition comprising at least one active agent, at least one lipid, and optionally at least one surfactant at a weight ratio of 1 to 50:1 to 50:0 to 17.5, wherein the composition comprise less than 10 wt. % water.
28. The nanoparticle composition of claim 27, wherein the active agent comprises one or more pharmaceutical, nutraceutical, cosmetic, pigment, or flavoring.
29. The nanoparticle composition of claim 27, wherein the composition comprises a mixture of nanoparticles selected from at least two of a liposome, a micelle, a nanoemulsion, a multi-lamellar particle, a double liposome particle, and a solid lipid particle.
30. The nanoparticle composition of claim 1, wherein the at least one nanoparticle comprises phosphatidylcholine, capric and caprylic triglycerides, one or more sterol, vitamin E, potassium sorbate, sodium benzoate, and citric acid.
31. A method of treating a disease, a disorder, and/or a symptom in an individual, the method comprising administering to the individual a therapeutically effective amount of the nanoparticle composition of claim 1.
32. The method of claim 31, wherein the disease is an autoimmune disease, a cancer, a degenerative disease, a blood disease, an infection, and/or a deficiency disease.
33. The method of claim 31, wherein the symptom comprises opioid withdrawal, pain, anxiety, depression, insomnia, inflammation, fever, fatigue, muscle aches, or a combination thereof.
34. The method of claim 31, wherein the administering step comprises local administration.
35. The method of claim 31, wherein the administering step comprises systemic administration.
36. The method of claim 31, wherein the administering step comprises oral administration.
37. The method of claim 31, wherein the therapeutically effective amount of the nanoparticle composition comprises 10 mg/kg to 200 mg/kg.
38. A method of distributing an active agent in a solution, the method comprising contacting the solution with the nanoparticle composition of claim 1.
39. The method of claim 38, wherein the nanoparticle composition has a density within 10% of a density of the solution.
40. The method of claim 38, wherein the nanoparticle composition comprises a mixture of nanoparticles selected from at least two of a liposome, a micelle, a nanoemulsion, a multi-lamellar particle, a double liposome particle, and a solid lipid particle.
41. A method of adjusting a density of the nanoparticle composition of claim 14, the method comprising adjusting the density by adjusting a ratio of at least two of a liposome, a micelle, a nanoemulsion, a multi-lamellar particle, a double liposome particle, and a solid lipid particle .
Il l
PCT/IB2023/053541 2022-04-08 2023-04-06 Compositions for supplementing products with therapeutic agents and methods of use thereof WO2023194953A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263329193P 2022-04-08 2022-04-08
US63/329,193 2022-04-08

Publications (1)

Publication Number Publication Date
WO2023194953A1 true WO2023194953A1 (en) 2023-10-12

Family

ID=86329147

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2023/053541 WO2023194953A1 (en) 2022-04-08 2023-04-06 Compositions for supplementing products with therapeutic agents and methods of use thereof

Country Status (1)

Country Link
WO (1) WO2023194953A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4783443A (en) 1986-03-03 1988-11-08 The University Of Chicago Amino acyl cephalosporin derivatives
US20180296493A1 (en) * 2015-03-10 2018-10-18 Nanosphere Health Sciences, Llc Lipid nanoparticle compositions and methods as carriers of cannabinoids in standardized precision-metered dosage forms
WO2020123407A1 (en) * 2018-12-11 2020-06-18 Disruption Labs Inc. Compositions for the delivery of therapeutic agents and methods of use and making thereof
WO2022217103A1 (en) * 2021-04-08 2022-10-13 Disruption Labs, Inc. Compositions for supplementing products with therapeutic agents and methods of use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4783443A (en) 1986-03-03 1988-11-08 The University Of Chicago Amino acyl cephalosporin derivatives
US20180296493A1 (en) * 2015-03-10 2018-10-18 Nanosphere Health Sciences, Llc Lipid nanoparticle compositions and methods as carriers of cannabinoids in standardized precision-metered dosage forms
WO2020123407A1 (en) * 2018-12-11 2020-06-18 Disruption Labs Inc. Compositions for the delivery of therapeutic agents and methods of use and making thereof
WO2022217103A1 (en) * 2021-04-08 2022-10-13 Disruption Labs, Inc. Compositions for supplementing products with therapeutic agents and methods of use thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Goodman and Gilman's: The Pharmacological Basis of Therapeutics", 1990, PERGAMON PRESS
"Remington: The Science and Practice of Pharmacy", 1 June 2003, LIPPINCOTT WILLIAMS & WILKINS
"Remington's Pharmaceutical Sciences", December 1985, MACK PUB. CO.
"The CTFA International Cosmetic Ingredient Dictionary and Handbook", 2004

Similar Documents

Publication Publication Date Title
EP3840730B1 (en) Compositions for the delivery of therapeutic agents and methods of use and making thereof
US20200138772A1 (en) Stabilized formulations of cannabinoid compositions
WO2022217103A1 (en) Compositions for supplementing products with therapeutic agents and methods of use thereof
US20230233466A1 (en) Compositions for supplementing products with therapeutic agents and methods of use thereof
US20210177043A1 (en) Oral product
US20210177037A1 (en) Oral product
US20220125867A1 (en) Cannabinoid containing composition, methods of preparation and use thereof
US11458092B2 (en) Composition with enhanced passenger molecule loading
EP3782602A1 (en) Composition with enhanced passenger molecule loading for use in a method for administration
WO2023194953A1 (en) Compositions for supplementing products with therapeutic agents and methods of use thereof
WO2023002201A1 (en) Compositions comprising constituents, derivatives or extracts of cannabis
CA3226606A1 (en) Nanoemulsion comprising cannabinoid and/or cannabimimetic
US20230210771A1 (en) Compositions for the delivery of therapeutic agents and methods of use and making thereof
WO2023067509A1 (en) Compositions for supplementing kombucha products with therapeutic agents and methods of making and use thereof
US20210177044A1 (en) Oral product
US20230225968A1 (en) Process for producing visibly clear aqueous consumable products

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23722040

Country of ref document: EP

Kind code of ref document: A1