WO2021113411A1 - Transdermal penetrant formulations for vitamins, minerals and supplements - Google Patents

Transdermal penetrant formulations for vitamins, minerals and supplements Download PDF

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Publication number
WO2021113411A1
WO2021113411A1 PCT/US2020/062956 US2020062956W WO2021113411A1 WO 2021113411 A1 WO2021113411 A1 WO 2021113411A1 US 2020062956 W US2020062956 W US 2020062956W WO 2021113411 A1 WO2021113411 A1 WO 2021113411A1
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formulation
transdermal delivery
amount
delivery formulation
transdermal
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PCT/US2020/062956
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French (fr)
Inventor
Nathan FITZSIMMONS
Ryan Beal
Brandon SAND
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Ampersand Biopharmaceuticals, Inc.
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Publication of WO2021113411A1 publication Critical patent/WO2021113411A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/24—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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • the invention relates generally to topical administration of medicaments. More specifically, it relates to methods and formulations for transdermal administration of health supplements, vitamins and minerals through the skin of a subject.
  • Topical administration describes the application of a substance to a surface of the skin.
  • the term is often used to describe the application of a cream, foam, gel, lotion or ointment to the skin or mucous membranes.
  • the high keratinization of skin cells and their dense packing creates, in most cases, a barrier impermeable to penetration. Because of this, most substances are not absorbed through the skin.
  • transdermal administration refers to applying a substance onto the skin so that it is absorbed into the body for local or systemic distribution.
  • a transdermal solution or transdermal patch is typically placed on one’s skin.
  • the solution or patch includes a medicament that is released into the skin. As the layers of skin absorb the solution, the medicament is absorbed via the blood vessels into the bloodstream. From there, the substance can be circulated through the body.
  • transdermal administration of medicaments.
  • the consumer does not have to schedule and remember to consume doses of pills.
  • transdermal administration is not affected by stomach or digestive issues. Administration across the skin enables drugs to avoid degradation in the gastrointestinal tract or liver. Transdermal delivery is therefore of particular interest for molecules with limited systemic bioavailabilities and short half-lives.
  • Transdermal administration can be effective in administering hydrophobic chemicals such as steroid hormones.
  • transdermal patches are a common means of administering steroidal drugs for birth control, hormone replacement therapy and prevention of motion sickness.
  • Common medicaments that can be administered by transdermal patches include pain relievers, nicotine, hormones, and drugs to treat angina and motion sickness.
  • Medicaments that are not hydrophobic chemicals are typically unsuited for topical administration.
  • the active drug or agent in a topical composition must penetrate the skin, which is structurally complex and relatively thick. Molecules moving through the skin must first penetrate the stratum corneum and any material on its surface. The molecules must then penetrate the epidermis, the papillary dermis, and the capillary walls into the vascular system or lymphatic system. To be absorbed, the molecules must overcome a different resistance to penetration in each layer.
  • Lecithin organogel is a common component of transdermal penetrants. LOs can help deliver different agents through the skin because they possess both the properties of oil and aqueous based formulations. LOs are typically gels that have an organic medium in liquid phase. They can have jelly-like structure that consists of three-dimensional networks of entangled reverse cylindrical micelles, which immobilize the continuous phase and thus convert from liquid to viscous gel.
  • CPEs Chemical Permeation Enhancers
  • SC stratum corneum
  • CPEs are molecules that interact with the constituents of skin's outermost layer, the stratum corneum (SC), and increase its permeability.
  • CPEs are minimally effective in increasing the rate at which drugs permeate the skin.
  • CPEs can also cause skin damage, irritation and sensitization. Further, they are generally ineffective with high molecular weight drugs such as peptides, proteins and nucleic acids.
  • creatine use can increase maximum power and performance in high- intensity anaerobic repetitive work. Creatine can also reduce and delay age-related muscle atrophy, by improving fat-free body mass, muscle strength and endurance, while simultaneously improving bone density. Transdermal administration of creatine could improve its bioavailability and allow small quantities to be released over time. Similarly, pyruvate and capsicum are often used as a weight-loss supplements. These agents could be more effective with transdermal administration.
  • An improved method of transdermal penetration should work with a variety of vitamins, minerals and supplements. It should overcome the barrier presented by the stratum corneum as well as the deeper layers of skin. Further, it should do so without harsh solvents and work with high molecular weight agents such as peptides, proteins and nucleic acids
  • the present disclosure relates to systems and methods of transdermal administration of vitamins, minerals and supplements for a range of benefits.
  • transdermal penetrant formulations for transdermal administration of a vitamin, mineral or supplement.
  • the vitamin, mineral or supplement can be creatine, nitrate ion, caffeine, fructose, curcumin, pychnogenol, anthocyanin, phenolic acid, a flavonoid, a flavonol, b-Alanine, b- Hydroxy b-methylbutyric acid (HMB), carnosine, an omega-3 fatty acid, leucine, isoleucine, valine, citrulline, a ketone ester, a ketone salt, pyruvate, carnitine, serotonin (5-HTP), arginine, glutamine, berberine, resveratrol, vitamin C, vitamin B12, vitamin B9, vitamin B6, vitamin E, calcium, potassium, zinc, iron, sodium, magnesium, chromium, capsaicin, ginger, capsicum, cinnamon or tetrahydrobiopterin.
  • a formulation for transdermal delivery of vitamins, minerals and supplements through the skin of a subject comprising: a therapeutically effective amount of a vitamin, mineral or supplement; lecithin (1 - 20%w/w), isopropyl palmitate (1 - 20 %w/w), sorbic acid (around 1%w/w), benzyl alcohol (around 1%w/w), polyglyceryl-4 Laurate (1 - 10%w/w), vitamin D3 (around 1%w/w), deionized water (35 - 70%w/w), sodium lauryl sulfate (1 - 5%w/w), and poloxamer 407 (5 - 20%w/w).
  • a method for transdermal delivery of a formulation for transdermal delivery of vitamin, mineral or supplement through the skin of a subject comprising: a therapeutically effective amount of a vitamin, mineral or supplement; lecithin (1 - 20%w/w), isopropyl palmitate (1 - 20 %w/w), sorbic acid (around 1%w/w), benzyl alcohol (around 1%w/w), polyglyceryl-4 Laurate (1 - 10%w/w), vitamin D3 (around 1%w/w), deionized water (35 - 70%w/w), sodium nitrate (5 - 25%w/w), sodium lauryl sulfate (1 - 5 %w/w), and poloxamer 407 (5 - 20%w/w).
  • transdermal delivery formulation of an active agent through the skin, nail or hair follicle of a subject wherein the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising: i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w.
  • transdermal delivery formulation of an active agent through the skin, nail or hair follicle of a subject wherein the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, and an active agent.
  • a method to effect transdermal delivery of an active ingredient comprising applying to the skin, nails or hair follicles of a subject an effective amount of a transdermal delivery formulation of an active agent through the skin, nail or hair follicle of a subject, wherein the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, and an active agent.
  • references in this specification to "one embodiment/aspect” or “an embodiment/aspect” means that a particular feature, structure, or characteristic described in connection with the embodiment/aspect is included in at least one embodiment/aspect of the disclosure.
  • the use of the phrase “in one embodiment/aspect” or “in another embodiment/aspect” in various places in the specification are not necessarily all referring to the same embodiment/aspect, nor are separate or alternative embodiments/aspects mutually exclusive of other embodiments/aspects.
  • various features are described which may be exhibited by some embodiments/aspects and not by others.
  • various requirements are described which may be requirements for some embodiments/aspects but not other embodiments/aspects.
  • Embodiment and aspect can in certain instances be used interchangeably.
  • subject refers to any single animal, more preferably a mammal (including such non-human animals as, for example, dogs, cats, horses, rabbits, zoo animals, cows, pigs, sheep, and non-human primates) for which treatment is desired. Most preferably, the patient herein is a human.
  • active agent refers to a substance, compound, or molecule, which is biologically active or otherwise, induces a biological or physiological effect on a subject to which it is administered to.
  • active agent or “active ingredient” refers to a component or components of a composition to which the whole or part of the effect of the composition is attributed.
  • An active agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed.
  • An active agent can be a secondary agent, or in other words, the component(s) of a composition to which an additional part and/or other effect of the composition is attributed.
  • a “pharmaceutical composition” is intended to include the combination of an active agent with a carrier, inert or active, in a sterile composition suitable for diagnostic or therapeutic use in vitro , in vivo or ex vivo.
  • the pharmaceutical composition is substantially free of endotoxins or is non-toxic to recipients at the dosage or concentration employed.
  • an effective amount refers to the amount of the defined component sufficient to achieve the desired chemical composition or the desired biological and/or therapeutic result.
  • that result can be the desired pH or chemical or biological characteristic, e.g., stability of the formulation.
  • the desired result is the alleviation or amelioration of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • the effective amount will vary depending upon the specific disease or symptom to be treated or alleviated, the age, gender and weight of the subject to be treated, the dosing regimen of the formulation, the severity of the disease condition, the manner of administration and the like, all of which can be determined readily by one of skill in the art.
  • a desired effect may, without necessarily being therapeutic, also be a cosmetic effect, in particular for treatment for disorders of the skin or muscles.
  • the terms “treating,” “treatment” and the like are used herein to mean obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disorder or sign or symptom thereof, and/or may be therapeutic in terms of amelioration of the symptoms of the disease or infection, or a partial or complete cure for a disorder and/or adverse effect attributable to the disorder. It can also refer to inhibiting or preventing muscle cramping, improving performance and recovery and/or maintaining levels of supplements, vitamins and minerals for general health and prevention of disease.
  • bioavailability refers to the fraction of an administered dose of unchanged drug that reaches the systemic circulation. For example, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (such as orally), its bioavailability generally decreases due to incomplete absorption and first-pass metabolism. Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration.
  • curcumin refers a diarylheptanoid, belonging to the group of curcuminoids, which are natural phenols responsible for turmeric's yellow color. It is a tautomeric compound existing in enolic form in organic solvents and in keto form in water.
  • pychnogenol refers to a product derived from the bark of a tree known as Pinus pinaster.
  • the active ingredients in pycnogenol can also be extracted from other sources, including peanut skin, grape seed, and witch hazel bark.
  • Pycnogenol can be beneficial for treating circulation problems, allergies, asthma, ringing in the ears, high blood pressure, muscle soreness, pain, osteoarthritis, diabetes, attention deficit-hyperactivity disorder (ADHD), endometriosis, menopausal symptoms, painful menstrual periods, erectile dysfunction (ED), retinopathy, stroke, heart disease, and varicose veins.
  • ADHD attention deficit-hyperactivity disorder
  • ED erectile dysfunction
  • retinopathy stroke, heart disease, and varicose veins.
  • anthocyanin refers to a type of flavonoid, a class of compounds with antioxidant effects. Found naturally in a number of foods, anthocyanins are the pigments that give red, purple, and blue plants their rich coloring. Anthocyanins have been shown to have antioxidant properties in vitro.
  • flavonoids refers to substances that give pigments for flower coloration, producing yellow or red/blue pigmentation in petals designed to attract pollinator animals.
  • flavonoids are involved in UV filtration, symbiotic nitrogen fixation and floral pigmentation. They may also act as chemical messengers, physiological regulators, and cell cycle inhibitors.
  • Chemically, flavonoids have the general structure of a 15-carbon skeleton, which consists of two phenyl rings (A and B) and a heterocyclic ring. Flavonoids may have health benefits to humans as antioxidants, anti-inflammatories, anti-cancer, anti-bacteria and in cardiovascular disease.
  • b-Hydroxy b-methy!butyric acid ⁇ MB
  • b-bydroxy b- methylbutyrate refers to a dietary supplement that can increase exercise-induced gains in muscle size, muscle strength, and lean body mass, reduce skeletal muscle damage from exercise, improve aerobic exercise performance, and expedite recovery from exercise.
  • berine refers to a quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids found in a group of shrubs called Berberis. it has been used to treat various ailments, particularly in Chinese medicine.
  • capsaicin refers to 8-methyl-N-vanillyl-6-nonenamide, an active component of chili peppers. Capsaicin has analgesic properties and is a neuropeptide releasing agent selective for primary sensory peripheral neurons. Used topically, capsaicin can aid in controlling peripheral nerve pain.
  • capsicum refers to an herb, red pepper or chili pepper.
  • Capsaicin is a resin derived from hot chili peppers of the Capsicum family. It can be used to treat nociceptive and neuropathic pain. Capsicum is most commonly used for rheumatoid arthritis (RA), osteoarthritis, and other painful conditions. It is also used for digestion problems, conditions of the heart and blood vessels.
  • Carnosine refers to beta-a!any!-L-histidine. It is a dipeptide molecule with a characteristic imidazole-ring made up of the amino acids beta- alanine and histidine. Carnosine acts as an antiglycating agent, reducing the rate of formation of advanced glycation end-products (substances that can be a factor in the development or worsening of many degenerative diseases, such as diabetes, atherosclerosis, chronic renal failure, and Alzheimer's disease), and ultimately reducing development of atherosclerotic plaque build-up.
  • carnitine refers to b-hydroxy-Y-N-trimethy!aminobutyric acid, 3- hydroxy-4-N,N,N-trimethylaminobutyrate which is a quaternary ammonium compound involved in metabolism in most mammals, plants and some bacteria.
  • flavonol refers to a class of flavonoids that have the 3- hydroxyflavone backbone (lUPAC name : 3-hydroxy-2-phenylchromen-4-one). Their diversity stems from the different positions of the phenolic -OH groups. They are distinct from flavanols (with "a") such as catechin, another class of flavonoids.
  • nitrate ion or “nitrate” refers to the compound NO3. Its presence can help modulate levels of nitric oxide (NO) which is important in muscle physiology. Tissue concentrations of nitrate and nitrite can be increased by consumption of green leafy vegetables such as lettuce, spinach and beetroot. Thus, dietary nitrate supplementation can be a practical way increase circulating plasma concentrations of NO2 and thus NO bioavailability. A nitrate supplement can also lower resting blood pressure, reduced pulmonary O2 uptake during submaximal exercise and, perhaps, enhance exercise tolerance or performance.
  • NO nitric oxide
  • phenolic acid refers to a type of phytochemical called a polyphenol.
  • Other types of polyphenols include flavonoids and stilbenes.
  • Phenolic acids are found in a variety of plant-based foods; the seeds and skins of fruits and the leaves of vegetables contain the highest concentrations.
  • Two important naturally occurring types of phenolic acids are hydroxybenzoic acids and hydroxycinnamic acids, which are derived from non-phenolic molecules of benzoic and cinnamic acid, respectively.
  • resveratrol refers to 3,5,4'-trihydroxy-trans-stilbene, a stilbenoid.
  • tetrahydrobiopterin (BH4, THB) or “sapropterin” refers to a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin. Tetrahydrobiopterin has multiple roles in human biochemistry. The major one is to convert amino acids such as phenylalanine, tyrosine, and tryptophan to precursors of dopamine and serotonin, major monoamine neurotransmitters. It works as a cofactor, being required for an enzyme's activity as a catalyst, mainly hydroxylases.
  • a “pharmaceutical composition” is intended to include, without limitation, the combination of an active agent with a carrier, inert or active, in a sterile composition suitable for diagnostic or therapeutic use in vitro , in vivo or ex vivo.
  • the pharmaceutical composition is substantially free of endotoxins or is non-toxic to recipients at the dosage or concentration employed.
  • an effective amount refers, without limitation, to the amount of the defined component sufficient to achieve the desired chemical composition or the desired biological and/or therapeutic result.
  • that result can be the desired pH or chemical or biological characteristic, e.g., stability of the formulation.
  • the desired result is the alleviation or amelioration of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • the effective amount will, without limitation, vary depending upon the specific disease or symptom to be treated or alleviated, the age, gender and weight of the subject to be treated, the dosing regimen of the formulation, the severity of the disease condition, the manner of administration and the like, all of which can be determined readily by one of skill in the art.
  • a desired effect may, without necessarily being therapeutic, also be a cosmetic effect, in particular for treatment for disorders of the skin described herein.
  • a “subject” of diagnosis or treatment is, without limitation, a prokaryotic or a eukaryotic cell, a tissue culture, a tissue or an animal, e.g. a mammal, including a human.
  • Non-human animals subject to diagnosis or treatment include, for example, without limitation, a simian, a murine, a canine, a leporid, such as a rabbit, livestock, sport animals, and pets.
  • the terms “treating,” “treatment” and the like are used herein, without limitation, to mean obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disorder or sign or symptom thereof, and/or may be therapeutic in terms of amelioration of the symptoms of the disease or infection, or a partial or complete cure for a disorder and/or adverse effect attributable to the disorder.
  • formulation(s) means a combination of at least one active ingredient with one or more other ingredient, also commonly referred to as excipients, which may be independently active or inactive.
  • excipients also commonly referred to as excipients, which may be independently active or inactive.
  • formulation may or may not refer to a pharmaceutically acceptable composition for administration to humans or animals and may include compositions that are useful intermediates for storage or research purposes.
  • the patients and subjects of the invention method are, in addition to humans, veterinary subjects, formulations suitable for these subjects are also appropriate.
  • Such subjects include livestock and pets as well as sports animals such as horses, greyhounds, and the like.
  • a formulation, a formulation for transdermal delivery and a transdermal delivery formulation are each a formulation for transdermal delivery, including, the transdermal delivery of an active ingredient for the treatment of a syndrome and or a disease in an individual.
  • Embodiments include a transdermal lotion or cream for administration of vitamins, minerals and supplements to a subject. It is placed on the skin to deliver a specific dose of an agent through the skin.
  • the agent can be delivered across the skin into a localized subdermal location.
  • a lotion can promote healing to an injured area of the body.
  • a mineral or supplement can be delivered to a sore muscle, joint or tendon from the lotion.
  • the agent can enter the circulation for systemic distribution.
  • a vitamin can be distributed throughout the body.
  • an agent can be administered using a transdermal or medicated adhesive patch.
  • a patch can utilize a porous membrane covering a reservoir of the agent.
  • the agent can be embedded in layers of the adhesive that release the agent as they dissolve or melt.
  • An advantage of a transdermal drug delivery route over other types of delivery is that the formulation can provide a controlled release of the agent.
  • Conventional transdermal delivery systems are generally ineffective for use with agents and medications that are large molecules and/or hydrophilic molecules.
  • Embodiments include a method and formulation for subdermal delivery of a variety of vitamins, minerals and supplements.
  • transdermal administration of medicaments. Proteins and peptides used, for example, in aging treatments can be degraded by the gastric acid and enzymes. Transdermal administration is not affected by stomach or digestive issues. Further, people can benefit from drugs that are absorbed slowly and regularly. With a transdermal formulation, a medicament can be released in small quantities over a long period of time.
  • vitamin A can cause dose-dependent toxicity in many cases.
  • oral administration of vitamin A can result in hypervitaminosis A.
  • the main problems associated with the vitamin A are its half-life, fast absorption (due to lipophilicity) and its toxicity (due to high loading and frequent dosing).
  • some drugs undergo first-pass metabolism, which prevents their delivery to the desired site of action.
  • many hydrophilic or lipophilic drugs show either poor dissolution or poor absorption on oral administration. With a transdermal formulation, the effective concentration of an agent can be applied at the desired site without painful delivery.
  • nutrients are supplied via transdermal administration.
  • a transdermal delivery formulation can deliver to tired muscles sufficient amounts of a neutralizing agent for lactic acid, such as a ketone component, to relieve the burning sensation felt by the athlete due to the buildup of lactic acid. This permits the athlete to continue to perform at optimum level for longer periods of time.
  • athletes or others "working out” are expending high amounts of energy and are in need of energy generation, especially in those areas of their musculature that are involved in performing workouts and, therefore, need to consume large numbers of calories.
  • These nutrients can be supplied directly rather than requiring oral ingestion which is counterproductive and relatively slow.
  • a wide variety of therapeutic agents can be used in a transdermal delivery formulation, such as vitamins, minerals and supplements.
  • a vitamin is administered transdermally.
  • a vitamin can be defined as an organic molecule (or related set of molecules) that is an essential micronutrient necessary in small quantities for the proper functioning of metabolism.
  • vitamin A acts as a regulator of cell and tissue growth and differentiation.
  • Vitamin D provides a hormone-like function, regulating mineral metabolism for bones and other organs.
  • the B complex vitamins function as enzyme cofactors (coenzymes) or the precursors for them.
  • Vitamins C and E function as antioxidants.
  • a mineral is administered transdermally.
  • a mineral can be defined as a chemical element required as an essential nutrient by organisms to perform functions necessary for life.
  • the five major minerals in the human body are calcium, phosphorus, potassium, sodium, and magnesium. All of the remaining elements in a human body can be referred to as "trace elements.”
  • the trace elements that have a specific biochemical function in the human body are sulfur, iron, chlorine, cobalt, copper, zinc, manganese, molybdenum, iodine and selenium.
  • a dietary supplement is administered transdermally.
  • a dietary supplement can be defined as a manufactured product intended to supplement the diet.
  • a supplement can provide nutrients either extracted from food sources or synthetic, individually or in combination, in order to increase the quantity of their consumption.
  • the class of nutrient compounds includes vitamins, minerals, fiber, fatty acids and amino acids. Dietary supplements can also contain substances that have not been confirmed as being essential to life, but are marketed as having a beneficial biological effect, such as plant pigments or polyphenols.
  • Table 1 lists several agents that can be administered transdermally according to some embodiments. The “% solution” indicates the relative dosing which is the amount in the transdermal solution.
  • the present disclosure herein demonstrates transdermal delivery of an agent without many of the negative effects on color, smell, grittiness and stability driven by the use of lecithin organogel. Moreover, the methods describe herein improve transdermal penetration.
  • a transdermal delivery formulation contains a phosphatide in a concentration of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70% or more w/w of the transdermal delivery formulation.
  • Phosphatides - Soy lecithin contains about 57.5 %w/w phosphatides.
  • the primary phosphatides found in Soy Lecithin are inositol phosphatides (20.5 %w/w of Soy lecithin), phosphatidylcholine (20%), and phosphatidylethanolamine (11 %w/w of Soy lecithin).
  • phosphatidylcholine is used for the full amount (57.5 %w/w of Soy lecithin) as it is known to aide in skin penetration.
  • Other phosphatides include phosphatidic acid, phosphatidylserine and phosphatidylinositol.
  • a transdermal delivery formulation contains a sterol or benzyl alcohol in a concentration of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30% or more w/w of the transdermal delivery formulation.
  • Sterols - Soy lecithin contains about 2.5 %w/w sterols.
  • benzyl alcohol is used in substitution of the sterol in a transdermal delivery formulation to act as a penetration enhancer.
  • a sterol is cholesterol, ergosterol, hopanoids, hydroxysteroid, phytosterol and/or other steroids.
  • a transdermal delivery formulation contains a carbohydrate in a concentration of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70% or more w/w of the transdermal delivery formulation.
  • Carbohydrates - Soy lecithin contains about 5 %w/w free carbohydrates.
  • glucose is used in substitution of a free carbohydrate to maintain the ratio of sugars in the transdermal delivery formulation disclosed herein.
  • a carbohydrate is a monosaccharide, a disaccharide, a polyol, a malto-oligosaccharide, an oligosaccharide, a starch, a polysaccharide.
  • a carbohydrate is glucose, galactose, fructose, xylose, sucrose, lactose, maltose, trehalose, sorbitol, mannitol, maltodextrins, raffinose, stachyose, fructo-oligosaccharide, amylose, amylopectin, modified starches, glycogen, cellulose, hemicellulose, pectin and/or hydrocolloid.
  • the transdermal delivery formulation maintains the about 1 %w/w of water contained in Soy lecithin.
  • a transdermal delivery formulation contains water in a concentration of at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70% or more w/w of the transdermal delivery formulation.
  • Fatty acids - Soy lecithin contains about 34 %w/w fatty acids, including 18- 19 %w/w linoleic acid, 1-2 %w/w alpha-linoleic acid, 8-9 %w/w oleic acid, about 5 %w/w Palmitic acid, and 1-2 %w/w stearic acids.
  • the fatty acids are similar to the fatty acids contained in soy lecithin.
  • alpha-linoleic is removed from the transdermal delivery formulation as it is known to oxidize and can become rancid.
  • the amount of stearic acid has been increased (i.e.
  • a seed oil such as purified safflower oil is used in a transdermal delivery formulation due to its similarity to the fatty acids found in Soy lecithin, its relative availability and its low cost.
  • the fatty acid content of a transdermal formulation can be adjusted with a different seed oil through the addition of smaller amounts of the fatty acids disclosed herein.
  • a fatty acid is a saturated or an unsaturated fatty acid.
  • an unsaturated fatty acid is myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, a-Linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and/or docosahexaenoic acid.
  • a saturated fatty acid is caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid and/or cerotic acid.
  • the fatty acid is a dietary fat and include duct fat, lard, tallow, butter, coconut oil, cocoa butter, palm kernel oil, palm oil, cottonseed oil, wheat germ oil, soybean oil, olive oil, corn oil, sunflower oil, safflower oil, hemp oil and/or canola/rapeseed oil.
  • a transdermal delivery formulation comprises the components of Table 2: Table 2
  • a transdermal delivery formulation comprises the components of Table 3:
  • the concentration of Phosphatidylcholine in a transdermal delivery formulation is at least 10%, at least 15%, at least 20%, at least 25%, at least 28.75%, at least 30%, at least 35%, at least 40% or more. In an aspect, the concentration of phosphatidylcholine in a transdermal delivery formulation is not more than 10%, not more than 15%, not more than 20%, not more than 25%, not more than 28.75%, not more than 30%, not more than 35%, not more than 40% or more.
  • the concentration of phosphatidylcholine in a transdermal delivery formulation is about 10%, about 15%, about 20%, about 25%, at least 28.75%, about 30%, about 35%, about 40% or more. In an aspect, the concentration of Phosphatidylcholine in a transdermal delivery formulation is from 10% to 40%, is from 15% to 35%, is from 20% to 30%, is from 25% to 30%, is from 28% to 29%.
  • the concentration of glucose in a transdermal delivery formulation is at least 1%, at least 2%, at least 2.5%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9% or more. In another aspect, the concentration of glucose in a transdermal delivery formulation is about 1%, about 2%, about 2.5%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or more.
  • the concentration of glucose in a transdermal delivery formulation is no more than 1%, no more than 2%, no more than 2.5%, no more than 3%, no more than 4%, no more than 5%, no more than 6%, no more than 7%, no more than 8%, no more than 9% or more.
  • the concentration of glucose in a transdermal delivery formulation is from 1% to 10%, is from 2% to 9%, is from 2.5% to 5%, is from 2% to 3%, is from 3% to 8%, if from 4% to 7%, if from 5% to 6%, is from 2% to 4%, is from 1.5% to 3.5.
  • the concentration of Benzyl Alcohol in a transdermal formulation is at least 0.25%, at least 0.5%, at least 0.75%, at least 1%, at least 2%, at least 2.5%, at least 3%, at least 4%, at least 5% or more. In an embodiment, the concentration of Benzyl Alcohol in a transdermal formulation is about 0.25%, about 0.5%, about 0.75%, about 1%, about 2%, about 2.5%, about 3%, about 4%, about 5% or more.
  • the concentration of Benzyl Alcohol in a transdermal formulation is at from 0.25% to 5 %; from 0.5% to 4%, from 0.75% to 3%, from 1% to 2.5% or from 0.5% to 2%. In a further embodiment, the concentration of Benzyl Alcohol in a transdermal formulation is no more than 0.25%, no more than 0.5%, no more than 0.75%, no more than 1%, no more than 2%, no more than 2.5%, no more than 3%, no more than 4%, no more than 5%.
  • the concentration of Deionized Water in a transdermal formulation is at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5% or more. In an embodiment, the concentration of Deionized Water in a transdermal formulation is about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5% or more.
  • the concentration of Deionized Water in a transdermal formulation is from 0.1% to 5%, from 0.2% to 4 %, from 0.3% to 3%, 0.4% - 2%, 0.5% to 1 %, from 0.6% t 0.9%, from 0.7% to 0.8%, from 0.4% to 1.5%, from 0.3% to 0.7% or from 0.4% to 0.6%.
  • the concentration of Deionized Water in a transdermal formulation is no more than 0.1%, no more than 0.2%, no more than 0.3%, no more than 0.4%, no more than 0.5%, no more than 0.6%, no more than 0.7%, no more than 0.8%, no more than 0.9%, no more than 1 %, no more than 2%, no more than 3%, no more than 4%, no more than 5% or more.
  • the concentration of Safflower oil in a transdermal delivery formulation is at least 1 %, at least 5%, at least 7.5%, at least 10%, at least 11 %, at least 11.06%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20 % or more.
  • the concentration of Safflower oil in a transdermal delivery formulation is about 1%, about 5%, about 7.5%, about 10%, about 11 %, about 11.06%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17 %, about 18%, about 19%, about 20 % or more.
  • the concentration of Safflower oil in a transdermal delivery formulation is from 1 % to 20%, from 5% to 19%, from 7.5% to 18%, from 10% to 17%, from 11 % to 16%, from 11.06%, 12% from 11 % to 12%, from 12% to 14%, from 13% to 14%, from 10% to 12%, from 10.5% to 12.5% or from 11% to 11.25%.
  • the concentration of Safflower oil in a transdermal delivery formulation is no more than 1%, no more than 5%, no more than 7.5%, no more than
  • the concentration of Oleic Acid in a transdermal delivery formulation is at least 1%, at least 2%, at least 3%, at least 3.65%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10% or more.
  • the concentration of Oleic Acid in a transdermal delivery formulation is about 1 %, about 2%, about 3%, about 3.65%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10% or more. In a further aspect, the concentration of Oleic Acid in a transdermal delivery formulation is no more than 1%, no more than 2%, no more than 3%, no more than 3.65%, no more than 4%, no more than 5%, no more than 6%, no more than 7%, no more than 8%, no more than 9%, no more than 10% or more.
  • the concentration of Oleic Acid in a transdermal formulation is from 1% to 10%, from 2% to 9%, from 2% to 3%, from 3% to 4%, from 3% to 8%, from 4% to 7%, from 5% to 6%, from 2 to 2.5% or from 2.5% to 4%.
  • the concentration of Stearic Acid in a transdermal formulation is at least 1%, at least 2%, at least 2.34%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10% or more.
  • the concentration of Stearic Acid in a transdermal formulation is no more than 1%, no more than 2%, no more than 2.34%, no more than 3%, no more than 4%, no more than 5%, no more than 6%, no more than 7%, no more than 8%, no more than 9%, no more than 10% or more.
  • the concentration of Stearic Acid in a transdermal formulation is about 1%, about 2%, about 2.34%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10% or more. In another aspect, the concentration of Stearic Acid in a transdermal formulation is from 1% to 10%, from 2% to 9%, from 2% to 3%, from 2.34% to 2.5%, from 3% to 8%, from 4% to 7%, from 5% to 6% or from 1.5% to 2.5%.
  • the concentration of Isopropyl Palmitate in a transdermal formulation is at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% or more. In an aspect, the concentration of Isopropyl Palmitate in a transdermal formulation is about 10%, about 20%, about 25%, about 30%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more.
  • the concentration of Isopropyl Palmitate in a transdermal formulation is no more than 10%, no more than 20%, no more than 25%, no more than 30%, no more than 40%, no more than 45%, no more than 50%, no more than 55%, no more than 60%, no more than 65%, no more than 70%, no more than 75% or more.
  • the concentration of Isopropyl Palmitate in a transdermal formulation is from 10% to 75%, from 20% to 70%, from 25% to 65%, from 30% to 60%, from 40% to 55%, from 45% to 50%, from 40% to 60%, from 45% to 55% or from 47% to 53%.
  • transdermal delivery formulation Certain components or ingredients of a transdermal delivery formulation provided herein may be supplemented with components described in greater detail in the inventor’s related applications mentioned above, including United states Application No. 16/132,358 filed September 14, 2018, entitled ‘Methods and Formulations For Transdermal Administration Of Buffering Agents’, International Patent Application No. PCT/US18/51250 filed September s, 2018, entitled ‘Methods of Administration and Treatment’, and International Patent Application PCT/US18/28017 by Bruce Sand filed April 17, 2018, entitled ‘Parental non-systemic administration of buffering agents for inhibiting metastasis of solid tumors, hyperpigmentation and gout’, all incorporated by reference in their entirety herein.
  • a transdermal delivery formulation containing iron can be formulated at acidic pH to minimize the spontaneous oxidation Fe(ll) into Fe(lll).
  • Suitable nonlimiting exemplary iron chelators include deferoxamine, ethylenediaminetetraacetic acid (EDTA), 1 ,2-diethyl-3-hydroxypyridin-4-one (CP94), Desferal, Deferiprone and Deferasirox, succimer, trientine, Desferrithiocin,
  • Suitable nonlimiting exemplary antioxidants include glutathione, vitamin C, vitamin E, superoxide dismutase, catalase, pNaKtide, Butylated hydroxytoluene, Butylated hydroxyanisole, tert-Butylhydroquinone, HP beta CD, resveratrol, retinol, coenzyme q10, niacinamide, polyphenols, flavonoids, beta-carotene, lutein, and lycopene.
  • a transdermal delivery formulation can include mixtures wherein the components interact synergistically and induce skin permeation enhancements better than that induced by the individual components. Synergies between chemicals can be exploited to design potent permeation enhancers that overcome the efficacy limitations of single enhancers. Several embodiments disclosed herein utilize three to five distinct permeation enhancers.
  • a transdermal delivery formulation comprises phosphatidylcholine in amount less than 12 %w/w or 18 %w/w of the formulation. In some embodiments, the transdermal delivery formulation comprises a phospholipid in amount less than 12 %w/w or 18 %w/w of the formulation. In some embodiments, the transdermal delivery formulation comprises a mixture of tridecane and undecane in amount less than 2 %w/w, 5 %w/w, or 8 %w/w of the formulation.
  • the formulation comprises Cetiol Ultimate® in an amount less than about 2 %w/w, 5 %w/w, or 10 %w/w, or an equivalent mixture of tridecane and undecane.
  • the transdermal delivery formulation comprises cetyl alcohol in amount less than 2 %w/w, 5 %w/w, or 8 %w/w of the formulation.
  • the transdermal delivery formulation comprises benzyl alcohol in an amount less than about 2 %w/w, 5 %w/w, or 8 %w/w.
  • the transdermal delivery formulation comprises stearic acid in an amount less than 2 %w/w, 5 %w/w, or 8 %w/w of the formulation.
  • any of the anesthetic compositions of a transdermal delivery formulation it may be desirable to administer the epinephrine in tandem with a transdermal anesthetic.
  • a chelator such as the iron chelator Desferal® may stabilize the epinephrine sufficiently to include it in the transdermal delivery formulation.
  • a suitable dose of iron or an iron containing transdermal delivery formulation administered topically as a transdermal delivery formulation for a subject e.g.
  • a human patient is at least about 500 mg, at least about 750 mg, at least about 1000 mg, at least about 1.5 g, at least about 2.0 g, at least about 2.5 g, at least about 3.0 g, at least about 3.5 g, at least about 4.0 g, at least about 4.5 g, at least about 5.0 g, at least about 6.0 g, at least about 7.0 g, at least about 8.0 g, at least about 9.0 g, at least about 10.0 g, at least about 11 g, at least about 12 g, at least about 13 g, at least about 14 g, at least about 15 g, at least about 20 g, at least about 25 g, at least about 30 g, at least about 35 g, at least about 40 g, at least about 45 g, at least about 50 g, or more.
  • This dose is typically administered daily, twice a day, or three times a day, but it may also be administered four times a day, five times a day, or more than
  • a suitable daily dose of iron or an iron containing transdermal delivery formulation administered topically as a transdermal delivery formulation for a subject is at least about 10 mg/kg, at least about 25 mg/kg, at least about 30 mg/kg, at least about 35 mg/kg, at least about 40 mg/kg, at least about 45 mg/kg, at least about 50 mg/kg, at least about 55 mg/kg, at least about 60 mg/kg, at least about 65 mg/kg, at least about 70 mg/kg, at least about 75 mg/kg, at least about 80 mg/kg, at least about 90 mg/kg, at least about 100 mg/kg, at least about 125 mg/kg, at least about 150 mg/kg, at least about 160 mg/kg, at least about 170 mg/kg, at least about 175 mg/kg, at least about 180 mg/kg, at least about 190 mg/kg, at least about 200 mg/kg, at least about 225 mg/kg, at least about 250 mg/kg, at least about 275 mg/kg, at least about 10 mg/kg
  • a suitable daily dose of iron or an iron containing transdermal delivery formulation administered topically as a transdermal delivery formulation for a subject is about 10 mg/kg to about 1.0 g/kg, and more typically the daily dose is about 10 mg/kg to about 500 mg/kg, about 25 mg/kg to about 500 mg/kg, about 50mg/kg to about 300 mg/kg, about 75 mg/kg to about 300 mg/kg, about 75mg/kg to about 250 mg/kg, about 100 mg/kg to about 300 mg/kg, about 75 mg/kg to about 200 mg/kg, about 100 mg/kg to about 200 mg/kg, or alternative ranges.
  • a transdermal delivery formulation for transdermal delivery ketone components through the skin of a subject comprising: a ketone component in an amount between about 10-60 %w/w; a transdermal delivery formulation in an amount less than about 60 %w/w, and water in an amount less than about 50 %w/w.
  • a method of inducing ketosis to treat a disorder and/or treating a disorder with ketone supplementation in a subject comprises administering an effective amount of a transdermal delivery formulation for transdermal delivery of one or more ketone components through the skin of a subject, comprising: a ketone component in an amount between about IQ- 60 %w/w; a transdermal delivery formulation in an amount less than about 60 %w/w, and water in an amount less than about 50 %w/w.
  • Particularly suitable formulation for transdermal delivery ketone components are described in the US Application No. 62/742,172, filed October 5, 2018, which is incorporated by reference herein.
  • a transdermal delivery formulation comprise mixtures wherein the components interact synergistically and induce skin permeation enhancements better than that induced by the individual components. Synergies between chemicals can be exploited to design potent permeation enhancers that overcome the efficacy limitations of single enhancers. Several embodiments disclosed herein utilize one or more distinct permeation enhancers.
  • a transdermal delivery formulation will comprise penetrants including either or both chemical penetrants (CPEs) and peptide-based cellular penetrating agents (CPPs) that encourage transmission across the dermis and/or across membranes including cell membranes, as would be the case in particular for administration by suppository or intranasal administration, but for transdermal administration as well.
  • CPEs chemical penetrants
  • CPPs peptide-based cellular penetrating agents
  • suitable penetrants include those that are described in the above- referenced US2009/0053290 ('290), W02014/209910 ('910), and WO2017/127834.
  • transdermal delivery can be effected by mechanically disrupting the surface of the skin to encourage penetration, or simply by supplying the formulation applied to the skin under an occlusive patch.
  • the transdermal delivery formulation comprises a completion component as well as one or more electrolytes sufficient to impart viscosity and viscoelasticity, one or more surfactants and an alcohol.
  • the completion component can be a polar liquid, a non-polar liquid or an amphiphilic substance.
  • the penetrant may further comprise a keratinolytic agent effective to reduce thiol linkages, disrupt hydrogen bonding and/or effect keratin lysis and/or a cell penetrating peptide (sometimes referred to as a skin-penetrating peptide) and/or a permeation enhancer.
  • Suitable gelling components also include isopropyl palmitate, ethyl laurate, ethyl myristate and isopropyl myristate.
  • a transdermal delivery formulation comprises a gelling agent in an amount less than 5 %w/w of a transdermal delivery formulation.
  • Certain hydrocarbons such as cyclopentane, cyclooctane, frans-decalin, trans- pinane, n-pentane, n-hexane, n-hexadecane may also be used.
  • the transdermal delivery formulation comprises a mixture of xanthan gum, sclerotium gum, pullulan, or a combination thereof in an amount less than 2 %w/w, 5 %w/w, or 10 %w/w of the formulation.
  • a transdermal delivery formulation comprises SiligelTM in an amount between about 1-5 % w/w or 5-15 % w/w, or an equivalent mixture of xanthan gum, sclerotium gum, and pullulan.
  • a transdermal delivery formulation comprises a mixture of caprylic triglycerides and capric triglycerides in amount less than 2 %w/w, 8 %w/w, or 10 %w/w of the formulation.
  • a transdermal delivery formulation comprises Myritol® 312 in an amount between about 0.5-10 %w/w, or an equivalent mixture of caprylic triglycerides and capric triglycerides.
  • a transdermal delivery formulation is in an amount between about 10-90 %w/w or 10-50 %w/w of the formulation or at least 10%w/w, at least 20%w/w, at least 30%w/w, at least 40 %w/w, at least 50%w/w, at least 60%w/w, at least 70%w/w, at least 80%w/w, at least 90%w/w or at least 95%w/w.
  • a transdermal delivery formulation comprises phosphatidyl choline in amount less than 7 %w/w, less than 8%w/w, less than 9%w/w, less than 10%w/w, less than 11%w/w, less than 12 %w/w, less than 13%w/w, less than 14%w/w, less than 15%w/w, less than 16%w/w, less than 17%w/w or less than 18 %w/w of the formulation.
  • a transdermal delivery formulation comprises a phospholipid in amount less than 20 %w/w, less than 30 % w/w, less than 40 % w/w, less than or 50 %w/w of the formulation.
  • a transdermal delivery formulation comprises a mixture of tridecane and undecane in amount less than 2 %w/w, 3 %w/w, 4 %w/w, 5 %w/w, 6 %w/w, 7 %w/w, or 8 %w/w of the formulation.
  • the formulation comprises Cetiol Ultimate® in an amount less than about 2 %w/w, 3 %w/w, 4 %w/w, 5 %w/w, 6 %w/w, 7 %w/w, 8 %w/w, 9 %w/w, or 10 %w/w, or an equivalent mixture of tridecane and undecane.
  • a transdermal delivery formulation comprises cetyl alcohol in amount less than 2 %w/w, 3 %w/w, 4 %w/w, 5 %w/w, 6 %w/w, 7 %w/w, 8 %w/w, 9 %w/w, or 10 %w/w of the formulation.
  • the formulation comprises benzyl alcohol in an amount less than about 2 %w/w, 3 %w/w, 4 %w/w, 5 %w/w, 6 %w/w, 7 %w/w, 8 %w/w, 9 %w/w, or 10 %w/w.
  • a transdermal delivery formulation comprises stearic acid in an amount less than 2 %w/w, 3 %w/w, 4 %w/w, 5 %w/w, 6 %w/w, 7 %w/w, 8 %w/w, 9 %w/w, or 10 %w/w of the formulation.
  • the transdermal delivery formulation comprises phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, one or more phosphatides, one or more Inositol phosphatides, or combinations thereof, in amount less than 30 %w/w or in amount less than 12 %w/w of the formulation.
  • An additional component in a transdermal delivery formulation of the disclosure is an alcohol. Benzyl alcohol and ethanol are illustrated in the Examples.
  • derivatives of benzyl alcohol which contain substituents on the benzene ring, such as halo, alkyl and the like.
  • the weight percentage of benzyl or other related alcohol in the final composition is 0.5-20% w/w, and again, intervening percentages such as 1 % w/w, 2% w/w, 3 %w/w, 4 %w/w, 5 %w/w, 6 %w/w, 7 %w/w, 8 %w/w, 9 %w/w, or 10 %w/w, and other intermediate weight percentages are included.
  • the molecule Due to the aromatic group present in a transdermal delivery formulation such as benzyl alcohol, the molecule has a polar end (the alcohol end) and a non polar end (the benzene end). This enables the agent to dissolve a wider variety of transdermal delivery formulation components.
  • the performance of a transdermal delivery formulation is further improved by including a nonionic detergent and polar gelling agent or including a powdered surfactant.
  • a nonionic detergent and polar gelling agent or including a powdered surfactant.
  • detergents typically nonionic detergents are added.
  • the nonionic detergent should be present in an amount between about 1% w/w to 30% w/w of a transdermal delivery formulation.
  • the amount of detergent is relatively low - e.g., 2-25 %w/w, or 5-15 %w/w or 7-12 %w/w of a transdermal delivery formulation.
  • relatively higher percentages are usually used - e.g., 20-60 %w/w.
  • a transdermal delivery formulation further comprises a detergent portion in an amount between about 1 to 70 %w/w or 1-60 %w/w of a transdermal delivery formulation.
  • the nonionic detergent provides suitable handling properties whereby the formulations are gel-like or creams at room temperature.
  • the detergent typically a poloxamer, is present in an amount between about 2-12 %w/w of a transdermal delivery formulation, preferably between about 5-25 %w/w in polar formulations.
  • the detergent is added in powdered or micronized form to bring the composition to 100% and higher amounts are used.
  • the nonionic detergent is added as a solution to bring the composition to 100%. If smaller amounts of detergent solutions are needed due to high levels of the remaining components, more concentrated solutions of the nonionic detergent are employed.
  • the percent detergent in the solution may be 10% to 40% or 20% or 30% and intermediate values depending on the percentages of the other components.
  • Suitable nonionic detergents include poloxamers such as the non-ionic surfactant Pluronic® and any other surfactant characterized by a combination of hydrophilic and hydrophobic moieties.
  • Poloxamers are triblock copolymers of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyethyleneoxide.
  • Other nonionic surfactants include long chain alcohols and copolymers of hydrophilic and hydrophobic monomers where blocks of hydrophilic and hydrophobic portions are used.
  • a transdermal delivery formulation also contains surfactant, typically, nonionic surfactant at 2-25% w/w of a transdermal delivery formulation along with a polar solvent wherein the polar solvent is present in an amount at least in molar excess of the nonionic surfactant.
  • the composition comprises the above-referenced amounts of a transdermal delivery formulation and benzyl alcohol along with a sufficient amount of a polar solution, typically an aqueous solution or polyethylene glycol solution that itself contains 10%-40% of surfactant, typically nonionic surfactant to bring the composition to 100%.
  • surfactants include polyoxyethylated castor oil derivatives such as HCO-60 surfactant sold by the HallStar Company; nonoxynol; octoxynol; phenylsulfonate; poloxamers such as those sold by BASF as Pluronic® F68, Pluronic® FI27, and Pluronic® L62; polyoleates; Rewopal® HVIO, sodium laurate, sodium lauryl sulfate (sodium dodecyl sulfate); sodium oleate; sorbitan dilaurate; sorbitan dioleate; sorbitan monolaurate such as Span® 20 sold by Sigma-Aldrich; sorbitan monooleates; sorbitan trilaurate; sorbitan trioleate; sorbitan monopalmitate such as Span® 40 sold by Sigma-Aldrich; sorbitan stearate such as Span® 85 sold by Sigma
  • the weight percentage range of nonionic surfactant is in the range of 3% w/w-15% w/w, and again includes intermediate percentages such as 5 %w/w, 7 %w/w, 10 %w/w, 12 %w/w, and the like.
  • the detergent portion comprises a nonionic surfactant in an amount between about 1-30 %w/w of the formulation; and a polar solvent in an amount less than 5 %w/w of the formulation.
  • the nonionic surfactant is a poloxamer and the polar solvent is water, an alcohol, or a combination thereof.
  • the detergent portion comprises poloxamer, propylene glycol, glycerin, ethanol, 50 %w/v sodium hydroxide solution, or a combination thereof. In some embodiments, the detergent portion comprises glycerin in an amount less than 3 %w/w of the formulation.
  • a micellular structure is also often achieved.
  • the polar agent is in molar excess of the nonionic detergent.
  • the inclusion of the nonionic detergent/polar gelling agent combination results in a more viscous and cream-like or gel-like formulation which is suitable for application directly to the skin. This is typical of the aqueous forms of the composition.
  • a gelling agent such as a gelling agent, a dispersing agent and a preservative.
  • a suitable gelling agent is hydroxypropylcellulose, which is generally available in grades from viscosities of from about 5 cps to about 25,000 cps such as about 1500 cps. All viscosity measurements are assumed to be made at room temperature unless otherwise stated. The concentration of hydroxypropylcellulose may range from about 1% w/w to about 2% w/w of the composition.
  • Other gelling agents are known in the art and can be used in place of, or in addition to hydroxypropylcellulose.
  • An example of a suitable dispersing agent is glycerin.
  • Glycerin is typically included at a concentration from about 5 %w/w to about 25 %w/w of the composition.
  • a preservative may be included at a concentration effective to inhibit microbial growth, ultraviolet light and/or oxygen-induced breakdown of composition components, and the like. When a preservative is included, it may range in concentration from about 0.01 %w/w to about 1 .5 %w/w of the composition.
  • a transdermal delivery formulation further comprises tranexamic acid in an amount less than 2 %w/w, 5 %w/w, or 10 %w/w of the formulation.
  • a transdermal delivery formulation further comprises a polar solvent in an amount less than 2 %w/w, 5 %w/w, 10 %w/w, or 20 %w/w of the transdermal delivery formulation.
  • a transdermal delivery formulation further comprises a humectant, an emulsifier, an emollient, or a combination thereof.
  • a transdermal delivery formulation further comprises almond oil in an amount less than about 5 %w/w.
  • a formulation further comprises a mixture of thermoplastic polyurethane and polycarbonate in an amount less than about 5 % w/w.
  • a transdermal delivery formulation further comprises phosphatidylethanolamine in an amount less than about 5 %w/w.
  • a transdermal delivery formulation further comprises an inositol phosphatide in an amount less than about 5 %w/w.
  • solvents and related compounds that can be used in some embodiments include acetamide and derivatives, acetone, n-alkanes (chain length between 7 and 16), alkanols, diols, short chain fatty acids, cyclohexyl- 1 ,1- dimethylethanol, dimethyl acetamide, dimethyl formamide, ethanol, ethanol/d- limonene combination, 2-ethyl- 1 ,3-hexanediol, ethoxydiglycol (Transcutol® by Gattefosse, Lyon, France), glycerol, glycols, lauryl chloride, limonene N- methylformamide, 2-phenylethanol, 3-phenyl-1 -propanol, 3-phenyl-2-propen-l-ol, polyethylene glycol, polyoxyethylene sorbitan monoesters, polypropylene glycol 425, primary alcohols (tridecanol), 1 ,2-propane diol
  • Fatty alcohols, fatty acids, fatty esters, are bilayer fluidizers that can be used in some embodiments.
  • suitable fatty alcohols include aliphatic alcohols, decanol, lauryl alcohol (dodecanol), unolenyl alcohol, nerolidol, 1-nonanol, n-octanol, and oleyl alcohol.
  • Suitable fatty acid esters include butyl acetate, cetyl lactate, decyl N,N-dimethylamino acetate, decyl N,N-dimethylamino isopropionate, diethyleneglycol oleate, diethyl sebacate, diethyl succinate, diisopropyl sebacate, dodecyl N,N-dimethyamino acetate, dodecyl (N,N-dimethylamino)-butyrate, dodecyl N,N-dimethylamino isopropionate, dodecyl 2-(dimethyamino) propionate, EO-5-oleyl ether, ethyl acetate, ethylaceto acetate, ethyl propionate, glycerol monoethers, glycerol monolaurate, glycerol monooleate, glycerol monolinoleate,
  • Suitable fatty acid- include alkanoic acids, caprid acid, diacid, ethyloctadecanoic acid, hexanoic acid, lactic acid, lauric acid, linoelaidic acid, linoleic acid, linolenic acid, neodecanoic acid, oleic acid, palmitic acid, pelargonic acid, propionic acid, and vaccenic acid.
  • Suitable fatty alcohol ethers include a-monoglyceryl ether, EO-2-oleyl ether, EO-5-oleyl ether, EO-10-oleyl ether, ether derivatives of polyglycerols and alcohols, and (1-0-dodecyl-3-0-methyl-2-0-(2',3 dihydroxypropyl glycerol).
  • Examples of completing agents that can be used in some embodiments include b- and g-cyclodextrin complexes, hydroxypropyl methylcellulose (e.g., Carbopol® 934), liposomes, naphthalene diamide diimide, and naphthalene diester diimide.
  • One or more anti-oxidants can be included, such as vitamin C, vitamin E, proanthocyanidin and a-lipoic acid typically in concentrations of 0.1 %-2.5% w/w.
  • the pH of a transdermal delivery formulation is adjusted to a level of pH 9- 11 or 10-11 which can be done by providing appropriate buffers or simply adjusting the pH with base.
  • a transdermal delivery formulation can include other components that act as excipients or serve purposes other than for muscle performance and recovery.
  • preservatives like antioxidants e.g., ascorbic acid or a-lipoic acid and antibacterial agents may be included.
  • Other components apart from therapeutically active ingredients and components that are the primary effectors of dermal penetration may include those provided for aesthetic purposes such as menthol or other aromatics, and components that affect the physical state of the composition such as emulsifiers, for example, Durosoft®.
  • these ingredients are present in very small percentages of the compositions. It is understood that these latter ancillary agents are neither therapeutically ingredients nor are they components that are primarily responsible for penetration of the skin.
  • the application method is determined by the nature of the treatment but may be less critical than the nature of the formulation itself. If the application is to a skin area, it may be helpful in some instances to prepare the skin by cleansing or exfoliation. In some instances, it is helpful to adjust the pH of the skin area prior to application of a transdermal delivery formulation itself.
  • the application of a transdermal delivery formulation may be by simple massaging onto the skin or by use of devices such as syringes or pumps. Patches could also be used. In some cases, it is helpful to cover the area of application to prevent evaporation or loss of a transdermal delivery formulation.
  • the application area is essentially skin
  • a convenient way to do this is to apply a composition comprising linoleic acid which effectively closes the entrance pathways that were provided by the penetrants of the invention. This application, too, is done by straightforward smearing onto the skin area or can be applied more precisely in measured amounts.
  • the methods can employ a subsequent treatment with linoleic acid.
  • transdermal treatments generally open up the skin barrier, which is, indeed, their purpose, it is useful to seal the area of application after the treatment is finished.
  • treatment with a transdermal delivery formulation may be followed by treating the skin area with a composition comprising linoleic acid to seal off the area of application.
  • the application of linoleic acid is applicable to any transdermal procedure that results in impairing the ability of the skin to act as a protective layer. Indeed, most transdermal treatments have this effect as their function is to allow the active component to pass through the epidermis to the dermis at least, and, if systemic administration is achieved, through the dermis itself.
  • hydrocortisone or hydrocortisone acetate may be included in an amount ranging from 0.25% w/w to about 0.5% w/w.
  • Menthol, phenol, and terpenoids, e.g., camphor can be incorporated for cooling pain relief.
  • menthol can be included in an amount ranging from about 0.1 % w/w to about 1.0% w/w.
  • compositions containing anesthetics are useful for temporary relief of pain and itching associated with minor burns, cuts, scrapes, skin irritations, inflammation and rashes due to soaps, detergents or cosmetics, or, as noted above, pain associated with removal of fat deposits.
  • Emergency medical treatment of individuals requiring, for example, blood balancing agents including electrolytes and readily-metabolized nutrients, such as glucose, that would otherwise be administered intravenously can instead be non- invasively treated by massaging the formulation through the skin and thus permitting systemic delivery so that levels in the bloodstream are altered.
  • a transdermal delivery formulation of the invention and methods of the invention are useful in promoting weight loss as the caloric intake required to assuage feelings of hunger is lower than that ordinarily experienced by consuming food conventionally.
  • suitable subjects for the methods of the invention include individuals seeking to control their caloric intake in order to adjust their weight. In view of the generally acknowledged obesity epidemic in the United States in particular, this is an important group of subjects benefitting from the methods of the invention.
  • the components for athletic performance include beta-alanine, L-carnitine, adenosine triphosphate, dextrose, creatine monohydrate, beta hydroxy-betamethylbutyrate (HMB), branched chain amino acids (leucine, isoleucine, valine), glutathione, sodium phosphate, and caffeine.
  • Components for medical nutrition include amino acids, dextrose, lipids, Na + , K + , Ca 2+ , Mg 2+ , acetate, Cl , P, multivitamin, and trace elements.
  • components for weight loss include conjugated linoleic acids, ephedra, caffeine, and salicin.
  • transdermal delivery formulation provided herein may be supplemented with formulation components described in greater detail in the inventor’s related applications, including United states Application No. 16/132,358 filed September 14, 2018, entitled ‘Methods and Formulations For Transdermal Administration Of Buffering Agents’, International Patent Application No.
  • a formulation for transdermal delivery may, for example, comprise: Aveeno®, for example in an amount between about 10-95 %w/w; between about 20-85 %w/w, between about 20-75 %w/w, between about 20- 50 %w/w.
  • certain embodiments are directed to a sustained release drug delivery platform releases a therapeutic compound or compounds disclosed and made as a formulation described herein over a period of, without limitation, about 3 days after administration, about 7 days after administration, about 10 days after administration, about 15 days after administration, about 20 days after administration, about 25 days after administration, about 30 days after administration, about 45 days after administration, about 60 days after administration, about 75 days after administration, or about 90 days after administration.
  • a sustained release drug delivery platform releases a therapeutic compound or compounds disclosed herein with substantially first order release kinetics over a period of, without limitation, at least 3 days after administration, at least 7 days after administration, at least 10 days after administration, at least 15 days after administration, at least 20 days after administration, at least 25 days after administration, at least 30 days after administration, at least 45 days after administration, at least 60 days after administration, at least 75 days after administration, or at least 90 days after administration.
  • a transdermal delivery formulation to be used for in vivo administration can be sterile. This can be accomplished, for instance, without limitation, by filtration through sterile filtration membranes, prior to, or following, preparation of a transdermal delivery formulation or other methods known in the art, including without limitation, pasteurization.
  • Packaging and instruments for administration may be determined by a variety of considerations, such as, without limitation, the volume of material to be administered, the conditions for storage, whether skilled healthcare practitioners will administer or patient self-compliance, the dosage regime, the geopolitical environment (e.g., exposure to extreme conditions of temperature for developing countries), and other practical considerations.
  • kits can comprise, without limitation, one or more cream or lotion comprising one or more formulations described herein.
  • the kit can comprise formulation components for transdermal, topical, or subcutaneous administration, formulated to be administered as an emulsion coated patch.
  • the kits can contain one or more lotion, cream, patch, or the like in accordance with any of the foregoing, wherein each patch contains a single unit dose for administration to a subject.
  • Imaging components can optionally be included, and the packaging also can include written or web-accessible instructions for using a transdermal delivery formulation.
  • a container can include, for example, a vial, bottle, patch, syringe, pre filled syringe, tube or any of a variety of formats well known in the art for multi dispenser packaging.
  • Methods for treating, preventing or ameliorating a disease, disorder, a condition, or a symptom thereof or a condition related thereto are provided herein using a transdermal delivery formulation for transdermal delivery described herein below.
  • the methods provided herein may comprise or consist of topically administering one or more of a transdermal delivery formulation described herein to skin of a subject in need thereof.
  • Preferred, but non-limiting embodiments are directed to methods for treating, preventing, inhibiting or ameliorating a disease, disorder, a condition, or a symptom described below.
  • An approach to make electrolyte balancing formulations is to avoid electrolyte imbalances by incorporating different buffers in different amount or ratios.
  • buffering agents that can be used together in different amounts or ratios include potassium bicarbonate, sodium bicarbonate, calcium carbonate, magnesium carbonate, and potassium carbonate. Mixtures of particular buffering agents including 2, 3, 4, 5, or more buffering agents are used depending on the formulation. Further, the relative amounts or ratio of each buffering agent may vary, for example, where the relative amounts are from 1 :1.10 w/w; 1 :1.15 w/w;
  • a formulation for transdermal delivery can, for example, comprise two components or it may comprise one or more buffering agent and a penetrant. Typically, however, a penetrant is less than 85 %w/w.
  • a transdermal delivery formulation may have a detergent of at least 1 %w/w.
  • a suitable formulation may comprise about 10-56 %w/w buffering agent and a penetrant.
  • a transdermal delivery formulation for transdermal delivery of one or more buffering agent through the skin of a subject, comprising: a buffering agent comprising a carbonate salt in an amount between about 10-56 %w/w; a transdermal delivery formulation in an amount between about 5 to 55 %w/w; a detergent portion in an amount of at least 1 %w/w; and wherein the formulation comprises water in an amount from none up to about 77 %w/w.
  • a carbonate, including sodium bicarbonate in a transdermal delivery formulation is in an amount of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more w/w.
  • a method for transdermal delivery of a carbonate salt of a % at least comprising: a buffering agent comprising a carbonate salt in an amount between about 10-45 %w/w; a transdermal delivery formulation in an amount between about 5 to 55 %w/w; a detergent portion in an amount between about 1 to 15 %w/w; and wherein the formulation comprises water in an amount between about 15 to 65 %w/w, through the skin of a subject, wherein the carbonate salt of the formulation is in an amount between about 15-32 %w/w of the formulation.
  • a buffering agent comprising a carbonate salt, including sodium bicarbonate in a transdermal delivery formulation is in an amount of at least 1 %, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more w/w.
  • a formulation for transdermal delivery of a therapeutic agent through the skin of a subject comprising at least one active agent in an amount effective for treatment of a condition in the subject and the formulation comprising: a buffering agent comprising a carbonate salt in an amount between about 10-45 %w/w; a transdermal delivery formulation in an amount between about 5 to 55 %w/w; a detergent portion in an amount between about 1 to 15 %w/w; wherein the formulation comprises water in an amount between about 15 to 65 %w/w, through the skin of a subject, wherein the carbonate salt of the formulation is in an amount between about 15-32 %w/w of the formulation, therapeutic, and wherein the alkalinity of the formulation enhances penetration of the therapeutic agent.
  • a formulation for transdermal delivery of one or more buffering agent through the skin of a subject comprising: a buffering agent comprising a carbonate salt in an amount between about 10-45 %w/w; a transdermal delivery formulation in an amount between about 5 to 55 %w/w; a detergent portion in an amount between about 1 to 15 %w/w; and wherein the formulation comprises water in an amount between about 15 to 65 %w/w, and wherein the formulation comprises less than about 12 %w/w of the transdermal delivery formulation.
  • a method for transdermal delivery of a carbonate salt of the formulation comprising: a buffering agent comprising a carbonate salt in an amount between about 10-45 %w/w; a transdermal delivery formulation in an amount between about 5 to 55 %w/w; a detergent portion in an amount between about 1 to 15 %w/w; and wherein the formulation comprises water in an amount between about 15 to 65 %w/w, and wherein the formulation comprises less than about 12 %w/w of the transdermal delivery formulation, through the skin of a subject, wherein the carbonate salt of the formulation is in an amount between about 15-32 %w/w of the formulation, wherein the formulation comprises less than about 12 %w/w of the transdermal delivery formulation, and wherein the alkalinity of the formulation enhances penetration of the therapeutic agent.
  • a formulation for transdermal delivery of a therapeutic agent through the skin of a subject comprising at least one active agent in an amount effective for treatment of a condition in the subject and the formulation comprising: a buffering agent comprising a carbonate salt in an amount between about 10-45 %w/w; a transdermal delivery formulation in an amount between about 5 to 55 %w/w; a detergent portion in an amount between about 1 to 15 %w/w; wherein the formulation comprises water in an amount between about 15 to 65 %w/w, through the skin of a subject, wherein the carbonate salt of the formulation is in an amount between about 15-32 %w/w of the formulation, and wherein the formulation comprises less than about 12 %w/w of the transdermal delivery formulation.
  • a suitable transdermal delivery formulation comprises: SiligelTM in an amount less than about 5 %w/w; water in an amount between about 10-65 %w/w; isopropyl palmitate in an amount between about 0.5-10 %w/w; stearic Acid in an amount between about 0.25-10 %w/w; cetyl alcohol in an amount between about 0.25-10 %w/w; glycerin in an amount between about 0.25-5 %w/w; a transdermal delivery formulation in an amount between about 0.25-10 %w/w; ethanol in an amount less than about 5 %w/w; benzyl alcohol in an amount less than about 5 %w/w; sodium hydroxide 50 %w/v in an amount between about 0.1-5 %w/w; and sodium bicarbonate in an amount between about 1-32 %w/w.
  • a suitable transdermal delivery formulation comprises: Aveeno® in an amount between about 20-85 %w/w; and sodium bicarbonate (3DF) in an amount between about 15-45 %w/w.
  • a transdermal delivery formulation formulation comprises: Aveeno® in an amount between about 20-85 %w/w; and sodium bicarbonate in an amount between about 15-45 %w/w.
  • a suitable transdermal delivery formulation comprises: SiligelTM in an amount less than about 5 %w/w; water in an amount between about 10-55 %w/w; isopropyl palmitate in an amount between about 0.5-10 %w/w; stearic Acid in an amount between about 0.25-5 %w/w; Cetyl alcohol in an amount between about 0.25-10 %w/w; almond oil in an amount between about 0.5- 10 %w/w; propylene glycol in an amount between about 0.25-10 %w/w; ethanol in an amount less than about 5 %w/w; benzyl alcohol in an amount less than about 5 %w/w; sodium hydroxide 50 %w/v in an amount between about 0.1-5 %w/
  • the surprising effects achieved by the formulations and methods of the present invention are in part attributable to an improved transdermal delivery formulation that enhances delivery of a carbonate salt through the skin.
  • the present transdermal delivery formulations may include a nonionic surfactant.
  • Applicant has found that by employing carbonate salts with particle sizes as disclosed herein, delivered with the penetrants as disclosed herein, and in some embodiments providing a combination of a nonionic surfactant and a polar gelling agent, the penetration capabilities of the carbonate salts of the resulting formulation and the effective level of delivery of the carbonate salts has been enhanced.
  • penetrants are based on combinations of an alcohol, such as benzyl alcohol to provide a concentration of 0.5-20%w/w of the final formulation with a transdermal delivery formulation present to provide 25- 70%w/w of the formulation. These penetrants are also useful when the agent is a buffer, such as sodium bicarbonate, but less of a transdermal delivery formulation may be required - e.g. less than 12 %w/w when the sodium bicarbonate is present at high concentration as disclosed herein.
  • the buffering component is any mildly basic compound or combination that will result in a pH of 7-8.
  • the formulation has a pH of 7-10.
  • buffers in addition to carbonate and/or bicarbonate salts, include lysine buffers, chloroacetate buffers, tris buffers (/.e., buffers employing tris (hydroxymethyl) aminoethane), phosphate buffers and buffers employing non-natural amino acids with similar pKa values to lysine.
  • the carbonate and/or bicarbonate salt is in an amount between about 7-32 %w/w of the formulation.
  • Histidine buffers may also be used.
  • the concentration of buffer in the compositions is in the range of 10-50 %w/w. More typical ranges for sodium bicarbonate or sodium carbonate or both are 10-35 %w/w.
  • the carbonate salt is in an amount between about 15-32 %w/w of the formulation.
  • the penetrant component comprises a completion component as well as one or more electrolytes sufficient to impart viscosity and viscoelasticity, one or more surfactants and an alcohol.
  • the completion component can be a polar liquid, a non-polar liquid or an amphiphilic substance.
  • the percentage of carbonate salt in a transdermal delivery formulation will depend upon the amount required to be delivered in order to have a useful effect on treating the disorder.
  • the carbonate salt may be present in the formulation in an amount as low as 1 %w/w up to about 50 %w/w. Typical concentrations may include 15-32 %w/w. Since the required percentage of carbonate salt depends on the frequency of administration, as well as the time allotted for administration for each application, the level of carbonate salt may be varied over a wide range.
  • the carbonate salt is sodium carbonate and/or sodium bicarbonate milled to a particle size less than 200 pm.
  • the carbonate salt is sodium carbonate and/or sodium bicarbonate milled to a particle size less than 70 pm. In some embodiments, the carbonate salt is sodium carbonate and/or sodium bicarbonate milled to a particle size less than 70 pm, wherein the sodium bicarbonate is solubilized in the formulation in an amount less than 20 %w/w of a transdermal delivery formulation. In some embodiments, the carbonate salt is sodium carbonate and/or sodium bicarbonate milled to a particle size less than 70 pm, wherein particle sizes less than about 10 pm have an enhanced penetration thru the skin of a subject. In some embodiments, the sodium carbonate and/or sodium bicarbonate are jet milled to a particle size less than about 70 pm. In some embodiments, the sodium bicarbonate is Sodium Bicarbonate USP Grade 3DF that has a particle size distribution less than 70 pm.
  • a transdermal delivery formulation of the disclosure may be prepared in a number of ways. Typically, the components of a transdermal delivery formulation are simply mixed together in the required amounts. However, it is also desirable in some instances to, for example, carry out dissolution of a carbonate salt and then add a separate preparation containing the components aiding the delivery of the carbonate salts in the form of a carrier. The concentrations of these components in the carrier, then, will be somewhat higher than the concentrations required in a final transdermal delivery formulation.
  • sodium bicarbonate may first be dissolved in water and then added to a carrier comprising an alcohol, a transdermal delivery formulation and optionally a combination of a nonionic surfactant and polar gelling agent, or of ionic detergent.
  • the water is in an amount between about 10-85 %w/w, 15-50 %w/w, or 15-45 %w/w of the formulation.
  • the transdermal delivery formulation is a multi-component mixture, whereby the particular concentrations of the penetration enhancers are informed in part by the molecular mass of the sodium bicarbonate, or sodium bicarbonate and the therapeutic agent to be transported.
  • a transdermal delivery formulation enables the sodium bicarbonate and/or therapeutic agent to become bio-available to the target site within minutes of topical administration.
  • a transdermal delivery formulation permit the use of minimal concentrations of therapeutic agents, as little as 1/1000th of concentrations required of alternative processes, while enabling bioactivity and positive clinical outcomes simultaneously.
  • the transdermal delivery formulation comprises an alcohol in an amount less than 5 %w/w of the formulation. Administration and Dosing
  • a transdermal delivery formulation provided herein can be topically administered in any form.
  • a sufficient amount of the topical composition can be applied onto a desired area and surrounding skin, for example, in an amount sufficient to cover a desired skin surface.
  • a transdermal delivery formulation can be applied to any skin surface, including for example, facial skin, and the skin of the hands, neck, chest and/or scalp.
  • a transdermal delivery formulation itself is simply placed on the skin and spread across the surface and/or massaged to aid in penetration.
  • the amount of transdermal delivery formulation used is typically sufficient to cover a desired surface area.
  • a protective cover is placed over the formulation once it is applied and left in place for a suitable amount of time, i.e., 5 minutes, 10 minutes, 20 minutes or more; in some embodiments an hour or two.
  • the protective cover can simply be a bandage including a bandage supplied with a cover that is impermeable to moisture. This essentially locks in the contact of a transdermal delivery formulation to the skin and prevents distortion of a transdermal delivery formulation by evaporation in some cases.
  • composition may be applied to the skin using standard procedures for application such as a brush, a syringe, a gauze pad, a dropper, or any convenient applicator. More complex application methods, including the use of delivery devices, may also be used, but are not required.
  • the surface of the skin may also be disrupted mechanically by the use of spring systems, laser powered systems, systems propelled by Lorentz force or by gas or shock waves including ultrasound and may employ microdermabrasion such as by the use of sandpaper or its equivalent or using microneedles or electroporation devices.
  • Simple solutions of the agent(s) as well as the above-listed formulations that penetrate intact skin may be applied using occlusive patches, such as those in the form micro-patches. External reservoirs of the formulations for extended administration may also be employed.
  • the surface of the skin may also be disrupted mechanically by the use of spring systems, laser powered systems, use of iontophoresis, systems propelled by Lorentz force or by gas or shock waves including ultrasound and may employ microdermabrasion such as by the use of sandpaper or its equivalent or using microneedles or electroporation devices.
  • Simple solutions of the agent(s) as well as the above-listed transdermal delivery formulations that penetrate intact skin may be applied using occlusive patches, such as those in the form of micro-patches. External reservoirs of the formulations for extended administration may also be employed.
  • alternative methods of administering one or more therapeutic compounds or agents e.g. supplements, vitamins and/or minerals
  • these alternative methods might be selected from the following lists: on basis of working mechanism, spring systems, laser powered, energy-propelled, Lorentz force, gas/air propelled, shock wave (including ultrasound), on basis of type of load, liquid, powder, projectile, on basis of drug delivery mechanism, nano-patches, sandpaper (microdermabrasion), iontophoresis enabled, microneedles, on basis of site of delivery, intradermal, intramuscular, and subcutaneous injection.
  • microneedle drug delivery such as 3M Systems, Glide SDI (pushes drug as opposed to “firing” drug), MIT low pressure injectors, micropatches (single use particle insertion device), microelectro mechanical systems (MEMS), dermoelectroporation devices (DEP), transderm ionto system (DEP), TTS transdermal therapeutic systems, membrane-moderated systems (drug reservoir totally encapsulated in a shallow compartment), adhesive diffusion-controlled system (drug reservoir in a compartment fabricated from drug- impermeable metallic plastic backing), matrix dispersion type system (drug reservoir formed by homogeneously dispersing drug solids in a hydrophilic or lipophilic polymer matrix molder into medicated disc), and microreservoir system (combination of reservoir and matrix dispersion-type drug delivery system).
  • 3M Systems Glide SDI (pushes drug as opposed to “firing” drug)
  • MIT low pressure injectors micropatches (single use particle insertion device), micro
  • the application method is determined by the nature of the treatment but may be less critical than the nature of a transdermal delivery formulation itself. If the application is to a skin area, it may be helpful in some instances to prepare the skin by cleansing or exfoliation. In some instances, it is helpful to adjust the pH of the skin area prior to application of the formulation itself.
  • the application of a transdermal delivery formulation may be by simple massaging onto the skin or by use of devices such as syringes or pumps. Patches could also be used. In some cases, it is helpful to cover the area of application to prevent evaporation or loss of a transdermal delivery formulation.
  • the application area is essentially skin
  • a convenient way to do this is to apply a composition comprising linoleic acid which effectively closes the entrance pathways that were provided by the penetrants of the invention. This application, too, is done by straightforward smearing onto the skin area or can be applied more precisely in measured amounts.
  • the methods may employ a subsequent treatment with linoleic acid.
  • transdermal treatments generally open up the skin barrier, which is, indeed, their purpose, it is useful to seal the area of application after the treatment is finished.
  • treatment with a transdermal delivery formulation may be followed by treating the skin area with a composition comprising linoleic acid to seal off the area of application.
  • the application of linoleic acid is applicable to any transdermal procedure that results in impairing the ability of the skin to act as a protective layer. Indeed, most transdermal treatments have this effect as their function is to allow active ingredients to pass through the epidermis to the dermis at least, and, if systemic administration is achieved, through the dermis itself.
  • hydrocortisone or hydrocortisone acetate may be included in an amount ranging from 0.25%w/w to about 0.5%w/w.
  • Menthol, phenol, and terpenoids, e.g., camphor can be incorporated for cooling pain relief.
  • menthol may be included in an amount ranging from about 0.1 %w/w to about 1.0%w/w.
  • a transdermal delivery formulation can be applied in a single, one-time application, once a week, once a bi-week, once a month, or from one to twelve times daily, for a period of time sufficient to alleviate a condition, disease, disorder, symptoms, for example, for a period of time of one week, from 1 to 12 weeks or more, from 1 to 6 weeks, from 2 to 12 weeks, from 2 to 8 weeks, from 2 to 6 weeks, from 2 to 4 weeks, from 4 to 12 weeks, from 4 to 8 weeks, or from 4 to 6 weeks.
  • the present compositions can be administered, for example, at a frequency of once per day to hourly if needed.
  • the presently described formulations can be topically administered once or more per day for a period of time from 1 week to 4 weeks, of from 1 week to 2 weeks, for 1 week, for 2 weeks, for 3 weeks, or for 4 weeks or more. In some instances, it may also be desirable to continue treatment indefinitely, for example, to inhibit or prevent muscle cramping, improve performance and recovery and/or maintain levels of supplements, vitamins and minerals for health and/or prevention of disease.
  • a suitable administration for a transdermal delivery formulation comprising a skin cream, lotion or ointment for example is once, twice, three, four times daily, or hourly if needed.
  • compositions As described above, if desired, other therapeutic agents can be employed in conjunction with those provided in the above-described compositions.
  • the amount of active ingredients that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the nature of the disease, disorder, or condition, and the nature of the active ingredients.
  • a specific dose level for any particular patient will vary depending upon a variety of factors, including the activity of the specific active agent; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; possible drug combinations; the severity of the particular condition being treated; the area to be treated and the form of administration.
  • One of ordinary skill in the art would appreciate the variability of such factors and would be able to establish specific dose levels using no more than routine experimentation.
  • Pharmacokinetic parameters such as bioavailability, absorption rate constant, apparent volume of distribution, unbound fraction, total clearance, fraction excreted unchanged, first-pass metabolism, elimination rate constant, half-life, and mean residence time can be determined by methods well known in the art.
  • a transdermal delivery formulation in accordance with the subject matter described herein may be a topical dosage form packaged in, for example, a multi use or single-use package, including for example, a tube, a bottle, a pump, a container or bottle, a vial, a jar, a packet, or a blister package.
  • Single dosage kits and packages containing a once per day amount of the transdermal delivery formulation may be prepared.
  • Single dose, unit dose, and once- daily disposable containers of the transdermal delivery formulation are also provided.
  • the present transdermal delivery formulation remains stable in storage for periods including up to about 5 years, between about 3 months and about 5 years, between about 3 months and about 4 years, between about 3 months and about 3 years, and alternately any time period between about 6 months and about 3 years.
  • a transdermal delivery formulation described herein remains stable for up to at least 3 years at a temperature of less than or equal to 40° C.
  • the presently described transdermal delivery formulation remains stable for at least 2 years at a temperature of less than or equal to 40° C.
  • the presently described transdermal delivery formulation remains stable for at least 3 years at a temperature of less than or equal to 40° C and at a humidity of up to 75% RH, for at least 2 years at a temperature of less than or equal to 40° C and at a humidity of up to 75% RH, or for at least 3 years at a temperature of less than or equal to 30°C. and at a humidity of up to 75% RH.
  • the presently described transdermal delivery formulation in accordance with the subject matter described herein remains stable for an extended period of time when packaged in a multi-use container such as a bottle dispenser or the like, and exhibits equal to or even greater stability when packaged in a single-use package.
  • the transdermal delivery formulation of certain embodiments comprises a daily dose of particular buffering compound (e.g. sodium bicarbonate, sodium carbonate, magnesium carbonate, potassium carbonate, potassium bicarbonate, TRIS, Lysine, IEPA, etc.).
  • buffering compound e.g. sodium bicarbonate, sodium carbonate, magnesium carbonate, potassium carbonate, potassium bicarbonate, TRIS, Lysine, IEPA, etc.
  • a daily dose for topical or transdermal administration of a transdermal delivery formulation depends on the compound and animal and may be easily determined by the skilled artisan, a suitable amount is about 1 mg/kg to about 5g/kg, and more typically the daily dose is about 10mg/kg to about 5g/kg, about 25mg/kg to about 2000 mg/kg, about 50mg/kg to about 2000 mg/kg, about 25mg/kg to about 1000mg/kg, about 50mg/kg to about 1000mg/kg, about 100mg/kg to about 700mg/kg, about 100mg/kg to about 500mg/kg, about 150mg/kg to about 500mg/kg, about 150mg/kg to about 400mg/kg, about 200mg/kg to about 500mg/kg, about 200mg/kg to about 450mg/kg, about 200mg/kg to about 400mg/kg, about 250mg/kg to about 450mg/kg, about 250mg/kg to about 400mg/kg
  • compositions can be combined with other therapeutic agents in conjunction with those provided in the above-described compositions.
  • amount of active ingredients that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the nature of the disease, disorder, or condition, and the nature of the active ingredients.
  • a specific dose level for any particular patient will vary depending upon a variety of factors, including the activity of the specific active agent; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; possible drug combinations; the severity of the particular condition being treated; the area to be treated and the form of administration.
  • One of ordinary skill in the art would appreciate the variability of such factors and would be able to establish specific dose levels using no more than routine experimentation.
  • Pharmacokinetic parameters such as bioavailability, absorption rate constant, apparent volume of distribution, unbound fraction, total clearance, fraction excreted unchanged, first-pass metabolism, elimination rate constant, half-life, and mean residence time can be determined by methods well known in the art.
  • a transdermal delivery formulation in accordance with the subject matter described herein may be a topical dosage form packaged in, for example, a multi use or single-use package, including for example, a tube, a bottle, a pump, a container or bottle, a vial, a jar, a packet, or a blister package.
  • Single dosage kits and packages containing a once per day amount of the transdermal delivery formulation may be prepared.
  • Single dose, unit dose, and once- daily disposable containers of the transdermal delivery formulation are also provided.
  • a suitable dose for topical or transdermal administration of each of one or more particular buffering compound e.g. sodium bicarbonate, sodium carbonate, magnesium carbonate, potassium carbonate, potassium bicarbonate, TRIS, Lysine, IEPA, etc.
  • a suitable dose for topical or transdermal administration of each of one or more particular buffering compound for subject is at least about 100 mg, at least about 500 mg, at least about 1 g, at least about 5 g, at least about 10 g, at least about 15 g, at least about 16 g, at least about 17 g, at least about 18 g, at least about 19 g, at least about 20 g, at least about 21 g, at least about 22 g, at least about 23 g, at least about 24 g, at least about 25 g, at least about 26 g, at least about 27 g, at least about 28 g, at least about 29 g, at least about 30 g, at least about 35 g, at least about 40 g, at least about 45 g,
  • aspects of the present specification disclose that the symptoms associated with a disease or disorder described herein are reduced following application of a transdermal delivery formulation by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% and the severity associated with a disease or disorder described herein is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.
  • aspects of the present specification disclose the symptoms associated with disease or disorder are reduced following application of a transdermal delivery formulation by about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.
  • aspects of the present specification disclose that the symptoms associated with a disease or disorder described herein are reduced following administration of a transdermal delivery formulation of the present invention by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% and the severity associated with a disease or disorder described herein is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.
  • aspects of the present specification disclose the symptoms associated with disease or disorder are reduced by about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.
  • a transdermal delivery formulation as described herein can be used in the manufacture of medicaments and for the treatment of humans and other animals by administration in accordance with conventional procedures.
  • Dosing can be single dosage or cumulative (serial dosing), and can be readily determined by one skilled in the art.
  • a transdermal delivery formulation of the present invention may be administered once, twice, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or more times to a subject.
  • treatment of a disease may comprise a one-time administration of an effective dose of a transdermal delivery formulation as disclosed herein.
  • treatment of a disease may comprise multiple administrations of an effective dose of a transdermal delivery formulation as carried out over a range of time periods, such as, e.g., once daily, twice daily, thrice daily, once every few days, or once weekly.
  • time periods such as, e.g., once daily, twice daily, thrice daily, once every few days, or once weekly.
  • the timing of administration can vary from individual to individual, depending upon such factors as the severity of an individual's symptoms.
  • an effective dose of a transdermal delivery formulation as disclosed herein can be administered to an individual once daily for an indefinite period of time, or until the individual no longer requires therapy.
  • a person of ordinary skill in the art will recognize that the condition of the individual can be monitored throughout the course of treatment and that the effective amount of a transdermal delivery formulation disclosed herein that is administered can be adjusted accordingly.
  • a transdermal delivery formulation as disclosed herein is capable of decreasing the time to resolve the symptoms of a disease, including in an individual suffering from a disease by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95% as compared to a patient not receiving the same treatment.
  • a transdermal delivery formulation and its derivatives have half-lives of 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day,
  • the period of administration of a transdermal delivery formulation is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.
  • a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days,
  • a therapeutically effective amount of a transdermal delivery formulation disclosed herein reduces or alleviates symptoms (e.g. muscle pain or cramping) of an ailment such as muscle cramping or soreness in an individual by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 100%.
  • symptoms e.g. muscle pain or cramping
  • a therapeutically effective amount of a transdermal delivery formulation disclosed herein reduces or alleviates symptoms of an ailment in an individual by, e.g., at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 95% or at most 100%.
  • a therapeutically effective amount of a transdermal delivery formulation disclosed herein reduces or alleviates symptoms of an ailment in an individual by, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.
  • a transdermal delivery formulation disclosed herein may comprise a transdermal delivery formulation in a therapeutically effective amount.
  • the term “effective amount” is synonymous with “therapeutically effective amount”, “effective dose”, or “therapeutically effective dose” and when used in reference to reducing or alleviate symptoms of an ailment in an individual refers to the minimum dose of a therapeutic disclosed herein necessary to achieve the desired therapeutic effect and includes a dose sufficient to reduce or alleviates symptoms of an ailment in an individual.
  • the effectiveness of a transdermal delivery formulation disclosed herein capable of reducing or alleviating symptoms of an ailment in an individual can be determined by observing an improvement in an individual based upon one or more clinical symptoms, and/or physiological indicators associated with improvements in muscle performance, reduced soreness and/or overall health. Maintenance or a reduction of symptoms of an ailment can also be subjective to a patient.
  • the effectiveness of a transdermal delivery formulation disclosed herein in an individual can be determined by observing an improvement in an individual based upon one or more clinical symptoms, and/or physiological indicators associated with signs/symptoms, muscle performance and general health.
  • the effectiveness of a transdermal delivery formulation disclosed herein is also capable of prolonging the life of an individual as compared to the same individual if the transdermal delivery formulation is not administered.
  • the effectiveness of the transdermal delivery formulation disclosed herein is also capable of enhancing the quality of life of an individual as compared to the same individual if the transdermal delivery formulation is not administered.
  • the appropriate effective amount of a transdermal delivery formulation disclosed herein to be administered to an individual can be determined by a person of ordinary skill in the art by taking into account factors, including, without limitation, an improvement in the individual based upon one or more clinical symptoms, and/or physiological indicators associated with improvements in muscle performance, reduced soreness and/or overall health, the particular characteristics, history and risk factors of the patient, such as, e.g., age, weight, general health and the like, or any combination thereof.
  • an effective amount of a transdermal delivery formulation will further depend upon factors, including, without limitation, the frequency of administration, the half-life of the transdermal delivery formulation, or any combination thereof. It is known by a person of ordinary skill in the art that an effective amount of a transdermal delivery formulation disclosed herein can be extrapolated from in vitro assays and in vivo administration studies using animal models prior to administration to humans or animals.
  • aspects of the present specification disclose, in part, a reduction or alleviation of symptoms of an ailment such as muscle cramping or soreness in an individual.
  • the term “treating,” refers to reduction or alleviation of muscle soreness or cramping as well as improved muscle performance and recovery.
  • the term “treating” can mean reduction or alleviation of symptoms in an individual by, e.g., at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% at least 95%, or at least 100%.
  • a first transdermal delivery formulation is administered to an individual and at a later date, a second transdermal delivery formulation is administered to the same individual.
  • a first transdermal delivery formulation is administered to an individual at the same time as a second transdermal delivery formulation is administered to the individual.
  • a transdermal delivery formulation as disclosed herein is administered to an individual.
  • An individual is typically a human being, but can be an animal, including, but not limited to, dogs, cats, birds, cattle, horses, sheep, goats, reptiles and other animals, whether domesticated or not.
  • a formulation for transdermal delivery of an active agent through the skin, nail or hair follicle of a subject comprising a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w.
  • the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, further comprises benzyl alcohol in an amount between about 0.5-5 %w/w.
  • the transdermal delivery formulation comprises benzyl alcohol in an amount less than 5 %w/w of the formulation.
  • the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, further comprises Isopropyl Palmitate in an amount between about 5-5 %w/w.
  • the water is deionized water and/or purified water.
  • the water is in an amount between about 15-40 %w/w of the formulation.
  • the one or more phosphatides in an amount between about 0.5-55 %w/w of the transdermal delivery formulation.
  • the transdermal delivery formulation comprises phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, or a combination thereof in amount less than 30 %w/w of the formulation.
  • the one or more phosphatides comprises phosphatidylcholine of the transdermal delivery formulation.
  • the one or more fatty acids in an amount between about 1-35 %w/w of the transdermal delivery formulation.
  • the one or more fatty acids in an amount between about 5-35 %w/w of the transdermal delivery formulation.
  • the one or more fatty acids comprises Linoleic Acid, Oleic Acid, Stearic Acid, safflower oil, or a combination thereof.
  • the one or more fatty acids comprises Linoleic Acid.
  • the one or more fatty acids comprises Oleic Acid.
  • the one or more fatty acids comprises Stearic Acid.
  • the one or more phosphatides are derived from a seed oil in an amount between about 0.5-55 %w/w of the transdermal delivery formulation.
  • the one or more phosphatides are derived from a seed oil in an amount between about 5-35 %w/w of the transdermal delivery formulation.
  • the one or more phosphatides are derived from a safflower oil in an amount between about 0.5-55 %w/w of the transdermal delivery formulation.
  • the one or more phosphatides are derived from a safflower oil in an amount between about 5-35 %w/w of the transdermal delivery formulation.
  • the one or more phosphatides are derived from an almond oil in an amount between about 0.5-55 %w/w of the transdermal delivery formulation.
  • the one or more phosphatides are derived from an almond oil in an amount between about 5-35 %w/w of the transdermal delivery formulation.
  • the one or more phosphatides comprises one or more fatty acids derived from soy lecithin.
  • the glucose in an amount between about 0.05-10 %w/w of the transdermal delivery formulation.
  • the glucose is anhydrous dextrose in an amount between about 0.05-10 %w/w of the transdermal delivery formulation.
  • the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, further comprises a nonionic surfactant in an amount between about 2-25 %w/w of the transdermal delivery formulation.
  • the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, further comprises a polar solvent at least in an amount in molar excess of the nonionic surfactant.
  • the nonionic surfactant is a poloxamer and the polar solvent is water.
  • the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, further comprises a polar solvent in an amount less than 5 %w/w of the formulation.
  • the transdermal delivery formulation further comprises a detergent portion in an amount between about 1-30 %w/w of the transdermal delivery formulation.
  • the detergent portion comprises a nonionic surfactant in an amount between about 2-25 %w/w of the transdermal delivery formulation; and a polar solvent in an amount less than 5 %w/w of the transdermal delivery formulation.
  • the transdermal delivery formulation is in an amount between about 10-60 %w/w of the transdermal delivery formulation.
  • the transdermal delivery formulation comprises an alcohol in an amount less than 10 %w/w of the transdermal delivery formulation.
  • the transdermal delivery formulation further comprises an alcohol, a surfactant, and a polar solvent.
  • the transdermal delivery formulation comprises cetyl alcohol in amount less than 5 %w/w of the formulation.
  • the transdermal delivery formulation comprises ethanol in an amount less than 5 %w/w of the formulation.
  • the transdermal delivery formulation comprises glycerine in an amount less than 5 %w/w of the formulation.
  • the transdermal delivery formulation comprises propylene glycol in an amount less than 8 %w/w of the formulation.
  • the formulation comprises a gelling agent in an amount less than 20 %w/w of the formulation.
  • the formulation comprises menthol in an amount between about 0.05-5 %w/w of the formulation.
  • the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w.
  • the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, further comprises a humectant, an emulsifier, an emollient, or a combination thereof.
  • the formulation has a pH of 9-11 .
  • the formulation has a pH of 7-10.5.
  • the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, further comprises an active agent.
  • the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, iii. one or more fatty acids; b) water in an amount less than about 50 %w/w, and an active agent component in an amount less than about 60 %w/w.
  • the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; b) water in an amount less than about 50 %w/w, and an active agent component in an amount less than about 60 %w/w, wherein the active agent is a vitamin, mineral or dietary supplement.
  • the buffering agent is sodium carbonate and/or sodium bicarbonate.
  • the formulation includes a dose of creatine (5 - 20 grams) that is up to 30% of the solution.
  • the formulation includes a dose of nitrate ion (approximately 500 mg) that is 5 - 15% of the solution.
  • the formulation includes a dose of caffeine (approximately 500 mg) that is 5 - 15% of the solution.
  • the formulation includes a dose of fructose (approximately 50 g) that is up to 30% of the solution.
  • the formulation includes a dose of curcumin (approximately 500 mg) that is 5 - 15% of the solution.
  • the formulation includes a dose of pychnogenol (approximately 1 g) that is 5 - 15% of the solution.
  • the formulation includes a dose of anthocyanins (approximately 1 g) that is 5 - 15% of the solution.
  • the formulation includes a dose of phenolic acid (approximately 1 g) that is 5 - 15% of the solution.
  • the formulation includes a dose of flavonoids (approximately 500 mg) that is 5 - 15% of the solution.
  • the formulation includes a dose of flavonols (approximately 500 mg) that is 5 - 15% of the solution.
  • the formulation includes a dose of b-Alanine (approximately 6 g) that is up to 30% of the solution.
  • the formulation includes a dose of b-Hydroxy b- methylbutyric acid (HMB) (approximately 3 g) that is 15 - 25% of the solution.
  • HMB b-Hydroxy b- methylbutyric acid
  • the formulation includes a dose of Carnosine (approximately 1 g) that is 15 - 25% of the solution.
  • the formulation includes a dose of Omega-3 fatty acids (approximately 2 g) that is 15 - 25% of the solution.
  • the formulation includes a dose of Leucine (approximately 2 g) that is up to 30% of the solution.
  • the formulation includes a dose of isoleucine (approximately 2 g) that is up to 30% of the solution.
  • the formulation includes a dose of Citrulline (approximately 6 g) that is up to 30% of the solution.
  • the formulation includes a dose of ketone esters (approximately 40 g) that is up to 30% of the solution.
  • the formulation includes a dose of ketone salts (approximately 12 g) that is up to 30% of the solution.
  • the formulation includes a dose of carnitine (approximately 2 g) that is 15 - 25% of the solution. [00263] In some embodiments, the formulation includes a dose of serotonin (5-HTP) (approximately 200 mg) that is 1 - 10% of the solution.
  • carnitine approximately 2 g
  • serotonin approximately 200 mg
  • the formulation includes a dose of arginine (approximately 10 g) that is up to 30% of the solution.
  • the formulation includes a dose of glutamine (approximately 10 g) that is up to 30% of the solution.
  • the formulation includes a dose of berberine (approximately 1.5 g) that is 15 - 25% of the solution.
  • the formulation includes a dose of resveratrol (approximately 2 g) that is 15 - 25% of the solution.
  • the formulation includes a dose of vitamin C (approximately 1000 mg) that is 15 - 25% of the solution.
  • the formulation includes a dose of vitamin B12 (approximately 2 pg) that is 15 - 25% of the solution.
  • the formulation includes a dose of vitamin B9 (approximately 400 pg) that is 0.5 - 5% of the solution.
  • the formulation includes a dose of vitamin B6 (approximately 100 pg) that is 1 - 10% of the solution.
  • the formulation includes a dose of vitamin E (approximately 15 mg) that is 1 - 10% of the solution.
  • the formulation includes a dose of calcium (approximately 1500 mg) that is 15 - 25% of the solution.
  • the formulation includes a dose of potassium (approximately 2.6 g) that is 15 - 25% of the solution (formulated for a female subject).
  • the formulation includes a dose of potassium (approximately 3.4 g) that is 15 - 25% of the solution (formulated for a male subject).
  • the formulation includes a dose of zinc (approximately 20 mg) that is 1 - 10% of the solution.
  • the formulation includes a dose of iron (approximately 18 mg) that is 1 - 10% of the solution (formulated for a female subject).
  • the formulation includes a dose of iron (approximately 8 mg) that is 1 - 10% of the solution (formulated for a male subject).
  • the formulation includes a dose of sodium (approximately 1.5 g) that is 15 - 25% of the solution.
  • the formulation includes a dose of magnesium (approximately 350 mg) that is 5 - 15% of the solution.
  • the formulation includes a dose of chromium (approximately 35 pg) that is 0.5 - 5% of the solution.
  • the formulation includes a dose of capsaicin that is 5 - 15% of the solution.
  • the formulation includes a dose of ginger (approximately 40 mg) that is 1 - 10% of the solution. [00284] In some embodiments, the formulation includes a dose of capsicum (approximately 500 mg) that is 5 - 15% of the solution.
  • the formulation includes a dose of cinnamon (approximately 750 mg) that is 5 - 15% of the solution.
  • the formulation includes a dose of Tetrahydrobiopterin (approximately 2.5 mg) that is approximately 20% of the solution.
  • a method to effect transdermal delivery of an active ingredient comprising applying to the skin, nails or hair follicles of a subject an effective amount of the formulation comprising a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, further comprises an active agent.
  • capsaicin is provided in a transdermal lotion or cream.
  • Capsaicin can be used to relieve nociceptive and neuropathic pain. Capsaicin is thought to work through several mechanisms of action.
  • Transdermal administration allows direct absorption into a specific area. For example, a lotion can be applied to a joint where there is arthritic pain. It can also be applied to a sore, achy muscle or a muscle that is cramping.
  • the lotion can include a transdermal delivery formulation and the active agent (collectively referred to as the solution).
  • the dose of the active agent i.e. capsicum
  • the transdermal delivery formulation can include less than about 60 %w/w of one or more phosphatides, glucose, one or more fatty acids and water.
  • P-Hydroxy b-methy!bufyric acid commonly referred to as “HMB” is often consumed as a nutritional supplement, particularly to help build lean muscle mass, increase strength and endurance, and maximize the results of training.
  • Transdermal administration allows direct absorption into a specific area. For example, a lotion can be applied to one or more areas with muscle soreness. Lotions/creams can be applied to the biceps and triceps of a subject during or after strength training.
  • the lotion or cream can include a transdermal delivery formulation and the active agent, HMB.
  • the dose of the active agent i.e. HMB
  • the transdermal delivery formulation can include less than about 60 %w/w of one or more phosphatides, glucose, one or more fatty acids and water.
  • the lotion/cream can be used to treat local pain and used, for example, over a 12-hour period.
  • Transdermal delivery formulations that include dietary supplements offer the benefit of prolonged absorption.
  • vitamin B12 is essential for preventing major birth defects, supporting bone health, improving mood and maintaining healthy skin and hair.
  • Oral administration of vitamin B12 can be ineffective for those who have trouble absorbing it from food.
  • An oral supplement can help but intramuscular injections can be necessary to increase levels.
  • a transdermal formulation offers a more practical option.
  • the formulation can include a transdermal lotion and the active agent, vitamin B12.
  • the transdermal delivery formulation can include less than about 60 %w/w of one or more phosphatides, glucose, one or more fatty acids and water.
  • the dose of the active agent i.e. vitamin B12
  • the lotion can be applied regularly (e.g. daily) to maintain circulating levels of vitamins.
  • a consumer can use a lotion based on needs or circumstances. For example, a user could use apply the lotion to boost her/her immune system. This could be desired when one is feeling susceptible to a cold, flu or infection due to fatigue or exposure to infected individuals.
  • Transdermal administration presents a good alternative to oral consumption as well as injections. The consumer does not have to schedule and remember to consume frequent doses or take injections. Administration of supplements across the skin improves bioavailability as the vitamin avoids degradation in the gastrointestinal tract or liver. Transdermal delivery can be particularly useful for molecules with limited systemic bioavailabilities and short half-lives.
  • a transdermal lotion/cream can include vitamin B12 along with a myriad other vitamins such as vitamin C, vitamin B9, vitamin B6, vitamin E, calcium, potassium, zinc, Iron, sodium, magnesium and chromium
  • Transdermal administration can also be effective for supplements that are not conducive to oral administration.
  • Vitamin A is important for growth and development, for the maintenance of the immune system and good vision.
  • oral administration of vitamin A can result in hypervitaminosis A.
  • the main problems associated with the vitamin A are its half-life, fast absorption (due to lipophilicity) and its toxicity (due to high loading and frequent dosing).
  • Transdermal administration presents a good alternative because it allows for effective control of drug release.

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Abstract

Embodiments include a transdermal delivery formulation and method for transdermal delivery of a vitamin, mineral or supplement. It can be applied to skin, nail or hair follicle of a subject for local or systemic distribution. The vitamin, mineral or supplement can treat a disease, ailment and/or promote health and well-being. The transdermal delivery formulation can include lecithin, isopropyl palmitate, sorbic acid, benzyl alcohol, polyglyceryl-4 Laurate, vitamin D3, deionized water, sodium lauryl sulfate, and poloxamer 407.

Description

TRANSDERMAL PENETRANT FORMULATIONS FOR VITAMINS, MINERALS AND SUPPLEMENTS
FIELD OF THE INVENTION
[0001] The invention relates generally to topical administration of medicaments. More specifically, it relates to methods and formulations for transdermal administration of health supplements, vitamins and minerals through the skin of a subject.
BACKGROUND
[0002] Topical administration describes the application of a substance to a surface of the skin. The term is often used to describe the application of a cream, foam, gel, lotion or ointment to the skin or mucous membranes. The high keratinization of skin cells and their dense packing creates, in most cases, a barrier impermeable to penetration. Because of this, most substances are not absorbed through the skin.
[0003] The term transdermal administration refers to applying a substance onto the skin so that it is absorbed into the body for local or systemic distribution. A transdermal solution or transdermal patch is typically placed on one’s skin. The solution or patch includes a medicament that is released into the skin. As the layers of skin absorb the solution, the medicament is absorbed via the blood vessels into the bloodstream. From there, the substance can be circulated through the body.
[0004] There are obvious advantages to transdermal administration of medicaments. The consumer does not have to schedule and remember to consume doses of pills. Further, transdermal administration is not affected by stomach or digestive issues. Administration across the skin enables drugs to avoid degradation in the gastrointestinal tract or liver. Transdermal delivery is therefore of particular interest for molecules with limited systemic bioavailabilities and short half-lives.
Drugs that are absorbed slowly can be more effective. With a transdermal patch, a medicament can be released in small quantities over a long period of time. [0005] Transdermal administration can be effective in administering hydrophobic chemicals such as steroid hormones. For example, transdermal patches are a common means of administering steroidal drugs for birth control, hormone replacement therapy and prevention of motion sickness. Common medicaments that can be administered by transdermal patches include pain relievers, nicotine, hormones, and drugs to treat angina and motion sickness.
[0006] Medicaments that are not hydrophobic chemicals are typically unsuited for topical administration. To be effective, the active drug or agent in a topical composition must penetrate the skin, which is structurally complex and relatively thick. Molecules moving through the skin must first penetrate the stratum corneum and any material on its surface. The molecules must then penetrate the epidermis, the papillary dermis, and the capillary walls into the vascular system or lymphatic system. To be absorbed, the molecules must overcome a different resistance to penetration in each layer.
[0007] Strategies have been devised to improve transdermal administration of medicaments. These strategies can be categorized as either physical, chemical, mechanical or biochemical. Combinations of these strategies can also increase efficacy or extend the time for transdermal delivery. Physical techniques include abrasion and tape stripping, which physically break open the skin. Another physical method is prolonged occlusion, which alters the barrier properties of the stratum corneum. After 24 to 28 hours of occlusion with resultant hydration, corneocytes swell, intercellular spaces become distended, and the lacunar network becomes dilated. Distention of the lacunae eventually leads to connections with an otherwise discontinuous system. This creates pores in the stratum corneum interstices through which polar and non-polar substances can penetrate more easily.
[0008] Lecithin organogel (LO) is a common component of transdermal penetrants. LOs can help deliver different agents through the skin because they possess both the properties of oil and aqueous based formulations. LOs are typically gels that have an organic medium in liquid phase. They can have jelly-like structure that consists of three-dimensional networks of entangled reverse cylindrical micelles, which immobilize the continuous phase and thus convert from liquid to viscous gel.
[0009] Other approaches include the use of Chemical Permeation Enhancers. Chemical Permeation Enhancers (CPEs) are molecules that interact with the constituents of skin's outermost layer, the stratum corneum (SC), and increase its permeability. However, despite efforts at improving them, CPEs are minimally effective in increasing the rate at which drugs permeate the skin. CPEs can also cause skin damage, irritation and sensitization. Further, they are generally ineffective with high molecular weight drugs such as peptides, proteins and nucleic acids.
[0010] Although a variety of methods can be used to enhance transdermal drug delivery, these methods have limitations. Most efforts to enhance transdermal penetration have focused on the outermost layer of the skin, the stratum corneum. They typically rely on harsh solvents (e.g., alcohols, DMSO) or patch-based systems. This approach limits the molecular size, lipophilicity, and potency of drugs that can be used. In essence, current approaches are largely limited to small, lipophilic, and highly potent drugs.
[0011] There is no effective means of transdermal delivery of a vitamin or mineral. For example, creatine use can increase maximum power and performance in high- intensity anaerobic repetitive work. Creatine can also reduce and delay age-related muscle atrophy, by improving fat-free body mass, muscle strength and endurance, while simultaneously improving bone density. Transdermal administration of creatine could improve its bioavailability and allow small quantities to be released over time. Similarly, pyruvate and capsicum are often used as a weight-loss supplements. These agents could be more effective with transdermal administration.
[0012] An improved method of transdermal penetration should work with a variety of vitamins, minerals and supplements. It should overcome the barrier presented by the stratum corneum as well as the deeper layers of skin. Further, it should do so without harsh solvents and work with high molecular weight agents such as peptides, proteins and nucleic acids
[0013] Therefore, there is a need for an improved transdermal formulation that addresses the aforementioned drawbacks for transdermal administration of vitamins, minerals and supplements. Aspects of the present invention fulfill these needs and provide further related advantages as described in the following summary.
SUMMARY OF THE INVENTION
[0014] Aspects of the present disclosure teach certain benefits in construction and use which give rise to the exemplary advantages described below.
[0015] The present disclosure relates to systems and methods of transdermal administration of vitamins, minerals and supplements for a range of benefits.
[0016] The present disclosure solves the problems described above by providing transdermal formulations with improved penetration. In at least one embodiment, disclosed herein are transdermal penetrant formulations for transdermal administration of a vitamin, mineral or supplement.
[0017] The vitamin, mineral or supplement can be creatine, nitrate ion, caffeine, fructose, curcumin, pychnogenol, anthocyanin, phenolic acid, a flavonoid, a flavonol, b-Alanine, b- Hydroxy b-methylbutyric acid (HMB), carnosine, an omega-3 fatty acid, leucine, isoleucine, valine, citrulline, a ketone ester, a ketone salt, pyruvate, carnitine, serotonin (5-HTP), arginine, glutamine, berberine, resveratrol, vitamin C, vitamin B12, vitamin B9, vitamin B6, vitamin E, calcium, potassium, zinc, iron, sodium, magnesium, chromium, capsaicin, ginger, capsicum, cinnamon or tetrahydrobiopterin.
[0018] In one aspect, disclosed herein is a formulation for transdermal delivery of vitamins, minerals and supplements through the skin of a subject, comprising: a therapeutically effective amount of a vitamin, mineral or supplement; lecithin (1 - 20%w/w), isopropyl palmitate (1 - 20 %w/w), sorbic acid (around 1%w/w), benzyl alcohol (around 1%w/w), polyglyceryl-4 Laurate (1 - 10%w/w), vitamin D3 (around 1%w/w), deionized water (35 - 70%w/w), sodium lauryl sulfate (1 - 5%w/w), and poloxamer 407 (5 - 20%w/w).
[0019] In another aspect, disclosed herein is a method for transdermal delivery of a formulation for transdermal delivery of vitamin, mineral or supplement through the skin of a subject, comprising: a therapeutically effective amount of a vitamin, mineral or supplement; lecithin (1 - 20%w/w), isopropyl palmitate (1 - 20 %w/w), sorbic acid (around 1%w/w), benzyl alcohol (around 1%w/w), polyglyceryl-4 Laurate (1 - 10%w/w), vitamin D3 (around 1%w/w), deionized water (35 - 70%w/w), sodium nitrate (5 - 25%w/w), sodium lauryl sulfate (1 - 5 %w/w), and poloxamer 407 (5 - 20%w/w).
[0020] In another aspect, disclosed herein is a transdermal delivery formulation of an active agent through the skin, nail or hair follicle of a subject, wherein the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising: i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w.
[0021] In another aspect, disclosed herein is a transdermal delivery formulation of an active agent through the skin, nail or hair follicle of a subject, wherein the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, and an active agent.
[0022] In another aspect, disclosed herein is a method to effect transdermal delivery of an active ingredient comprising applying to the skin, nails or hair follicles of a subject an effective amount of a transdermal delivery formulation of an active agent through the skin, nail or hair follicle of a subject, wherein the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, and an active agent. [0023] Other features and advantages of aspects of the present invention will become apparent from the following more detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles of aspects of the invention.
Definitions
[0024] Reference in this specification to "one embodiment/aspect" or "an embodiment/aspect" means that a particular feature, structure, or characteristic described in connection with the embodiment/aspect is included in at least one embodiment/aspect of the disclosure. The use of the phrase "in one embodiment/aspect" or "in another embodiment/aspect" in various places in the specification are not necessarily all referring to the same embodiment/aspect, nor are separate or alternative embodiments/aspects mutually exclusive of other embodiments/aspects. Moreover, various features are described which may be exhibited by some embodiments/aspects and not by others. Similarly, various requirements are described which may be requirements for some embodiments/aspects but not other embodiments/aspects. Embodiment and aspect can in certain instances be used interchangeably.
[0025] The terms used in this specification generally have their ordinary meanings in the art, within the context of the disclosure, and in the specific context where each term is used. Certain terms that are used to describe the disclosure are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the disclosure. It will be appreciated that the same thing can be said in more than one way.
[0026] Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein. Nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and is not intended to further limit the scope and meaning of the disclosure or of any exemplified term. Likewise, the disclosure is not limited to various embodiments given in this specification.
[0027] Without intent to further limit the scope of the disclosure, examples of instruments, apparatus, methods and their related results according to the embodiments of the present disclosure are given below. Note that titles or subtitles may be used in the examples for convenience of a reader, which in no way should limit the scope of the disclosure. 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 disclosure pertains. In the case of conflict, the present document, including definitions, will control.
[0028] As applicable, the terms "about" or "generally", as used herein in the specification and appended claims, and unless otherwise indicated, means a margin of +/- 20%. Also, as applicable, the term "substantially" as used herein in the specification and appended claims, unless otherwise indicated, means a margin of +/- 10%. It is to be appreciated that not all uses of the above terms are quantifiable such that the referenced ranges can be applied.
[0029] The term “subject” or "patient" refers to any single animal, more preferably a mammal (including such non-human animals as, for example, dogs, cats, horses, rabbits, zoo animals, cows, pigs, sheep, and non-human primates) for which treatment is desired. Most preferably, the patient herein is a human.
[0030] The term “active agent” or “active ingredient” refers to a substance, compound, or molecule, which is biologically active or otherwise, induces a biological or physiological effect on a subject to which it is administered to. In other words, “active agent” or “active ingredient” refers to a component or components of a composition to which the whole or part of the effect of the composition is attributed. An active agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed. An active agent can be a secondary agent, or in other words, the component(s) of a composition to which an additional part and/or other effect of the composition is attributed.
[0031] All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are to be understood as approximations in accordance with common practice in the art. When used herein, the term “about” may connote variation (+) or (-) 1%, 5% or 10% of the stated amount, as appropriate given the context. It is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.
[0032] In an embodiment, a “pharmaceutical composition” is intended to include the combination of an active agent with a carrier, inert or active, in a sterile composition suitable for diagnostic or therapeutic use in vitro , in vivo or ex vivo. In one aspect, the pharmaceutical composition is substantially free of endotoxins or is non-toxic to recipients at the dosage or concentration employed.
[0033] In an embodiment, “an effective amount” refers to the amount of the defined component sufficient to achieve the desired chemical composition or the desired biological and/or therapeutic result. In an embodiment, that result can be the desired pH or chemical or biological characteristic, e.g., stability of the formulation. In other embodiments, the desired result is the alleviation or amelioration of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. When the desired result is a therapeutic response, the effective amount will vary depending upon the specific disease or symptom to be treated or alleviated, the age, gender and weight of the subject to be treated, the dosing regimen of the formulation, the severity of the disease condition, the manner of administration and the like, all of which can be determined readily by one of skill in the art. A desired effect may, without necessarily being therapeutic, also be a cosmetic effect, in particular for treatment for disorders of the skin or muscles.
[0034] In an embodiment, as used herein, the terms “treating,” “treatment” and the like are used herein to mean obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disorder or sign or symptom thereof, and/or may be therapeutic in terms of amelioration of the symptoms of the disease or infection, or a partial or complete cure for a disorder and/or adverse effect attributable to the disorder. It can also refer to inhibiting or preventing muscle cramping, improving performance and recovery and/or maintaining levels of supplements, vitamins and minerals for general health and prevention of disease.
[0035] The term “bioavailability” refers to the fraction of an administered dose of unchanged drug that reaches the systemic circulation. For example, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (such as orally), its bioavailability generally decreases due to incomplete absorption and first-pass metabolism. Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration.
[0036] The term “curcumin” refers a diarylheptanoid, belonging to the group of curcuminoids, which are natural phenols responsible for turmeric's yellow color. It is a tautomeric compound existing in enolic form in organic solvents and in keto form in water.
[0037] The term “pychnogenol” refers to a product derived from the bark of a tree known as Pinus pinaster. The active ingredients in pycnogenol can also be extracted from other sources, including peanut skin, grape seed, and witch hazel bark. Pycnogenol can be beneficial for treating circulation problems, allergies, asthma, ringing in the ears, high blood pressure, muscle soreness, pain, osteoarthritis, diabetes, attention deficit-hyperactivity disorder (ADHD), endometriosis, menopausal symptoms, painful menstrual periods, erectile dysfunction (ED), retinopathy, stroke, heart disease, and varicose veins.
[0038] The term “anthocyanin” refers to a type of flavonoid, a class of compounds with antioxidant effects. Found naturally in a number of foods, anthocyanins are the pigments that give red, purple, and blue plants their rich coloring. Anthocyanins have been shown to have antioxidant properties in vitro.
[0039] The term “flavonoid” refers to substances that give pigments for flower coloration, producing yellow or red/blue pigmentation in petals designed to attract pollinator animals. In higher plants, flavonoids are involved in UV filtration, symbiotic nitrogen fixation and floral pigmentation. They may also act as chemical messengers, physiological regulators, and cell cycle inhibitors. Chemically, flavonoids have the general structure of a 15-carbon skeleton, which consists of two phenyl rings (A and B) and a heterocyclic ring. Flavonoids may have health benefits to humans as antioxidants, anti-inflammatories, anti-cancer, anti-bacteria and in cardiovascular disease.
[0040] The term “b-Hydroxy b-methy!butyric acid,” ΉMB,” or “b-bydroxy b- methylbutyrate” refers to a dietary supplement that can increase exercise-induced gains in muscle size, muscle strength, and lean body mass, reduce skeletal muscle damage from exercise, improve aerobic exercise performance, and expedite recovery from exercise.
[0041] The term “berberine” refers to a quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids found in a group of shrubs called Berberis. it has been used to treat various ailments, particularly in Chinese medicine.
[0042] The term “capsaicin” refers to 8-methyl-N-vanillyl-6-nonenamide, an active component of chili peppers. Capsaicin has analgesic properties and is a neuropeptide releasing agent selective for primary sensory peripheral neurons. Used topically, capsaicin can aid in controlling peripheral nerve pain.
[0043] The term “capsicum” refers to an herb, red pepper or chili pepper.
Capsaicin is a resin derived from hot chili peppers of the Capsicum family. It can be used to treat nociceptive and neuropathic pain. Capsicum is most commonly used for rheumatoid arthritis (RA), osteoarthritis, and other painful conditions. It is also used for digestion problems, conditions of the heart and blood vessels.
[0044] The term “carnosine” refers to beta-a!any!-L-histidine. It is a dipeptide molecule with a characteristic imidazole-ring made up of the amino acids beta- alanine and histidine. Carnosine acts as an antiglycating agent, reducing the rate of formation of advanced glycation end-products (substances that can be a factor in the development or worsening of many degenerative diseases, such as diabetes, atherosclerosis, chronic renal failure, and Alzheimer's disease), and ultimately reducing development of atherosclerotic plaque build-up.
[0045] The term “carnitine” refers to b-hydroxy-Y-N-trimethy!aminobutyric acid, 3- hydroxy-4-N,N,N-trimethylaminobutyrate which is a quaternary ammonium compound involved in metabolism in most mammals, plants and some bacteria.
[0046] The term “flavonol” refers to a class of flavonoids that have the 3- hydroxyflavone backbone (lUPAC name : 3-hydroxy-2-phenylchromen-4-one). Their diversity stems from the different positions of the phenolic -OH groups. They are distinct from flavanols (with "a") such as catechin, another class of flavonoids.
[0047] The term “nitrate ion” or “nitrate” refers to the compound NO3. Its presence can help modulate levels of nitric oxide (NO) which is important in muscle physiology. Tissue concentrations of nitrate and nitrite can be increased by consumption of green leafy vegetables such as lettuce, spinach and beetroot. Thus, dietary nitrate supplementation can be a practical way increase circulating plasma concentrations of NO2 and thus NO bioavailability. A nitrate supplement can also lower resting blood pressure, reduced pulmonary O2 uptake during submaximal exercise and, perhaps, enhance exercise tolerance or performance.
[0048] The term “phenolic acid” refers to a type of phytochemical called a polyphenol. Other types of polyphenols include flavonoids and stilbenes. Phenolic acids are found in a variety of plant-based foods; the seeds and skins of fruits and the leaves of vegetables contain the highest concentrations. Two important naturally occurring types of phenolic acids are hydroxybenzoic acids and hydroxycinnamic acids, which are derived from non-phenolic molecules of benzoic and cinnamic acid, respectively.
[0049] The term “resveratrol” refers to 3,5,4'-trihydroxy-trans-stilbene, a stilbenoid.
It is a type of natural phenol, and a phytoalexin produced by several plants in response to injury or, when the plant is under attack by pathogens such as bacteria or fungi. It can have positive health effects in humans, including lowering blood pressure.
[0050] The term “tetrahydrobiopterin” (BH4, THB) or “sapropterin” refers to a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin. Tetrahydrobiopterin has multiple roles in human biochemistry. The major one is to convert amino acids such as phenylalanine, tyrosine, and tryptophan to precursors of dopamine and serotonin, major monoamine neurotransmitters. It works as a cofactor, being required for an enzyme's activity as a catalyst, mainly hydroxylases.
[0051] In an embodiment, a “pharmaceutical composition” is intended to include, without limitation, the combination of an active agent with a carrier, inert or active, in a sterile composition suitable for diagnostic or therapeutic use in vitro , in vivo or ex vivo. In one aspect, the pharmaceutical composition is substantially free of endotoxins or is non-toxic to recipients at the dosage or concentration employed.
[0052] In an embodiment, “an effective amount” refers, without limitation, to the amount of the defined component sufficient to achieve the desired chemical composition or the desired biological and/or therapeutic result. In an embodiment, that result can be the desired pH or chemical or biological characteristic, e.g., stability of the formulation. In other embodiments, the desired result is the alleviation or amelioration of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. When the desired result is a therapeutic response, the effective amount will, without limitation, vary depending upon the specific disease or symptom to be treated or alleviated, the age, gender and weight of the subject to be treated, the dosing regimen of the formulation, the severity of the disease condition, the manner of administration and the like, all of which can be determined readily by one of skill in the art. A desired effect may, without necessarily being therapeutic, also be a cosmetic effect, in particular for treatment for disorders of the skin described herein.
[0053] In an embodiment, a “subject” of diagnosis or treatment is, without limitation, a prokaryotic or a eukaryotic cell, a tissue culture, a tissue or an animal, e.g. a mammal, including a human. Non-human animals subject to diagnosis or treatment include, for example, without limitation, a simian, a murine, a canine, a leporid, such as a rabbit, livestock, sport animals, and pets.
[0054] In an embodiment, as used herein, the terms “treating,” “treatment” and the like are used herein, without limitation, to mean obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disorder or sign or symptom thereof, and/or may be therapeutic in terms of amelioration of the symptoms of the disease or infection, or a partial or complete cure for a disorder and/or adverse effect attributable to the disorder.
[0055] All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are to be understood as approximations in accordance with common practice in the art. When used herein, the term “about” may connote variation (+) or (-) 1%, 5% or 10% of the stated amount, as appropriate given the context. It is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.
[0056] Many known and useful compounds and the like can be found in Remington’s Pharmaceutical Sciences (13th Ed), Mack Publishing Company, Easton, PA — a standard reference for various types of administration. As used herein, the term “formulation(s)” means a combination of at least one active ingredient with one or more other ingredient, also commonly referred to as excipients, which may be independently active or inactive. The term “formulation” may or may not refer to a pharmaceutically acceptable composition for administration to humans or animals and may include compositions that are useful intermediates for storage or research purposes.
[0057] As the patients and subjects of the invention method are, in addition to humans, veterinary subjects, formulations suitable for these subjects are also appropriate. Such subjects include livestock and pets as well as sports animals such as horses, greyhounds, and the like.
[0058] For purposes herein, a formulation, a formulation for transdermal delivery and a transdermal delivery formulation are each a formulation for transdermal delivery, including, the transdermal delivery of an active ingredient for the treatment of a syndrome and or a disease in an individual.
Description of Embodiments of the Invention Transdermal delivery formulation components
[0059] Embodiments include a transdermal lotion or cream for administration of vitamins, minerals and supplements to a subject. It is placed on the skin to deliver a specific dose of an agent through the skin. The agent can be delivered across the skin into a localized subdermal location. For example, a lotion can promote healing to an injured area of the body. A mineral or supplement can be delivered to a sore muscle, joint or tendon from the lotion. Alternatively, the agent can enter the circulation for systemic distribution. For example, a vitamin can be distributed throughout the body.
[0060] In an alternative embodiment, an agent can be administered using a transdermal or medicated adhesive patch. To release an agent, a patch can utilize a porous membrane covering a reservoir of the agent. Alternatively, the agent can be embedded in layers of the adhesive that release the agent as they dissolve or melt. [0061] An advantage of a transdermal drug delivery route over other types of delivery is that the formulation can provide a controlled release of the agent. Conventional transdermal delivery systems are generally ineffective for use with agents and medications that are large molecules and/or hydrophilic molecules. Embodiments include a method and formulation for subdermal delivery of a variety of vitamins, minerals and supplements.
[0062] There are other advantages to transdermal administration of medicaments. Proteins and peptides used, for example, in aging treatments can be degraded by the gastric acid and enzymes. Transdermal administration is not affected by stomach or digestive issues. Further, people can benefit from drugs that are absorbed slowly and regularly. With a transdermal formulation, a medicament can be released in small quantities over a long period of time.
[0063] Other advantages are related to dosing. Large doses of agents can cause dose-dependent toxicity in many cases. For example, oral administration of vitamin A can result in hypervitaminosis A. The main problems associated with the vitamin A are its half-life, fast absorption (due to lipophilicity) and its toxicity (due to high loading and frequent dosing). Also, some drugs undergo first-pass metabolism, which prevents their delivery to the desired site of action. Furthermore, many hydrophilic or lipophilic drugs show either poor dissolution or poor absorption on oral administration. With a transdermal formulation, the effective concentration of an agent can be applied at the desired site without painful delivery.
[0064] In one embodiment, nutrients are supplied via transdermal administration. There are many occasions in which the formulations of the invention are useful. For athletes, a transdermal delivery formulation can deliver to tired muscles sufficient amounts of a neutralizing agent for lactic acid, such as a ketone component, to relieve the burning sensation felt by the athlete due to the buildup of lactic acid. This permits the athlete to continue to perform at optimum level for longer periods of time. In addition, athletes or others "working out" are expending high amounts of energy and are in need of energy generation, especially in those areas of their musculature that are involved in performing workouts and, therefore, need to consume large numbers of calories. These nutrients can be supplied directly rather than requiring oral ingestion which is counterproductive and relatively slow.
Transdermal Administration of Vitamins
[0065] A wide variety of therapeutic agents can be used in a transdermal delivery formulation, such as vitamins, minerals and supplements. In one embodiment, a vitamin is administered transdermally. A vitamin can be defined as an organic molecule (or related set of molecules) that is an essential micronutrient necessary in small quantities for the proper functioning of metabolism. For example, vitamin A acts as a regulator of cell and tissue growth and differentiation. Vitamin D provides a hormone-like function, regulating mineral metabolism for bones and other organs. The B complex vitamins function as enzyme cofactors (coenzymes) or the precursors for them. Vitamins C and E function as antioxidants.
Transdermal Administration of Minerals
[0066] In one embodiment, a mineral is administered transdermally. A mineral can be defined as a chemical element required as an essential nutrient by organisms to perform functions necessary for life. The five major minerals in the human body are calcium, phosphorus, potassium, sodium, and magnesium. All of the remaining elements in a human body can be referred to as "trace elements." The trace elements that have a specific biochemical function in the human body are sulfur, iron, chlorine, cobalt, copper, zinc, manganese, molybdenum, iodine and selenium.
Transdermal Administration of Dietary Supplements
[0067] In one embodiment, a dietary supplement is administered transdermally. A dietary supplement can be defined as a manufactured product intended to supplement the diet. A supplement can provide nutrients either extracted from food sources or synthetic, individually or in combination, in order to increase the quantity of their consumption. The class of nutrient compounds includes vitamins, minerals, fiber, fatty acids and amino acids. Dietary supplements can also contain substances that have not been confirmed as being essential to life, but are marketed as having a beneficial biological effect, such as plant pigments or polyphenols. [0068] Table 1 lists several agents that can be administered transdermally according to some embodiments. The “% solution” indicates the relative dosing which is the amount in the transdermal solution.
Table 1
Figure imgf000018_0001
Figure imgf000019_0001
Transdermal delivery formulation components
[0069] The present disclosure herein demonstrates transdermal delivery of an agent without many of the negative effects on color, smell, grittiness and stability driven by the use of lecithin organogel. Moreover, the methods describe herein improve transdermal penetration.
[0070] In an embodiment, a transdermal delivery formulation contains a phosphatide in a concentration of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70% or more w/w of the transdermal delivery formulation.
[0071] Phosphatides - Soy lecithin contains about 57.5 %w/w phosphatides. The primary phosphatides found in Soy Lecithin are inositol phosphatides (20.5 %w/w of Soy lecithin), phosphatidylcholine (20%), and phosphatidylethanolamine (11 %w/w of Soy lecithin). In some embodiments, phosphatidylcholine is used for the full amount (57.5 %w/w of Soy lecithin) as it is known to aide in skin penetration. Other phosphatides include phosphatidic acid, phosphatidylserine and phosphatidylinositol. [0072] In an embodiment, a transdermal delivery formulation contains a sterol or benzyl alcohol in a concentration of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30% or more w/w of the transdermal delivery formulation.
[0073] Sterols - Soy lecithin contains about 2.5 %w/w sterols. In some embodiments, benzyl alcohol is used in substitution of the sterol in a transdermal delivery formulation to act as a penetration enhancer. In another embodiment, a sterol is cholesterol, ergosterol, hopanoids, hydroxysteroid, phytosterol and/or other steroids.
[0074] In an embodiment, a transdermal delivery formulation contains a carbohydrate in a concentration of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70% or more w/w of the transdermal delivery formulation.
[0075] Carbohydrates - Soy lecithin contains about 5 %w/w free carbohydrates. In some embodiments, glucose is used in substitution of a free carbohydrate to maintain the ratio of sugars in the transdermal delivery formulation disclosed herein. In another embodiment, a carbohydrate is a monosaccharide, a disaccharide, a polyol, a malto-oligosaccharide, an oligosaccharide, a starch, a polysaccharide. In a further embodiment, a carbohydrate is glucose, galactose, fructose, xylose, sucrose, lactose, maltose, trehalose, sorbitol, mannitol, maltodextrins, raffinose, stachyose, fructo-oligosaccharide, amylose, amylopectin, modified starches, glycogen, cellulose, hemicellulose, pectin and/or hydrocolloid.
[0076] Moisture - In some embodiments, the transdermal delivery formulation maintains the about 1 %w/w of water contained in Soy lecithin.
[0077] In an embodiment, a transdermal delivery formulation contains water in a concentration of at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70% or more w/w of the transdermal delivery formulation.
[0078] Fatty acids - Soy lecithin contains about 34 %w/w fatty acids, including 18- 19 %w/w linoleic acid, 1-2 %w/w alpha-linoleic acid, 8-9 %w/w oleic acid, about 5 %w/w Palmitic acid, and 1-2 %w/w stearic acids. In some embodiments, the fatty acids are similar to the fatty acids contained in soy lecithin. In an embodiment, alpha-linoleic is removed from the transdermal delivery formulation as it is known to oxidize and can become rancid. In some embodiments, the amount of stearic acid has been increased (i.e. , enhancing stability of the formulation) or linoleic acid (i.e. , enhances skin penetration). In some embodiments, a seed oil such as purified safflower oil is used in a transdermal delivery formulation due to its similarity to the fatty acids found in Soy lecithin, its relative availability and its low cost. In some embodiments, the fatty acid content of a transdermal formulation can be adjusted with a different seed oil through the addition of smaller amounts of the fatty acids disclosed herein.
[0079] In a further embodiment, a fatty acid is a saturated or an unsaturated fatty acid. In another embodiment, an unsaturated fatty acid is myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, a-Linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and/or docosahexaenoic acid. In an embodiment, a saturated fatty acid is caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid and/or cerotic acid. In another embodiment, the fatty acid is a dietary fat and include duct fat, lard, tallow, butter, coconut oil, cocoa butter, palm kernel oil, palm oil, cottonseed oil, wheat germ oil, soybean oil, olive oil, corn oil, sunflower oil, safflower oil, hemp oil and/or canola/rapeseed oil.
[0080] In some embodiments, carotenoids are excluded from the formulations disclosed. In an embodiment, a transdermal delivery formulation comprises the components of Table 2: Table 2
Figure imgf000022_0001
[0081] In some another embodiment, a transdermal delivery formulation comprises the components of Table 3:
Table 3
Figure imgf000022_0002
[0082] In an aspect, the concentration of Phosphatidylcholine in a transdermal delivery formulation is at least 10%, at least 15%, at least 20%, at least 25%, at least 28.75%, at least 30%, at least 35%, at least 40% or more. In an aspect, the concentration of phosphatidylcholine in a transdermal delivery formulation is not more than 10%, not more than 15%, not more than 20%, not more than 25%, not more than 28.75%, not more than 30%, not more than 35%, not more than 40% or more. In an aspect, the concentration of phosphatidylcholine in a transdermal delivery formulation is about 10%, about 15%, about 20%, about 25%, at least 28.75%, about 30%, about 35%, about 40% or more. In an aspect, the concentration of Phosphatidylcholine in a transdermal delivery formulation is from 10% to 40%, is from 15% to 35%, is from 20% to 30%, is from 25% to 30%, is from 28% to 29%.
[0083] In another aspect, the concentration of glucose in a transdermal delivery formulation is at least 1%, at least 2%, at least 2.5%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9% or more. In another aspect, the concentration of glucose in a transdermal delivery formulation is about 1%, about 2%, about 2.5%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or more. In another aspect, the concentration of glucose in a transdermal delivery formulation is no more than 1%, no more than 2%, no more than 2.5%, no more than 3%, no more than 4%, no more than 5%, no more than 6%, no more than 7%, no more than 8%, no more than 9% or more. In another aspect, the concentration of glucose in a transdermal delivery formulation is from 1% to 10%, is from 2% to 9%, is from 2.5% to 5%, is from 2% to 3%, is from 3% to 8%, if from 4% to 7%, if from 5% to 6%, is from 2% to 4%, is from 1.5% to 3.5.
[0084] In a further embodiment, the concentration of Benzyl Alcohol in a transdermal formulation is at least 0.25%, at least 0.5%, at least 0.75%, at least 1%, at least 2%, at least 2.5%, at least 3%, at least 4%, at least 5% or more. In an embodiment, the concentration of Benzyl Alcohol in a transdermal formulation is about 0.25%, about 0.5%, about 0.75%, about 1%, about 2%, about 2.5%, about 3%, about 4%, about 5% or more. In another embodiment, the concentration of Benzyl Alcohol in a transdermal formulation is at from 0.25% to 5 %; from 0.5% to 4%, from 0.75% to 3%, from 1% to 2.5% or from 0.5% to 2%. In a further embodiment, the concentration of Benzyl Alcohol in a transdermal formulation is no more than 0.25%, no more than 0.5%, no more than 0.75%, no more than 1%, no more than 2%, no more than 2.5%, no more than 3%, no more than 4%, no more than 5%. [0085] In an embodiment, the concentration of Deionized Water in a transdermal formulation is at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5% or more. In an embodiment, the concentration of Deionized Water in a transdermal formulation is about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5% or more. In an embodiment, the concentration of Deionized Water in a transdermal formulation is from 0.1% to 5%, from 0.2% to 4 %, from 0.3% to 3%, 0.4% - 2%, 0.5% to 1 %, from 0.6% t 0.9%, from 0.7% to 0.8%, from 0.4% to 1.5%, from 0.3% to 0.7% or from 0.4% to 0.6%. In an embodiment, the concentration of Deionized Water in a transdermal formulation is no more than 0.1%, no more than 0.2%, no more than 0.3%, no more than 0.4%, no more than 0.5%, no more than 0.6%, no more than 0.7%, no more than 0.8%, no more than 0.9%, no more than 1 %, no more than 2%, no more than 3%, no more than 4%, no more than 5% or more.
[0086] In an aspect, the concentration of Safflower oil in a transdermal delivery formulation is at least 1 %, at least 5%, at least 7.5%, at least 10%, at least 11 %, at least 11.06%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20 % or more. In an aspect, the concentration of Safflower oil in a transdermal delivery formulation is about 1%, about 5%, about 7.5%, about 10%, about 11 %, about 11.06%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17 %, about 18%, about 19%, about 20 % or more. In an aspect, the concentration of Safflower oil in a transdermal delivery formulation is from 1 % to 20%, from 5% to 19%, from 7.5% to 18%, from 10% to 17%, from 11 % to 16%, from 11.06%, 12% from 11 % to 12%, from 12% to 14%, from 13% to 14%, from 10% to 12%, from 10.5% to 12.5% or from 11% to 11.25%. In an aspect, the concentration of Safflower oil in a transdermal delivery formulation is no more than 1%, no more than 5%, no more than 7.5%, no more than
10%, no more than 11%, no more than 11.06%, no more than 12%, no more than
13%, no more than 14%, no more than 15%, no more than 16%, no more than 17 %, no more than 18%, no more than 19%, no more than 20 %. [0087] In a further aspect, the concentration of Oleic Acid in a transdermal delivery formulation is at least 1%, at least 2%, at least 3%, at least 3.65%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10% or more. In a further aspect, the concentration of Oleic Acid in a transdermal delivery formulation is about 1 %, about 2%, about 3%, about 3.65%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10% or more. In a further aspect, the concentration of Oleic Acid in a transdermal delivery formulation is no more than 1%, no more than 2%, no more than 3%, no more than 3.65%, no more than 4%, no more than 5%, no more than 6%, no more than 7%, no more than 8%, no more than 9%, no more than 10% or more. In another aspect, the concentration of Oleic Acid in a transdermal formulation is from 1% to 10%, from 2% to 9%, from 2% to 3%, from 3% to 4%, from 3% to 8%, from 4% to 7%, from 5% to 6%, from 2 to 2.5% or from 2.5% to 4%.
[0088] In another aspect, the concentration of Stearic Acid in a transdermal formulation is at least 1%, at least 2%, at least 2.34%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10% or more. In another aspect, the concentration of Stearic Acid in a transdermal formulation is no more than 1%, no more than 2%, no more than 2.34%, no more than 3%, no more than 4%, no more than 5%, no more than 6%, no more than 7%, no more than 8%, no more than 9%, no more than 10% or more. In another aspect, the concentration of Stearic Acid in a transdermal formulation is about 1%, about 2%, about 2.34%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10% or more. In another aspect, the concentration of Stearic Acid in a transdermal formulation is from 1% to 10%, from 2% to 9%, from 2% to 3%, from 2.34% to 2.5%, from 3% to 8%, from 4% to 7%, from 5% to 6% or from 1.5% to 2.5%.
[0089] In an aspect, the concentration of Isopropyl Palmitate in a transdermal formulation is at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% or more. In an aspect, the concentration of Isopropyl Palmitate in a transdermal formulation is about 10%, about 20%, about 25%, about 30%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more. In an aspect, the concentration of Isopropyl Palmitate in a transdermal formulation is no more than 10%, no more than 20%, no more than 25%, no more than 30%, no more than 40%, no more than 45%, no more than 50%, no more than 55%, no more than 60%, no more than 65%, no more than 70%, no more than 75% or more. In an aspect, the concentration of Isopropyl Palmitate in a transdermal formulation is from 10% to 75%, from 20% to 70%, from 25% to 65%, from 30% to 60%, from 40% to 55%, from 45% to 50%, from 40% to 60%, from 45% to 55% or from 47% to 53%.
[0090] Certain components or ingredients of a transdermal delivery formulation provided herein may be supplemented with components described in greater detail in the inventor’s related applications mentioned above, including United states Application No. 16/132,358 filed September 14, 2018, entitled ‘Methods and Formulations For Transdermal Administration Of Buffering Agents’, International Patent Application No. PCT/US18/51250 filed September s, 2018, entitled ‘Methods of Administration and Treatment’, and International Patent Application PCT/US18/28017 by Bruce Sand filed April 17, 2018, entitled ‘Parental non-systemic administration of buffering agents for inhibiting metastasis of solid tumors, hyperpigmentation and gout’, all incorporated by reference in their entirety herein.
Iron
[0091] A transdermal delivery formulation containing iron can be formulated at acidic pH to minimize the spontaneous oxidation Fe(ll) into Fe(lll).
[0092] Suitable nonlimiting exemplary iron chelators include deferoxamine, ethylenediaminetetraacetic acid (EDTA), 1 ,2-diethyl-3-hydroxypyridin-4-one (CP94), Desferal, Deferiprone and Deferasirox, succimer, trientine, Desferrithiocin,
Clioquinol, O-trensox, Tachpyr, Dexrazoxane, Triapine, Pyridoxal isonicotinoyl hydrazone, Di-2-pyridylketone thiosemicarbazone series, Flavan-3-ol, Curcumin, Apocynin, Kolaviron, Floranol, Baicalein, Baicalin, ligustrazine, Quercetin, Epigallocatechin gallate, Theaflavin, Phytic acid, and Genistein. [0093] Suitable nonlimiting exemplary antioxidants include glutathione, vitamin C, vitamin E, superoxide dismutase, catalase, pNaKtide, Butylated hydroxytoluene, Butylated hydroxyanisole, tert-Butylhydroquinone, HP beta CD, resveratrol, retinol, coenzyme q10, niacinamide, polyphenols, flavonoids, beta-carotene, lutein, and lycopene.
[0094] A transdermal delivery formulation can include mixtures wherein the components interact synergistically and induce skin permeation enhancements better than that induced by the individual components. Synergies between chemicals can be exploited to design potent permeation enhancers that overcome the efficacy limitations of single enhancers. Several embodiments disclosed herein utilize three to five distinct permeation enhancers.
[0095] In some embodiments, a transdermal delivery formulation comprises phosphatidylcholine in amount less than 12 %w/w or 18 %w/w of the formulation. In some embodiments, the transdermal delivery formulation comprises a phospholipid in amount less than 12 %w/w or 18 %w/w of the formulation. In some embodiments, the transdermal delivery formulation comprises a mixture of tridecane and undecane in amount less than 2 %w/w, 5 %w/w, or 8 %w/w of the formulation. In some embodiments, the formulation comprises Cetiol Ultimate® in an amount less than about 2 %w/w, 5 %w/w, or 10 %w/w, or an equivalent mixture of tridecane and undecane. In some embodiments, the transdermal delivery formulation comprises cetyl alcohol in amount less than 2 %w/w, 5 %w/w, or 8 %w/w of the formulation. In some embodiments, the transdermal delivery formulation comprises benzyl alcohol in an amount less than about 2 %w/w, 5 %w/w, or 8 %w/w. In some embodiments, the transdermal delivery formulation comprises stearic acid in an amount less than 2 %w/w, 5 %w/w, or 8 %w/w of the formulation.
[0096] In any of the anesthetic compositions of a transdermal delivery formulation, it may be desirable to administer the epinephrine in tandem with a transdermal anesthetic. Alternatively, treatment of the epinephrine with a chelator, such as the iron chelator Desferal® may stabilize the epinephrine sufficiently to include it in the transdermal delivery formulation. [0097] A suitable dose of iron or an iron containing transdermal delivery formulation administered topically as a transdermal delivery formulation for a subject (e.g. a human patient) is at least about 500 mg, at least about 750 mg, at least about 1000 mg, at least about 1.5 g, at least about 2.0 g, at least about 2.5 g, at least about 3.0 g, at least about 3.5 g, at least about 4.0 g, at least about 4.5 g, at least about 5.0 g, at least about 6.0 g, at least about 7.0 g, at least about 8.0 g, at least about 9.0 g, at least about 10.0 g, at least about 11 g, at least about 12 g, at least about 13 g, at least about 14 g, at least about 15 g, at least about 20 g, at least about 25 g, at least about 30 g, at least about 35 g, at least about 40 g, at least about 45 g, at least about 50 g, or more. This dose is typically administered daily, twice a day, or three times a day, but it may also be administered four times a day, five times a day, or more than five times a day.
[0098] Alternatively, a suitable daily dose of iron or an iron containing transdermal delivery formulation administered topically as a transdermal delivery formulation for a subject is at least about 10 mg/kg, at least about 25 mg/kg, at least about 30 mg/kg, at least about 35 mg/kg, at least about 40 mg/kg, at least about 45 mg/kg, at least about 50 mg/kg, at least about 55 mg/kg, at least about 60 mg/kg, at least about 65 mg/kg, at least about 70 mg/kg, at least about 75 mg/kg, at least about 80 mg/kg, at least about 90 mg/kg, at least about 100 mg/kg, at least about 125 mg/kg, at least about 150 mg/kg, at least about 160 mg/kg, at least about 170 mg/kg, at least about 175 mg/kg, at least about 180 mg/kg, at least about 190 mg/kg, at least about 200 mg/kg, at least about 225 mg/kg, at least about 250 mg/kg, at least about 275 mg/kg, at least about 300 mg/kg, at least about 325 mg/kg, at least about 350 mg/kg, at least about 375 mg/kg, at least about 400 mg/kg, at least about 425 mg/kg, at least about 450mg/kg, at least about 475 mg/kg, up to at least about 500 mg/kg or more.
[0099] In another aspect, a suitable daily dose of iron or an iron containing transdermal delivery formulation administered topically as a transdermal delivery formulation for a subject is about 10 mg/kg to about 1.0 g/kg, and more typically the daily dose is about 10 mg/kg to about 500 mg/kg, about 25 mg/kg to about 500 mg/kg, about 50mg/kg to about 300 mg/kg, about 75 mg/kg to about 300 mg/kg, about 75mg/kg to about 250 mg/kg, about 100 mg/kg to about 300 mg/kg, about 75 mg/kg to about 200 mg/kg, about 100 mg/kg to about 200 mg/kg, or alternative ranges.
[00100] In one aspect, disclosed herein is a transdermal delivery formulation for transdermal delivery ketone components through the skin of a subject, comprising: a ketone component in an amount between about 10-60 %w/w; a transdermal delivery formulation in an amount less than about 60 %w/w, and water in an amount less than about 50 %w/w.
[00101] In another aspect disclosed herein is a method of inducing ketosis to treat a disorder and/or treating a disorder with ketone supplementation in a subject, wherein the method comprises administering an effective amount of a transdermal delivery formulation for transdermal delivery of one or more ketone components through the skin of a subject, comprising: a ketone component in an amount between about IQ- 60 %w/w; a transdermal delivery formulation in an amount less than about 60 %w/w, and water in an amount less than about 50 %w/w. Particularly suitable formulation for transdermal delivery ketone components are described in the US Application No. 62/742,172, filed October 5, 2018, which is incorporated by reference herein.
[00102] A transdermal delivery formulation comprise mixtures wherein the components interact synergistically and induce skin permeation enhancements better than that induced by the individual components. Synergies between chemicals can be exploited to design potent permeation enhancers that overcome the efficacy limitations of single enhancers. Several embodiments disclosed herein utilize one or more distinct permeation enhancers.
[00103] For topical administration, and in particular transdermal administration, a transdermal delivery formulation will comprise penetrants including either or both chemical penetrants (CPEs) and peptide-based cellular penetrating agents (CPPs) that encourage transmission across the dermis and/or across membranes including cell membranes, as would be the case in particular for administration by suppository or intranasal administration, but for transdermal administration as well. In some embodiments, suitable penetrants include those that are described in the above- referenced US2009/0053290 ('290), W02014/209910 ('910), and WO2017/127834.
In addition to transdermal delivery formulations with penetrants, transdermal delivery can be effected by mechanically disrupting the surface of the skin to encourage penetration, or simply by supplying the formulation applied to the skin under an occlusive patch.
[00104] Alternatively, the transdermal delivery formulation comprises a completion component as well as one or more electrolytes sufficient to impart viscosity and viscoelasticity, one or more surfactants and an alcohol. The completion component can be a polar liquid, a non-polar liquid or an amphiphilic substance. The penetrant may further comprise a keratinolytic agent effective to reduce thiol linkages, disrupt hydrogen bonding and/or effect keratin lysis and/or a cell penetrating peptide (sometimes referred to as a skin-penetrating peptide) and/or a permeation enhancer.
[00105] Suitable gelling components also include isopropyl palmitate, ethyl laurate, ethyl myristate and isopropyl myristate. In some embodiments, a transdermal delivery formulation comprises a gelling agent in an amount less than 5 %w/w of a transdermal delivery formulation. Certain hydrocarbons, such as cyclopentane, cyclooctane, frans-decalin, trans- pinane, n-pentane, n-hexane, n-hexadecane may also be used. In some embodiments, the transdermal delivery formulation comprises a mixture of xanthan gum, sclerotium gum, pullulan, or a combination thereof in an amount less than 2 %w/w, 5 %w/w, or 10 %w/w of the formulation. In some embodiments, a transdermal delivery formulation comprises Siligel™ in an amount between about 1-5 % w/w or 5-15 % w/w, or an equivalent mixture of xanthan gum, sclerotium gum, and pullulan. In some embodiments, a transdermal delivery formulation comprises a mixture of caprylic triglycerides and capric triglycerides in amount less than 2 %w/w, 8 %w/w, or 10 %w/w of the formulation. In some embodiments, a transdermal delivery formulation comprises Myritol® 312 in an amount between about 0.5-10 %w/w, or an equivalent mixture of caprylic triglycerides and capric triglycerides. [00106] In some embodiments, a transdermal delivery formulation is in an amount between about 10-90 %w/w or 10-50 %w/w of the formulation or at least 10%w/w, at least 20%w/w, at least 30%w/w, at least 40 %w/w, at least 50%w/w, at least 60%w/w, at least 70%w/w, at least 80%w/w, at least 90%w/w or at least 95%w/w. In some embodiments, a transdermal delivery formulation comprises phosphatidyl choline in amount less than 7 %w/w, less than 8%w/w, less than 9%w/w, less than 10%w/w, less than 11%w/w, less than 12 %w/w, less than 13%w/w, less than 14%w/w, less than 15%w/w, less than 16%w/w, less than 17%w/w or less than 18 %w/w of the formulation. In some embodiments, a transdermal delivery formulation comprises a phospholipid in amount less than 20 %w/w, less than 30 % w/w, less than 40 % w/w, less than or 50 %w/w of the formulation. In some embodiments, a transdermal delivery formulation comprises a mixture of tridecane and undecane in amount less than 2 %w/w, 3 %w/w, 4 %w/w, 5 %w/w, 6 %w/w, 7 %w/w, or 8 %w/w of the formulation. In some embodiments, the formulation comprises Cetiol Ultimate® in an amount less than about 2 %w/w, 3 %w/w, 4 %w/w, 5 %w/w, 6 %w/w, 7 %w/w, 8 %w/w, 9 %w/w, or 10 %w/w, or an equivalent mixture of tridecane and undecane. In some embodiments, a transdermal delivery formulation comprises cetyl alcohol in amount less than 2 %w/w, 3 %w/w, 4 %w/w, 5 %w/w, 6 %w/w, 7 %w/w, 8 %w/w, 9 %w/w, or 10 %w/w of the formulation. In some embodiments, the formulation comprises benzyl alcohol in an amount less than about 2 %w/w, 3 %w/w, 4 %w/w, 5 %w/w, 6 %w/w, 7 %w/w, 8 %w/w, 9 %w/w, or 10 %w/w. In some embodiments, a transdermal delivery formulation comprises stearic acid in an amount less than 2 %w/w, 3 %w/w, 4 %w/w, 5 %w/w, 6 %w/w, 7 %w/w, 8 %w/w, 9 %w/w, or 10 %w/w of the formulation. In some embodiments, the transdermal delivery formulation comprises phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, one or more phosphatides, one or more Inositol phosphatides, or combinations thereof, in amount less than 30 %w/w or in amount less than 12 %w/w of the formulation.
[00107] An additional component in a transdermal delivery formulation of the disclosure is an alcohol. Benzyl alcohol and ethanol are illustrated in the Examples.
In particular, derivatives of benzyl alcohol which contain substituents on the benzene ring, such as halo, alkyl and the like. The weight percentage of benzyl or other related alcohol in the final composition is 0.5-20% w/w, and again, intervening percentages such as 1 % w/w, 2% w/w, 3 %w/w, 4 %w/w, 5 %w/w, 6 %w/w, 7 %w/w, 8 %w/w, 9 %w/w, or 10 %w/w, and other intermediate weight percentages are included. Due to the aromatic group present in a transdermal delivery formulation such as benzyl alcohol, the molecule has a polar end (the alcohol end) and a non polar end (the benzene end). This enables the agent to dissolve a wider variety of transdermal delivery formulation components.
[00108] In some embodiments, as noted above, the performance of a transdermal delivery formulation is further improved by including a nonionic detergent and polar gelling agent or including a powdered surfactant. In both aqueous and anhydrous forms of the composition, detergents, typically nonionic detergents are added. In general, the nonionic detergent should be present in an amount between about 1% w/w to 30% w/w of a transdermal delivery formulation. Typically, in the compositions wherein a transdermal delivery formulation is topped off with a polar or aqueous solution containing detergent, the amount of detergent is relatively low - e.g., 2-25 %w/w, or 5-15 %w/w or 7-12 %w/w of a transdermal delivery formulation. However, in compositions that are essentially anhydrous and are topped-off by powdered detergent, relatively higher percentages are usually used - e.g., 20-60 %w/w.
[00109] In some embodiments, a transdermal delivery formulation further comprises a detergent portion in an amount between about 1 to 70 %w/w or 1-60 %w/w of a transdermal delivery formulation. In some embodiments, the nonionic detergent provides suitable handling properties whereby the formulations are gel-like or creams at room temperature. To exert this effect, the detergent, typically a poloxamer, is present in an amount between about 2-12 %w/w of a transdermal delivery formulation, preferably between about 5-25 %w/w in polar formulations. In the anhydrous forms of the compositions, the detergent is added in powdered or micronized form to bring the composition to 100% and higher amounts are used. In compositions with polar constituents, rather than bile salts, the nonionic detergent is added as a solution to bring the composition to 100%. If smaller amounts of detergent solutions are needed due to high levels of the remaining components, more concentrated solutions of the nonionic detergent are employed. Thus, for example, the percent detergent in the solution may be 10% to 40% or 20% or 30% and intermediate values depending on the percentages of the other components.
[00110] Suitable nonionic detergents include poloxamers such as the non-ionic surfactant Pluronic® and any other surfactant characterized by a combination of hydrophilic and hydrophobic moieties. Poloxamers are triblock copolymers of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyethyleneoxide. Other nonionic surfactants include long chain alcohols and copolymers of hydrophilic and hydrophobic monomers where blocks of hydrophilic and hydrophobic portions are used.
[00111] In some embodiments, a transdermal delivery formulation also contains surfactant, typically, nonionic surfactant at 2-25% w/w of a transdermal delivery formulation along with a polar solvent wherein the polar solvent is present in an amount at least in molar excess of the nonionic surfactant. In these embodiments, typically, the composition comprises the above-referenced amounts of a transdermal delivery formulation and benzyl alcohol along with a sufficient amount of a polar solution, typically an aqueous solution or polyethylene glycol solution that itself contains 10%-40% of surfactant, typically nonionic surfactant to bring the composition to 100%.
[00112] Other examples of surfactants include polyoxyethylated castor oil derivatives such as HCO-60 surfactant sold by the HallStar Company; nonoxynol; octoxynol; phenylsulfonate; poloxamers such as those sold by BASF as Pluronic® F68, Pluronic® FI27, and Pluronic® L62; polyoleates; Rewopal® HVIO, sodium laurate, sodium lauryl sulfate (sodium dodecyl sulfate); sodium oleate; sorbitan dilaurate; sorbitan dioleate; sorbitan monolaurate such as Span® 20 sold by Sigma-Aldrich; sorbitan monooleates; sorbitan trilaurate; sorbitan trioleate; sorbitan monopalmitate such as Span® 40 sold by Sigma-Aldrich; sorbitan stearate such as Span® 85 sold by Sigma-Aldrich; polyethylene glycol nonylphenyl ether such as Synperonic® NP sold by Sigma-Aldrich; p-(1 ,1 ,3,3-tetramethylbutyl)-phenyl ether sold as Triton™ X- 100 sold by Sigma-Aldrich; and polysorbates such as polyoxyethylene (20) sorbitan monolaurate sold as Tween® 20, polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate) sold as Tween® 40, polysorbate 60 (polyoxyethylene (20) sorbitan monostearate) sold as Tween® 60, polysorbate 80 (polyoxyethylene (20) sorbitan monooleate) sold as Tween® 80, and polyoxyethylenesorbitan trioleate sold as Tween® 85 by Sigma-Aldrich. The weight percentage range of nonionic surfactant is in the range of 3% w/w-15% w/w, and again includes intermediate percentages such as 5 %w/w, 7 %w/w, 10 %w/w, 12 %w/w, and the like. In some embodiments, the detergent portion comprises a nonionic surfactant in an amount between about 1-30 %w/w of the formulation; and a polar solvent in an amount less than 5 %w/w of the formulation. In some embodiments, the nonionic surfactant is a poloxamer and the polar solvent is water, an alcohol, or a combination thereof. In some embodiments, the detergent portion comprises poloxamer, propylene glycol, glycerin, ethanol, 50 %w/v sodium hydroxide solution, or a combination thereof. In some embodiments, the detergent portion comprises glycerin in an amount less than 3 %w/w of the formulation.
[00113] In the presence of a polar gelling agent, such as water, glycerol, ethylene glycol orformamide, a micellular structure is also often achieved. Typically, the polar agent is in molar excess of the nonionic detergent. The inclusion of the nonionic detergent/polar gelling agent combination results in a more viscous and cream-like or gel-like formulation which is suitable for application directly to the skin. This is typical of the aqueous forms of the composition.
[00114] In some embodiments other additives are included such as a gelling agent, a dispersing agent and a preservative. An example of a suitable gelling agent is hydroxypropylcellulose, which is generally available in grades from viscosities of from about 5 cps to about 25,000 cps such as about 1500 cps. All viscosity measurements are assumed to be made at room temperature unless otherwise stated. The concentration of hydroxypropylcellulose may range from about 1% w/w to about 2% w/w of the composition. Other gelling agents are known in the art and can be used in place of, or in addition to hydroxypropylcellulose. An example of a suitable dispersing agent is glycerin. Glycerin is typically included at a concentration from about 5 %w/w to about 25 %w/w of the composition. A preservative may be included at a concentration effective to inhibit microbial growth, ultraviolet light and/or oxygen-induced breakdown of composition components, and the like. When a preservative is included, it may range in concentration from about 0.01 %w/w to about 1 .5 %w/w of the composition.
[00115] Additional components that can also be included in a transdermal delivery formulation are fatty acids, terpenes, lipids, and cationic, and anionic detergents. In some embodiments, a transdermal delivery formulation further comprises tranexamic acid in an amount less than 2 %w/w, 5 %w/w, or 10 %w/w of the formulation. In some embodiments, a transdermal delivery formulation further comprises a polar solvent in an amount less than 2 %w/w, 5 %w/w, 10 %w/w, or 20 %w/w of the transdermal delivery formulation. In some embodiments, a transdermal delivery formulation further comprises a humectant, an emulsifier, an emollient, or a combination thereof. In some embodiments, a transdermal delivery formulation further comprises almond oil in an amount less than about 5 %w/w. In some embodiments, a formulation further comprises a mixture of thermoplastic polyurethane and polycarbonate in an amount less than about 5 % w/w. In some embodiments, a transdermal delivery formulation further comprises phosphatidylethanolamine in an amount less than about 5 %w/w. In some embodiments, a transdermal delivery formulation further comprises an inositol phosphatide in an amount less than about 5 %w/w.
[00116] Other solvents and related compounds that can be used in some embodiments include acetamide and derivatives, acetone, n-alkanes (chain length between 7 and 16), alkanols, diols, short chain fatty acids, cyclohexyl- 1 ,1- dimethylethanol, dimethyl acetamide, dimethyl formamide, ethanol, ethanol/d- limonene combination, 2-ethyl- 1 ,3-hexanediol, ethoxydiglycol (Transcutol® by Gattefosse, Lyon, France), glycerol, glycols, lauryl chloride, limonene N- methylformamide, 2-phenylethanol, 3-phenyl-1 -propanol, 3-phenyl-2-propen-l-ol, polyethylene glycol, polyoxyethylene sorbitan monoesters, polypropylene glycol 425, primary alcohols (tridecanol), 1 ,2-propane diol, butanediol, C3-C6 triols or their mixtures and a polar lipid compound selected from Cie or C18 monounsaturated alcohol, C16 or Ci8 branched saturated alcohol and their mixtures, propylene glycol, sorbitan monolaurate sold as Span® 20 by Sigma-Aldrich, squalene, triacetin, trichloroethanol, trifluoroethanol, trimethylene glycol and xylene.
[00117] Fatty alcohols, fatty acids, fatty esters, are bilayer fluidizers that can be used in some embodiments. Examples of suitable fatty alcohols include aliphatic alcohols, decanol, lauryl alcohol (dodecanol), unolenyl alcohol, nerolidol, 1-nonanol, n-octanol, and oleyl alcohol. Examples of suitable fatty acid esters include butyl acetate, cetyl lactate, decyl N,N-dimethylamino acetate, decyl N,N-dimethylamino isopropionate, diethyleneglycol oleate, diethyl sebacate, diethyl succinate, diisopropyl sebacate, dodecyl N,N-dimethyamino acetate, dodecyl (N,N-dimethylamino)-butyrate, dodecyl N,N-dimethylamino isopropionate, dodecyl 2-(dimethyamino) propionate, EO-5-oleyl ether, ethyl acetate, ethylaceto acetate, ethyl propionate, glycerol monoethers, glycerol monolaurate, glycerol monooleate, glycerol monolinoleate, isopropyl isostearate, isopropyl linoleate, isopropyl myristate, isopropyl myristate/fatty acid monoglyceride combination, isopropyl palmitate, methyl acetate, methyl caprate, methyl laurate, methyl propionate, methyl valerate, 1-monocaproyl glycerol, monoglycerides (medium chain length), nicotinic esters (benzyl), octyl acetate, octyl N,N-dimethylamino acetate, oleyl oleate, n-pentyl N-acetylprolinate, propylene glycol monolaurate, sorbitan dilaurate, sorbitan dioleate, sorbitan monolaurate, sorbitan monooleate, sorbitan trilaurate, sorbitan trioleate, sucrose coconut fatty ester mixtures, sucrose monolaurate, sucrose monooleate, tetradecyl N.N-dimethylamino acetate. Examples of suitable fatty acid- include alkanoic acids, caprid acid, diacid, ethyloctadecanoic acid, hexanoic acid, lactic acid, lauric acid, linoelaidic acid, linoleic acid, linolenic acid, neodecanoic acid, oleic acid, palmitic acid, pelargonic acid, propionic acid, and vaccenic acid. Examples of suitable fatty alcohol ethers include a-monoglyceryl ether, EO-2-oleyl ether, EO-5-oleyl ether, EO-10-oleyl ether, ether derivatives of polyglycerols and alcohols, and (1-0-dodecyl-3-0-methyl-2-0-(2',3 dihydroxypropyl glycerol).
[00118] Examples of completing agents that can be used in some embodiments include b- and g-cyclodextrin complexes, hydroxypropyl methylcellulose (e.g., Carbopol® 934), liposomes, naphthalene diamide diimide, and naphthalene diester diimide. [00119] One or more anti-oxidants can be included, such as vitamin C, vitamin E, proanthocyanidin and a-lipoic acid typically in concentrations of 0.1 %-2.5% w/w.
[00120] In some applications, it is desirable to adjust the pH of a transdermal delivery formulation to assist in permeation or to adjust the nature of the target compounds in the subject. In some instances, the pH is adjusted to a level of pH 9- 11 or 10-11 which can be done by providing appropriate buffers or simply adjusting the pH with base.
[00121] A transdermal delivery formulation can include other components that act as excipients or serve purposes other than for muscle performance and recovery. For example, preservatives like antioxidants e.g., ascorbic acid or a-lipoic acid and antibacterial agents may be included. Other components apart from therapeutically active ingredients and components that are the primary effectors of dermal penetration may include those provided for aesthetic purposes such as menthol or other aromatics, and components that affect the physical state of the composition such as emulsifiers, for example, Durosoft®. Typically, these ingredients are present in very small percentages of the compositions. It is understood that these latter ancillary agents are neither therapeutically ingredients nor are they components that are primarily responsible for penetration of the skin. The components that primarily effect skin penetration have been detailed as described above. However, some of these substances have some capability for effecting skin penetration. See, for example, Kunta, J.R. et al, J. Pharm. Sci. (1997) 86:1369-1373, describing penetration properties of menthol.
[00122] The application method is determined by the nature of the treatment but may be less critical than the nature of the formulation itself. If the application is to a skin area, it may be helpful in some instances to prepare the skin by cleansing or exfoliation. In some instances, it is helpful to adjust the pH of the skin area prior to application of a transdermal delivery formulation itself. The application of a transdermal delivery formulation may be by simple massaging onto the skin or by use of devices such as syringes or pumps. Patches could also be used. In some cases, it is helpful to cover the area of application to prevent evaporation or loss of a transdermal delivery formulation.
[00123] Where the application area is essentially skin, it is helpful to seal-off the area of application subsequent to supplying a transdermal delivery formulation and allowing the penetration to occur so as to restore the skin barrier. A convenient way to do this is to apply a composition comprising linoleic acid which effectively closes the entrance pathways that were provided by the penetrants of the invention. This application, too, is done by straightforward smearing onto the skin area or can be applied more precisely in measured amounts.
[00124] In addition to the compositions and formulations of the invention perse, the methods can employ a subsequent treatment with linoleic acid. As transdermal treatments generally open up the skin barrier, which is, indeed, their purpose, it is useful to seal the area of application after the treatment is finished. Thus, treatment with a transdermal delivery formulation may be followed by treating the skin area with a composition comprising linoleic acid to seal off the area of application. The application of linoleic acid is applicable to any transdermal procedure that results in impairing the ability of the skin to act as a protective layer. Indeed, most transdermal treatments have this effect as their function is to allow the active component to pass through the epidermis to the dermis at least, and, if systemic administration is achieved, through the dermis itself.
[00125] Additional therapeutic agents can be included in the compositions. For example, hydrocortisone or hydrocortisone acetate may be included in an amount ranging from 0.25% w/w to about 0.5% w/w. Menthol, phenol, and terpenoids, e.g., camphor, can be incorporated for cooling pain relief. For example, menthol can be included in an amount ranging from about 0.1 % w/w to about 1.0% w/w.
[00126] The compositions containing anesthetics are useful for temporary relief of pain and itching associated with minor burns, cuts, scrapes, skin irritations, inflammation and rashes due to soaps, detergents or cosmetics, or, as noted above, pain associated with removal of fat deposits. [00127] Emergency medical treatment of individuals requiring, for example, blood balancing agents including electrolytes and readily-metabolized nutrients, such as glucose, that would otherwise be administered intravenously can instead be non- invasively treated by massaging the formulation through the skin and thus permitting systemic delivery so that levels in the bloodstream are altered.
[00128] In addition to these applications, it has been noted that the administration of nutrients according to the invention also assuages feelings of hunger. Therefore, a transdermal delivery formulation of the invention and methods of the invention are useful in promoting weight loss as the caloric intake required to assuage feelings of hunger is lower than that ordinarily experienced by consuming food conventionally. Thus, in addition to individuals requiring extra calories or metabolic balancers because of exertion and in addition to those unable to feed themselves orally, suitable subjects for the methods of the invention include individuals seeking to control their caloric intake in order to adjust their weight. In view of the generally acknowledged obesity epidemic in the United States in particular, this is an important group of subjects benefitting from the methods of the invention.
[00129] It is clear that the nature of the desired ingredients will vary depending on the object of the administration. Simple nutrients such as amino acids, glucose, fructose, simple fats, various vitamins, cofactors and antioxidants as well as somewhat more complex foodstuffs can be administered as well as neutralizing agents, depending on the need.
[00130] In some embodiments, the components for athletic performance include beta-alanine, L-carnitine, adenosine triphosphate, dextrose, creatine monohydrate, beta hydroxy-betamethylbutyrate (HMB), branched chain amino acids (leucine, isoleucine, valine), glutathione, sodium phosphate, and caffeine. Components for medical nutrition include amino acids, dextrose, lipids, Na+, K+, Ca2+, Mg2+, acetate, Cl , P, multivitamin, and trace elements. While components for weight loss include conjugated linoleic acids, ephedra, caffeine, and salicin. [00131] Certain embodiments of a transdermal delivery formulation provided herein may be supplemented with formulation components described in greater detail in the inventor’s related applications, including United states Application No. 16/132,358 filed September 14, 2018, entitled ‘Methods and Formulations For Transdermal Administration Of Buffering Agents’, International Patent Application No.
PCT/US 18/51250 filed September 14, 2018, entitled ‘Methods of Administration and Treatment’, and International Patent Application PCT/US18/28017 by Bruce Sand filed April 17, 2018, entitled ‘Parental non-systemic administration of buffering agents for inhibiting metastasis of solid tumors, hyperpigmentation and gout’, all incorporated by reference in their entirety herein.
[00132] In some particular embodiments it is desirable to adjust the pH of a transdermal delivery formulation and the pH is adjusted to a level of pH 9-11 or 10- 11 , which can be done by providing appropriate buffers or simply adjusting the pH with base. In other embodiments, it is desirable to adjust the pH of a transdermal delivery formulation to a level of pH 4-6, which can be done by providing appropriate buffers or simply adjusting the pH with an acid.
[00133] In some applications a formulation for transdermal delivery may, for example, comprise: Aveeno®, for example in an amount between about 10-95 %w/w; between about 20-85 %w/w, between about 20-75 %w/w, between about 20- 50 %w/w.
[00134] In another aspect, certain embodiments are directed to a sustained release drug delivery platform releases a therapeutic compound or compounds disclosed and made as a formulation described herein over a period of, without limitation, about 3 days after administration, about 7 days after administration, about 10 days after administration, about 15 days after administration, about 20 days after administration, about 25 days after administration, about 30 days after administration, about 45 days after administration, about 60 days after administration, about 75 days after administration, or about 90 days after administration. In other aspects of this embodiment, a sustained release drug delivery platform releases a therapeutic compound or compounds disclosed herein with substantially first order release kinetics over a period of, without limitation, at least 3 days after administration, at least 7 days after administration, at least 10 days after administration, at least 15 days after administration, at least 20 days after administration, at least 25 days after administration, at least 30 days after administration, at least 45 days after administration, at least 60 days after administration, at least 75 days after administration, or at least 90 days after administration.
[00135] The formulation described in this specification may also comprise more than one therapeutic compound as desired for the particular indication being treated, preferably those with complementary activities that do not adversely affect the other proteins. A transdermal delivery formulation to be used for in vivo administration can be sterile. This can be accomplished, for instance, without limitation, by filtration through sterile filtration membranes, prior to, or following, preparation of a transdermal delivery formulation or other methods known in the art, including without limitation, pasteurization.
[00136] Packaging and instruments for administration may be determined by a variety of considerations, such as, without limitation, the volume of material to be administered, the conditions for storage, whether skilled healthcare practitioners will administer or patient self-compliance, the dosage regime, the geopolitical environment (e.g., exposure to extreme conditions of temperature for developing nations), and other practical considerations.
[00137] In certain embodiments, kits can comprise, without limitation, one or more cream or lotion comprising one or more formulations described herein. In various embodiments, the kit can comprise formulation components for transdermal, topical, or subcutaneous administration, formulated to be administered as an emulsion coated patch. In all of these embodiments and others, the kits can contain one or more lotion, cream, patch, or the like in accordance with any of the foregoing, wherein each patch contains a single unit dose for administration to a subject. [00138] Imaging components can optionally be included, and the packaging also can include written or web-accessible instructions for using a transdermal delivery formulation. A container can include, for example, a vial, bottle, patch, syringe, pre filled syringe, tube or any of a variety of formats well known in the art for multi dispenser packaging.
Methods
[00139] Methods for treating, preventing or ameliorating a disease, disorder, a condition, or a symptom thereof or a condition related thereto are provided herein using a transdermal delivery formulation for transdermal delivery described herein below. The methods provided herein may comprise or consist of topically administering one or more of a transdermal delivery formulation described herein to skin of a subject in need thereof. Preferred, but non-limiting embodiments are directed to methods for treating, preventing, inhibiting or ameliorating a disease, disorder, a condition, or a symptom described below.
[00140] An approach to make electrolyte balancing formulations is to avoid electrolyte imbalances by incorporating different buffers in different amount or ratios. Non-limiting examples of buffering agents that can be used together in different amounts or ratios include potassium bicarbonate, sodium bicarbonate, calcium carbonate, magnesium carbonate, and potassium carbonate. Mixtures of particular buffering agents including 2, 3, 4, 5, or more buffering agents are used depending on the formulation. Further, the relative amounts or ratio of each buffering agent may vary, for example, where the relative amounts are from 1 :1.10 w/w; 1 :1.15 w/w;
1 :1.20 w/w; 1 :1.25 w/w; 1 :1.30 w/w; 1 :1.35 w/w; 1 :1.40 w/w; 1 :1 .45 w/w; 1 :1 .50 w/w; 1 :1.55 w/w; 1 :1.60 w/w; 1 :1.65 w/w; 1 :1.70 w/w; 1 :1.75 w/w; 1 :1.80 w/w;
1 : 1.85 w/w; 1 : 1.90 w/w; 1 : 1.95 w/w; 1 :2 w/w; 1 :2.5 w/w; 1 :3 w/w; 1 :3.5 w/w; 1 :4 w/w, 1 :4.5 w/w; 1 :5 w/w, 1 :5.5 w/w; 1 :6 w/w; 1 :6.5 w/w; 1 :7 w/w; 1 :8 w/w; 1 :9 w/w; or 1 :10 w/w. These ratios of buffering agents are applicable when two buffering agents are present, or more than two and the ratios are applicable between any two buffering agents.
Formulations [00141] A formulation for transdermal delivery can, for example, comprise two components or it may comprise one or more buffering agent and a penetrant. Typically, however, a penetrant is less than 85 %w/w. A transdermal delivery formulation may have a detergent of at least 1 %w/w. For example, a suitable formulation may comprise about 10-56 %w/w buffering agent and a penetrant. In one aspect, disclosed herein is a transdermal delivery formulation for transdermal delivery of one or more buffering agent through the skin of a subject, comprising: a buffering agent comprising a carbonate salt in an amount between about 10-56 %w/w; a transdermal delivery formulation in an amount between about 5 to 55 %w/w; a detergent portion in an amount of at least 1 %w/w; and wherein the formulation comprises water in an amount from none up to about 77 %w/w.
[00142] In an embodiment, a carbonate, including sodium bicarbonate in a transdermal delivery formulation is in an amount of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more w/w.
[00143] In another aspect, disclosed herein is a method for transdermal delivery of a carbonate salt of a %, at least comprising: a buffering agent comprising a carbonate salt in an amount between about 10-45 %w/w; a transdermal delivery formulation in an amount between about 5 to 55 %w/w; a detergent portion in an amount between about 1 to 15 %w/w; and wherein the formulation comprises water in an amount between about 15 to 65 %w/w, through the skin of a subject, wherein the carbonate salt of the formulation is in an amount between about 15-32 %w/w of the formulation.
[00144] In another embodiment, a buffering agent comprising a carbonate salt, including sodium bicarbonate in a transdermal delivery formulation is in an amount of at least 1 %, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more w/w.
[00145] In yet another aspect, disclosed herein is a formulation for transdermal delivery of a therapeutic agent through the skin of a subject, wherein the formulation comprises at least one active agent in an amount effective for treatment of a condition in the subject and the formulation comprising: a buffering agent comprising a carbonate salt in an amount between about 10-45 %w/w; a transdermal delivery formulation in an amount between about 5 to 55 %w/w; a detergent portion in an amount between about 1 to 15 %w/w; wherein the formulation comprises water in an amount between about 15 to 65 %w/w, through the skin of a subject, wherein the carbonate salt of the formulation is in an amount between about 15-32 %w/w of the formulation, therapeutic, and wherein the alkalinity of the formulation enhances penetration of the therapeutic agent.
[00146] In one aspect, disclosed herein is a formulation for transdermal delivery of one or more buffering agent through the skin of a subject, comprising: a buffering agent comprising a carbonate salt in an amount between about 10-45 %w/w; a transdermal delivery formulation in an amount between about 5 to 55 %w/w; a detergent portion in an amount between about 1 to 15 %w/w; and wherein the formulation comprises water in an amount between about 15 to 65 %w/w, and wherein the formulation comprises less than about 12 %w/w of the transdermal delivery formulation.
[00147] In another aspect, disclosed herein is a method for transdermal delivery of a carbonate salt of the formulation comprising: a buffering agent comprising a carbonate salt in an amount between about 10-45 %w/w; a transdermal delivery formulation in an amount between about 5 to 55 %w/w; a detergent portion in an amount between about 1 to 15 %w/w; and wherein the formulation comprises water in an amount between about 15 to 65 %w/w, and wherein the formulation comprises less than about 12 %w/w of the transdermal delivery formulation, through the skin of a subject, wherein the carbonate salt of the formulation is in an amount between about 15-32 %w/w of the formulation, wherein the formulation comprises less than about 12 %w/w of the transdermal delivery formulation, and wherein the alkalinity of the formulation enhances penetration of the therapeutic agent.
[00148] In yet another aspect, disclosed herein is a formulation for transdermal delivery of a therapeutic agent through the skin of a subject, wherein the formulation comprises at least one active agent in an amount effective for treatment of a condition in the subject and the formulation comprising: a buffering agent comprising a carbonate salt in an amount between about 10-45 %w/w; a transdermal delivery formulation in an amount between about 5 to 55 %w/w; a detergent portion in an amount between about 1 to 15 %w/w; wherein the formulation comprises water in an amount between about 15 to 65 %w/w, through the skin of a subject, wherein the carbonate salt of the formulation is in an amount between about 15-32 %w/w of the formulation, and wherein the formulation comprises less than about 12 %w/w of the transdermal delivery formulation.
[00149] In some embodiments, a suitable transdermal delivery formulation comprises: Siligel™ in an amount less than about 5 %w/w; water in an amount between about 10-65 %w/w; isopropyl palmitate in an amount between about 0.5-10 %w/w; stearic Acid in an amount between about 0.25-10 %w/w; cetyl alcohol in an amount between about 0.25-10 %w/w; glycerin in an amount between about 0.25-5 %w/w; a transdermal delivery formulation in an amount between about 0.25-10 %w/w; ethanol in an amount less than about 5 %w/w; benzyl alcohol in an amount less than about 5 %w/w; sodium hydroxide 50 %w/v in an amount between about 0.1-5 %w/w; and sodium bicarbonate in an amount between about 1-32 %w/w.
[00150] In some embodiments, a suitable transdermal delivery formulation comprises: Aveeno® in an amount between about 20-85 %w/w; and sodium bicarbonate (3DF) in an amount between about 15-45 %w/w.
[00151] In some embodiments, a transdermal delivery formulation formulation comprises: Aveeno® in an amount between about 20-85 %w/w; and sodium bicarbonate in an amount between about 15-45 %w/w. [00152] In some embodiments, a suitable transdermal delivery formulation comprises: Siligel™ in an amount less than about 5 %w/w; water in an amount between about 10-55 %w/w; isopropyl palmitate in an amount between about 0.5-10 %w/w; stearic Acid in an amount between about 0.25-5 %w/w; Cetyl alcohol in an amount between about 0.25-10 %w/w; almond oil in an amount between about 0.5- 10 %w/w; propylene glycol in an amount between about 0.25-10 %w/w; ethanol in an amount less than about 5 %w/w; benzyl alcohol in an amount less than about 5 %w/w; sodium hydroxide 50 %w/v in an amount between about 0.1-5 %w/w; and sodium bicarbonate in an amount between about 1-32 %w/w.
[00153] The surprising effects achieved by the formulations and methods of the present invention are in part attributable to an improved transdermal delivery formulation that enhances delivery of a carbonate salt through the skin. The present transdermal delivery formulations may include a nonionic surfactant. Applicant has found that by employing carbonate salts with particle sizes as disclosed herein, delivered with the penetrants as disclosed herein, and in some embodiments providing a combination of a nonionic surfactant and a polar gelling agent, the penetration capabilities of the carbonate salts of the resulting formulation and the effective level of delivery of the carbonate salts has been enhanced.
[00154] In a transdermal delivery formulation, penetrants are based on combinations of an alcohol, such as benzyl alcohol to provide a concentration of 0.5-20%w/w of the final formulation with a transdermal delivery formulation present to provide 25- 70%w/w of the formulation. These penetrants are also useful when the agent is a buffer, such as sodium bicarbonate, but less of a transdermal delivery formulation may be required - e.g. less than 12 %w/w when the sodium bicarbonate is present at high concentration as disclosed herein.
[00155] In some embodiments, the buffering component is any mildly basic compound or combination that will result in a pH of 7-8. In some embodiments, the formulation has a pH of 7-10. Such buffers, in addition to carbonate and/or bicarbonate salts, include lysine buffers, chloroacetate buffers, tris buffers (/.e., buffers employing tris (hydroxymethyl) aminoethane), phosphate buffers and buffers employing non-natural amino acids with similar pKa values to lysine. In some embodiments, the carbonate and/or bicarbonate salt is in an amount between about 7-32 %w/w of the formulation. For example, the enantiomers of native forms of such amino acids or analogs of lysine with longer or shorter carbon chains or branched forms thereof. Histidine buffers may also be used. Typically, the concentration of buffer in the compositions is in the range of 10-50 %w/w. More typical ranges for sodium bicarbonate or sodium carbonate or both are 10-35 %w/w. In some embodiments, the carbonate salt is in an amount between about 15-32 %w/w of the formulation.
[00156] Alternatively, the penetrant component comprises a completion component as well as one or more electrolytes sufficient to impart viscosity and viscoelasticity, one or more surfactants and an alcohol. The completion component can be a polar liquid, a non-polar liquid or an amphiphilic substance.
[00157] The percentage of carbonate salt in a transdermal delivery formulation will depend upon the amount required to be delivered in order to have a useful effect on treating the disorder. In general, the carbonate salt may be present in the formulation in an amount as low as 1 %w/w up to about 50 %w/w. Typical concentrations may include 15-32 %w/w. Since the required percentage of carbonate salt depends on the frequency of administration, as well as the time allotted for administration for each application, the level of carbonate salt may be varied over a wide range. In some embodiments, the carbonate salt is sodium carbonate and/or sodium bicarbonate milled to a particle size less than 200 pm. In some embodiments, the carbonate salt is sodium carbonate and/or sodium bicarbonate milled to a particle size less than 70 pm. In some embodiments, the carbonate salt is sodium carbonate and/or sodium bicarbonate milled to a particle size less than 70 pm, wherein the sodium bicarbonate is solubilized in the formulation in an amount less than 20 %w/w of a transdermal delivery formulation. In some embodiments, the carbonate salt is sodium carbonate and/or sodium bicarbonate milled to a particle size less than 70 pm, wherein particle sizes less than about 10 pm have an enhanced penetration thru the skin of a subject. In some embodiments, the sodium carbonate and/or sodium bicarbonate are jet milled to a particle size less than about 70 pm. In some embodiments, the sodium bicarbonate is Sodium Bicarbonate USP Grade 3DF that has a particle size distribution less than 70 pm.
[00158] A transdermal delivery formulation of the disclosure may be prepared in a number of ways. Typically, the components of a transdermal delivery formulation are simply mixed together in the required amounts. However, it is also desirable in some instances to, for example, carry out dissolution of a carbonate salt and then add a separate preparation containing the components aiding the delivery of the carbonate salts in the form of a carrier. The concentrations of these components in the carrier, then, will be somewhat higher than the concentrations required in a final transdermal delivery formulation. Thus, sodium bicarbonate may first be dissolved in water and then added to a carrier comprising an alcohol, a transdermal delivery formulation and optionally a combination of a nonionic surfactant and polar gelling agent, or of ionic detergent. Alternatively, some subset of these components can first be mixed and then "topped off with the remaining components either simultaneously or sequentially. The precise manner of preparing a transdermal delivery formulation will depend on the choice of carbonates and the percentages of the remaining components that are desirable with respect to that carbonate salt. In some embodiments, the water is in an amount between about 10-85 %w/w, 15-50 %w/w, or 15-45 %w/w of the formulation.
[00159] The transdermal delivery formulation is a multi-component mixture, whereby the particular concentrations of the penetration enhancers are informed in part by the molecular mass of the sodium bicarbonate, or sodium bicarbonate and the therapeutic agent to be transported. A transdermal delivery formulation enables the sodium bicarbonate and/or therapeutic agent to become bio-available to the target site within minutes of topical administration. A transdermal delivery formulation permit the use of minimal concentrations of therapeutic agents, as little as 1/1000th of concentrations required of alternative processes, while enabling bioactivity and positive clinical outcomes simultaneously. In some embodiments, the transdermal delivery formulation comprises an alcohol in an amount less than 5 %w/w of the formulation. Administration and Dosing
[00160] A transdermal delivery formulation provided herein can be topically administered in any form. For administration for the treatment of skin conditions a sufficient amount of the topical composition can be applied onto a desired area and surrounding skin, for example, in an amount sufficient to cover a desired skin surface. A transdermal delivery formulation can be applied to any skin surface, including for example, facial skin, and the skin of the hands, neck, chest and/or scalp.
[00161] In applying a transdermal delivery formulation of the invention, a transdermal delivery formulation itself is simply placed on the skin and spread across the surface and/or massaged to aid in penetration. The amount of transdermal delivery formulation used is typically sufficient to cover a desired surface area. In some embodiments, a protective cover is placed over the formulation once it is applied and left in place for a suitable amount of time, i.e., 5 minutes, 10 minutes, 20 minutes or more; in some embodiments an hour or two. The protective cover can simply be a bandage including a bandage supplied with a cover that is impermeable to moisture. This essentially locks in the contact of a transdermal delivery formulation to the skin and prevents distortion of a transdermal delivery formulation by evaporation in some cases. The composition may be applied to the skin using standard procedures for application such as a brush, a syringe, a gauze pad, a dropper, or any convenient applicator. More complex application methods, including the use of delivery devices, may also be used, but are not required. In an alternative to administering topically to intact skin, the surface of the skin may also be disrupted mechanically by the use of spring systems, laser powered systems, systems propelled by Lorentz force or by gas or shock waves including ultrasound and may employ microdermabrasion such as by the use of sandpaper or its equivalent or using microneedles or electroporation devices. Simple solutions of the agent(s) as well as the above-listed formulations that penetrate intact skin may be applied using occlusive patches, such as those in the form micro-patches. External reservoirs of the formulations for extended administration may also be employed. [00162] In an alternative to administering topically to intact skin, the surface of the skin may also be disrupted mechanically by the use of spring systems, laser powered systems, use of iontophoresis, systems propelled by Lorentz force or by gas or shock waves including ultrasound and may employ microdermabrasion such as by the use of sandpaper or its equivalent or using microneedles or electroporation devices. Simple solutions of the agent(s) as well as the above-listed transdermal delivery formulations that penetrate intact skin may be applied using occlusive patches, such as those in the form of micro-patches. External reservoirs of the formulations for extended administration may also be employed.
[00163] Accordingly, in certain embodiments alternative methods of administering one or more therapeutic compounds or agents (e.g. supplements, vitamins and/or minerals) through intact skin are provided. As nonlimiting examples, these alternative methods might be selected from the following lists: on basis of working mechanism, spring systems, laser powered, energy-propelled, Lorentz force, gas/air propelled, shock wave (including ultrasound), on basis of type of load, liquid, powder, projectile, on basis of drug delivery mechanism, nano-patches, sandpaper (microdermabrasion), iontophoresis enabled, microneedles, on basis of site of delivery, intradermal, intramuscular, and subcutaneous injection. Other suitable delivery mechanisms include, without limitation, microneedle drug delivery, such as 3M Systems, Glide SDI (pushes drug as opposed to “firing” drug), MIT low pressure injectors, micropatches (single use particle insertion device), microelectro mechanical systems (MEMS), dermoelectroporation devices (DEP), transderm ionto system (DEP), TTS transdermal therapeutic systems, membrane-moderated systems (drug reservoir totally encapsulated in a shallow compartment), adhesive diffusion-controlled system (drug reservoir in a compartment fabricated from drug- impermeable metallic plastic backing), matrix dispersion type system (drug reservoir formed by homogeneously dispersing drug solids in a hydrophilic or lipophilic polymer matrix molder into medicated disc), and microreservoir system (combination of reservoir and matrix dispersion-type drug delivery system).
[00164] The application method is determined by the nature of the treatment but may be less critical than the nature of a transdermal delivery formulation itself. If the application is to a skin area, it may be helpful in some instances to prepare the skin by cleansing or exfoliation. In some instances, it is helpful to adjust the pH of the skin area prior to application of the formulation itself. The application of a transdermal delivery formulation may be by simple massaging onto the skin or by use of devices such as syringes or pumps. Patches could also be used. In some cases, it is helpful to cover the area of application to prevent evaporation or loss of a transdermal delivery formulation.
[00165] Where the application area is essentially skin, it is helpful to seal-off the area of application subsequent to supplying a transdermal delivery formulation and allowing the penetration to occur so as to restore the skin barrier. A convenient way to do this is to apply a composition comprising linoleic acid which effectively closes the entrance pathways that were provided by the penetrants of the invention. This application, too, is done by straightforward smearing onto the skin area or can be applied more precisely in measured amounts.
[00166] In addition to a transdermal delivery formulation of the invention perse, the methods may employ a subsequent treatment with linoleic acid. As transdermal treatments generally open up the skin barrier, which is, indeed, their purpose, it is useful to seal the area of application after the treatment is finished. Thus, treatment with a transdermal delivery formulation may be followed by treating the skin area with a composition comprising linoleic acid to seal off the area of application. The application of linoleic acid is applicable to any transdermal procedure that results in impairing the ability of the skin to act as a protective layer. Indeed, most transdermal treatments have this effect as their function is to allow active ingredients to pass through the epidermis to the dermis at least, and, if systemic administration is achieved, through the dermis itself.
[00167] Additional therapeutic agents may be included in the compositions. For example, hydrocortisone or hydrocortisone acetate may be included in an amount ranging from 0.25%w/w to about 0.5%w/w. Menthol, phenol, and terpenoids, e.g., camphor, can be incorporated for cooling pain relief. For example, menthol may be included in an amount ranging from about 0.1 %w/w to about 1.0%w/w.
[00168] A transdermal delivery formulation can be applied in a single, one-time application, once a week, once a bi-week, once a month, or from one to twelve times daily, for a period of time sufficient to alleviate a condition, disease, disorder, symptoms, for example, for a period of time of one week, from 1 to 12 weeks or more, from 1 to 6 weeks, from 2 to 12 weeks, from 2 to 8 weeks, from 2 to 6 weeks, from 2 to 4 weeks, from 4 to 12 weeks, from 4 to 8 weeks, or from 4 to 6 weeks. The present compositions can be administered, for example, at a frequency of once per day to hourly if needed. The presently described formulations can be topically administered once or more per day for a period of time from 1 week to 4 weeks, of from 1 week to 2 weeks, for 1 week, for 2 weeks, for 3 weeks, or for 4 weeks or more. In some instances, it may also be desirable to continue treatment indefinitely, for example, to inhibit or prevent muscle cramping, improve performance and recovery and/or maintain levels of supplements, vitamins and minerals for health and/or prevention of disease. A suitable administration for a transdermal delivery formulation comprising a skin cream, lotion or ointment, for example is once, twice, three, four times daily, or hourly if needed.
[00169] As described above, if desired, other therapeutic agents can be employed in conjunction with those provided in the above-described compositions. The amount of active ingredients that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the nature of the disease, disorder, or condition, and the nature of the active ingredients.
[00170] It is understood that a specific dose level for any particular patient will vary depending upon a variety of factors, including the activity of the specific active agent; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; possible drug combinations; the severity of the particular condition being treated; the area to be treated and the form of administration. One of ordinary skill in the art would appreciate the variability of such factors and would be able to establish specific dose levels using no more than routine experimentation.
[00171] Pharmacokinetic parameters such as bioavailability, absorption rate constant, apparent volume of distribution, unbound fraction, total clearance, fraction excreted unchanged, first-pass metabolism, elimination rate constant, half-life, and mean residence time can be determined by methods well known in the art.
[00172] A transdermal delivery formulation in accordance with the subject matter described herein may be a topical dosage form packaged in, for example, a multi use or single-use package, including for example, a tube, a bottle, a pump, a container or bottle, a vial, a jar, a packet, or a blister package.
[00173] Single dosage kits and packages containing a once per day amount of the transdermal delivery formulation may be prepared. Single dose, unit dose, and once- daily disposable containers of the transdermal delivery formulation are also provided.
[00174] The present transdermal delivery formulation remains stable in storage for periods including up to about 5 years, between about 3 months and about 5 years, between about 3 months and about 4 years, between about 3 months and about 3 years, and alternately any time period between about 6 months and about 3 years.
[00175] A transdermal delivery formulation described herein remains stable for up to at least 3 years at a temperature of less than or equal to 40° C. In an embodiment, the presently described transdermal delivery formulation remains stable for at least 2 years at a temperature of less than or equal to 40° C. In an embodiment, the presently described transdermal delivery formulation remains stable for at least 3 years at a temperature of less than or equal to 40° C and at a humidity of up to 75% RH, for at least 2 years at a temperature of less than or equal to 40° C and at a humidity of up to 75% RH, or for at least 3 years at a temperature of less than or equal to 30°C. and at a humidity of up to 75% RH. In a further embodiment, the presently described transdermal delivery formulation in accordance with the subject matter described herein remains stable for an extended period of time when packaged in a multi-use container such as a bottle dispenser or the like, and exhibits equal to or even greater stability when packaged in a single-use package.
[00176] In another aspect, the transdermal delivery formulation of certain embodiments comprises a daily dose of particular buffering compound (e.g. sodium bicarbonate, sodium carbonate, magnesium carbonate, potassium carbonate, potassium bicarbonate, TRIS, Lysine, IEPA, etc.). A daily dose for topical or transdermal administration of a transdermal delivery formulation depends on the compound and animal and may be easily determined by the skilled artisan, a suitable amount is about 1 mg/kg to about 5g/kg, and more typically the daily dose is about 10mg/kg to about 5g/kg, about 25mg/kg to about 2000 mg/kg, about 50mg/kg to about 2000 mg/kg, about 25mg/kg to about 1000mg/kg, about 50mg/kg to about 1000mg/kg, about 100mg/kg to about 700mg/kg, about 100mg/kg to about 500mg/kg, about 150mg/kg to about 500mg/kg, about 150mg/kg to about 400mg/kg, about 200mg/kg to about 500mg/kg, about 200mg/kg to about 450mg/kg, about 200mg/kg to about 400mg/kg, about 250mg/kg to about 450mg/kg, about 250mg/kg to about 400mg/kg, about 250mg/kg to about 350mg/kg, and about 275mg/kg to about 325 mg/kg.
[00177] If desired, other therapeutic agents can be employed in conjunction with those provided in the above-described compositions. The amount of active ingredients that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the nature of the disease, disorder, or condition, and the nature of the active ingredients.
[00178] It is understood that a specific dose level for any particular patient will vary depending upon a variety of factors, including the activity of the specific active agent; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; possible drug combinations; the severity of the particular condition being treated; the area to be treated and the form of administration. One of ordinary skill in the art would appreciate the variability of such factors and would be able to establish specific dose levels using no more than routine experimentation.
[00179] Pharmacokinetic parameters such as bioavailability, absorption rate constant, apparent volume of distribution, unbound fraction, total clearance, fraction excreted unchanged, first-pass metabolism, elimination rate constant, half-life, and mean residence time can be determined by methods well known in the art.
[00180] A transdermal delivery formulation in accordance with the subject matter described herein may be a topical dosage form packaged in, for example, a multi use or single-use package, including for example, a tube, a bottle, a pump, a container or bottle, a vial, a jar, a packet, or a blister package.
[00181] Single dosage kits and packages containing a once per day amount of the transdermal delivery formulation may be prepared. Single dose, unit dose, and once- daily disposable containers of the transdermal delivery formulation are also provided.
[00182] Alternatively, a suitable dose for topical or transdermal administration of each of one or more particular buffering compound (e.g. sodium bicarbonate, sodium carbonate, magnesium carbonate, potassium carbonate, potassium bicarbonate, TRIS, Lysine, IEPA, etc.) for subject is at least about 100 mg, at least about 500 mg, at least about 1 g, at least about 5 g, at least about 10 g, at least about 15 g, at least about 16 g, at least about 17 g, at least about 18 g, at least about 19 g, at least about 20 g, at least about 21 g, at least about 22 g, at least about 23 g, at least about 24 g, at least about 25 g, at least about 26 g, at least about 27 g, at least about 28 g, at least about 29 g, at least about 30 g, at least about 35 g, at least about 40 g, at least about 45 g, at least about 50 g, at least about 60 g, at least about 75 g, at least about 100 g, at least about 200 g, at least about 500 g, or at least about 1.0 kg. This dose may be administered daily, twice a day, three times a day, four times a day, five times a day, or more than five times a day.
[00183] Aspects of the present specification disclose that the symptoms associated with a disease or disorder described herein are reduced following application of a transdermal delivery formulation by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% and the severity associated with a disease or disorder described herein is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. Aspects of the present specification disclose the symptoms associated with disease or disorder are reduced following application of a transdermal delivery formulation by about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.
[00184] Aspects of the present specification disclose that the symptoms associated with a disease or disorder described herein are reduced following administration of a transdermal delivery formulation of the present invention by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% and the severity associated with a disease or disorder described herein is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. Aspects of the present specification disclose the symptoms associated with disease or disorder are reduced by about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.
[00185] A transdermal delivery formulation as described herein can be used in the manufacture of medicaments and for the treatment of humans and other animals by administration in accordance with conventional procedures.
[00186] Dosing can be single dosage or cumulative (serial dosing), and can be readily determined by one skilled in the art. A transdermal delivery formulation of the present invention may be administered once, twice, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or more times to a subject. For instance, treatment of a disease may comprise a one-time administration of an effective dose of a transdermal delivery formulation as disclosed herein. Alternatively, treatment of a disease may comprise multiple administrations of an effective dose of a transdermal delivery formulation as carried out over a range of time periods, such as, e.g., once daily, twice daily, thrice daily, once every few days, or once weekly. The timing of administration can vary from individual to individual, depending upon such factors as the severity of an individual's symptoms. For example, an effective dose of a transdermal delivery formulation as disclosed herein can be administered to an individual once daily for an indefinite period of time, or until the individual no longer requires therapy. A person of ordinary skill in the art will recognize that the condition of the individual can be monitored throughout the course of treatment and that the effective amount of a transdermal delivery formulation disclosed herein that is administered can be adjusted accordingly. In one embodiment, a transdermal delivery formulation as disclosed herein is capable of decreasing the time to resolve the symptoms of a disease, including in an individual suffering from a disease by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95% as compared to a patient not receiving the same treatment.
[00187] In a further embodiment, a transdermal delivery formulation and its derivatives have half-lives of 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day,
2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, one month, two months, three months, four months or more.
[00188] In an embodiment, the period of administration of a transdermal delivery formulation is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days,
10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks,
7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.
[00189] In aspects of this embodiment, a therapeutically effective amount of a transdermal delivery formulation disclosed herein reduces or alleviates symptoms (e.g. muscle pain or cramping) of an ailment such as muscle cramping or soreness in an individual by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 100%. In other aspects of this embodiment, a therapeutically effective amount of a transdermal delivery formulation disclosed herein reduces or alleviates symptoms of an ailment in an individual by, e.g., at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 95% or at most 100%. In yet other aspects of this embodiment, a therapeutically effective amount of a transdermal delivery formulation disclosed herein reduces or alleviates symptoms of an ailment in an individual by, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.
[00190] A transdermal delivery formulation disclosed herein may comprise a transdermal delivery formulation in a therapeutically effective amount. As used herein, the term “effective amount” is synonymous with “therapeutically effective amount”, “effective dose”, or “therapeutically effective dose” and when used in reference to reducing or alleviate symptoms of an ailment in an individual refers to the minimum dose of a therapeutic disclosed herein necessary to achieve the desired therapeutic effect and includes a dose sufficient to reduce or alleviates symptoms of an ailment in an individual. The effectiveness of a transdermal delivery formulation disclosed herein capable of reducing or alleviating symptoms of an ailment in an individual can be determined by observing an improvement in an individual based upon one or more clinical symptoms, and/or physiological indicators associated with improvements in muscle performance, reduced soreness and/or overall health. Maintenance or a reduction of symptoms of an ailment can also be subjective to a patient. The effectiveness of a transdermal delivery formulation disclosed herein in an individual can be determined by observing an improvement in an individual based upon one or more clinical symptoms, and/or physiological indicators associated with signs/symptoms, muscle performance and general health. The effectiveness of a transdermal delivery formulation disclosed herein is also capable of prolonging the life of an individual as compared to the same individual if the transdermal delivery formulation is not administered. The effectiveness of the transdermal delivery formulation disclosed herein is also capable of enhancing the quality of life of an individual as compared to the same individual if the transdermal delivery formulation is not administered. [00191] The appropriate effective amount of a transdermal delivery formulation disclosed herein to be administered to an individual can be determined by a person of ordinary skill in the art by taking into account factors, including, without limitation, an improvement in the individual based upon one or more clinical symptoms, and/or physiological indicators associated with improvements in muscle performance, reduced soreness and/or overall health, the particular characteristics, history and risk factors of the patient, such as, e.g., age, weight, general health and the like, or any combination thereof. Additionally, where repeated administration of a transdermal delivery formulation is used, an effective amount of a transdermal delivery formulation will further depend upon factors, including, without limitation, the frequency of administration, the half-life of the transdermal delivery formulation, or any combination thereof. It is known by a person of ordinary skill in the art that an effective amount of a transdermal delivery formulation disclosed herein can be extrapolated from in vitro assays and in vivo administration studies using animal models prior to administration to humans or animals.
[00192] Wide variations in the necessary effective amount are to be expected in view of the differing efficiencies of the various routes of administration. For instance, oral administration of a transdermal delivery formulation disclosed herein generally would be expected to require higher dosage levels than administration by inhalation. Similarly, systemic administration of a transdermal delivery formulation disclosed herein would be expected to require higher dosage levels than a local administration. Variations in these dosage levels can be adjusted using standard empirical routines of optimization, which are well-known to a person of ordinary skill in the art. The precise therapeutically effective dosage levels and patterns are preferably determined by the attending physician in consideration of the above-identified factors. One skilled in the art will recognize that the condition of the individual can be monitored throughout the course of therapy and that the effective amount of a therapeutic disclosed herein that is administered can be adjusted accordingly.
[00193] Aspects of the present specification disclose, in part, a reduction or alleviation of symptoms of an ailment such as muscle cramping or soreness in an individual. As used herein, the term “treating,” refers to reduction or alleviation of muscle soreness or cramping as well as improved muscle performance and recovery. For example, the term “treating” can mean reduction or alleviation of symptoms in an individual by, e.g., at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% at least 95%, or at least 100%. The actual symptoms associated with an ailment such as muscle cramping and soreness are well known and can be determined by a person of ordinary skill in the art by using commonly known testing means. Those of skill in the art will know the appropriate symptoms or indicators associated with health and muscle performance and will know how to determine if an individual is a candidate for treatment as disclosed herein.
[00194] In an embodiment, a first transdermal delivery formulation is administered to an individual and at a later date, a second transdermal delivery formulation is administered to the same individual. In an embodiment, a first transdermal delivery formulation is administered to an individual at the same time as a second transdermal delivery formulation is administered to the individual.
[00195] A transdermal delivery formulation as disclosed herein is administered to an individual. An individual is typically a human being, but can be an animal, including, but not limited to, dogs, cats, birds, cattle, horses, sheep, goats, reptiles and other animals, whether domesticated or not.
[00196] In one aspect, disclosed herein is a formulation for transdermal delivery of an active agent through the skin, nail or hair follicle of a subject, wherein the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w.
[00197] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, further comprises benzyl alcohol in an amount between about 0.5-5 %w/w.
[00198] In some embodiments, the transdermal delivery formulation comprises benzyl alcohol in an amount less than 5 %w/w of the formulation.
[00199] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, further comprises Isopropyl Palmitate in an amount between about 5-5 %w/w.
[00200] In some embodiments, the water is deionized water and/or purified water.
[00201] In some embodiments, the water is in an amount between about 15-40 %w/w of the formulation.
[00202] In some embodiments, the one or more phosphatides in an amount between about 0.5-55 %w/w of the transdermal delivery formulation.
[00203] In some embodiments, the transdermal delivery formulation comprises phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, or a combination thereof in amount less than 30 %w/w of the formulation.
[00204] In some embodiments, the one or more phosphatides comprises phosphatidylcholine of the transdermal delivery formulation.
[00205] In some embodiments, the one or more fatty acids in an amount between about 1-35 %w/w of the transdermal delivery formulation.
[00206] In some embodiments, the one or more fatty acids in an amount between about 5-35 %w/w of the transdermal delivery formulation. [00207] In some embodiments, the one or more fatty acids comprises Linoleic Acid, Oleic Acid, Stearic Acid, safflower oil, or a combination thereof.
[00208] In some embodiments, the one or more fatty acids comprises Linoleic Acid.
[00209] In some embodiments, the one or more fatty acids comprises Oleic Acid.
[00210] In some embodiments, the one or more fatty acids comprises Stearic Acid.
[00211] In some embodiments, the one or more phosphatides are derived from a seed oil in an amount between about 0.5-55 %w/w of the transdermal delivery formulation.
[00212] In some embodiments, the one or more phosphatides are derived from a seed oil in an amount between about 5-35 %w/w of the transdermal delivery formulation.
[00213] In some embodiments, the one or more phosphatides are derived from a safflower oil in an amount between about 0.5-55 %w/w of the transdermal delivery formulation.
[00214] In some embodiments, the one or more phosphatides are derived from a safflower oil in an amount between about 5-35 %w/w of the transdermal delivery formulation.
[00215] In some embodiments, the one or more phosphatides are derived from an almond oil in an amount between about 0.5-55 %w/w of the transdermal delivery formulation.
[00216] In some embodiments, the one or more phosphatides are derived from an almond oil in an amount between about 5-35 %w/w of the transdermal delivery formulation. [00217] In some embodiments, the one or more phosphatides comprises one or more fatty acids derived from soy lecithin.
[00218] In some embodiments, the glucose in an amount between about 0.05-10 %w/w of the transdermal delivery formulation.
[00219] In some embodiments, the glucose is anhydrous dextrose in an amount between about 0.05-10 %w/w of the transdermal delivery formulation.
[00220] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, further comprises a nonionic surfactant in an amount between about 2-25 %w/w of the transdermal delivery formulation.
[00221] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, further comprises a polar solvent at least in an amount in molar excess of the nonionic surfactant.
[00222] In some embodiments, the nonionic surfactant is a poloxamer and the polar solvent is water.
[00223] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, further comprises a polar solvent in an amount less than 5 %w/w of the formulation. [00224] In some embodiments, the transdermal delivery formulation further comprises a detergent portion in an amount between about 1-30 %w/w of the transdermal delivery formulation.
[00225] In some embodiments, the detergent portion comprises a nonionic surfactant in an amount between about 2-25 %w/w of the transdermal delivery formulation; and a polar solvent in an amount less than 5 %w/w of the transdermal delivery formulation.
[00226] In some embodiments, the transdermal delivery formulation is in an amount between about 10-60 %w/w of the transdermal delivery formulation.
[00227] In some embodiments, the transdermal delivery formulation comprises an alcohol in an amount less than 10 %w/w of the transdermal delivery formulation.
[00228] In some embodiments, the transdermal delivery formulation further comprises an alcohol, a surfactant, and a polar solvent.
[00229] In some embodiments, the transdermal delivery formulation comprises cetyl alcohol in amount less than 5 %w/w of the formulation.
[00230] In some embodiments, the transdermal delivery formulation comprises ethanol in an amount less than 5 %w/w of the formulation.
[00231] In some embodiments, the transdermal delivery formulation comprises glycerine in an amount less than 5 %w/w of the formulation.
[00232] In some embodiments, the transdermal delivery formulation comprises propylene glycol in an amount less than 8 %w/w of the formulation.
[00233] In some embodiments, the formulation comprises a gelling agent in an amount less than 20 %w/w of the formulation. [00234] In some embodiments, the formulation comprises menthol in an amount between about 0.05-5 %w/w of the formulation.
[00235] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w.
[00236] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, further comprises a humectant, an emulsifier, an emollient, or a combination thereof.
[00237] In some embodiments, the formulation has a pH of 9-11 .
[00238] In some embodiments, the formulation has a pH of 7-10.5.
[00239] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, further comprises an active agent.
[00240] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, iii. one or more fatty acids; b) water in an amount less than about 50 %w/w, and an active agent component in an amount less than about 60 %w/w.
[00241] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; b) water in an amount less than about 50 %w/w, and an active agent component in an amount less than about 60 %w/w, wherein the active agent is a vitamin, mineral or dietary supplement.
[00242] In some embodiments, the buffering agent is sodium carbonate and/or sodium bicarbonate.
[00243] In some embodiments, the formulation includes a dose of creatine (5 - 20 grams) that is up to 30% of the solution.
[00244] In some embodiments, the formulation includes a dose of nitrate ion (approximately 500 mg) that is 5 - 15% of the solution.
[00245] In some embodiments, the formulation includes a dose of caffeine (approximately 500 mg) that is 5 - 15% of the solution.
[00246] In some embodiments, the formulation includes a dose of fructose (approximately 50 g) that is up to 30% of the solution.
[00247] In some embodiments, the formulation includes a dose of curcumin (approximately 500 mg) that is 5 - 15% of the solution.
[00248] In some embodiments, the formulation includes a dose of pychnogenol (approximately 1 g) that is 5 - 15% of the solution.
[00249] In some embodiments, the formulation includes a dose of anthocyanins (approximately 1 g) that is 5 - 15% of the solution.
[00250] In some embodiments, the formulation includes a dose of phenolic acid (approximately 1 g) that is 5 - 15% of the solution.
[00251] In some embodiments, the formulation includes a dose of flavonoids (approximately 500 mg) that is 5 - 15% of the solution. [00252] In some embodiments, the formulation includes a dose of flavonols (approximately 500 mg) that is 5 - 15% of the solution.
[00253] In some embodiments, the formulation includes a dose of b-Alanine (approximately 6 g) that is up to 30% of the solution.
[00254] In some embodiments, the formulation includes a dose of b-Hydroxy b- methylbutyric acid (HMB) (approximately 3 g) that is 15 - 25% of the solution.
[00255] In some embodiments, the formulation includes a dose of Carnosine (approximately 1 g) that is 15 - 25% of the solution.
[00256] In some embodiments, the formulation includes a dose of Omega-3 fatty acids (approximately 2 g) that is 15 - 25% of the solution.
[00257] In some embodiments, the formulation includes a dose of Leucine (approximately 2 g) that is up to 30% of the solution.
[00258] In some embodiments, the formulation includes a dose of isoleucine (approximately 2 g) that is up to 30% of the solution.
[00259] In some embodiments, the formulation includes a dose of Citrulline (approximately 6 g) that is up to 30% of the solution.
[00260] In some embodiments, the formulation includes a dose of ketone esters (approximately 40 g) that is up to 30% of the solution.
[00261] In some embodiments, the formulation includes a dose of ketone salts (approximately 12 g) that is up to 30% of the solution.
[00262] In some embodiments, the formulation includes a dose of carnitine (approximately 2 g) that is 15 - 25% of the solution. [00263] In some embodiments, the formulation includes a dose of serotonin (5-HTP) (approximately 200 mg) that is 1 - 10% of the solution.
[00264] In some embodiments, the formulation includes a dose of arginine (approximately 10 g) that is up to 30% of the solution.
[00265] In some embodiments, the formulation includes a dose of glutamine (approximately 10 g) that is up to 30% of the solution.
[00266] In some embodiments, the formulation includes a dose of berberine (approximately 1.5 g) that is 15 - 25% of the solution.
[00267] In some embodiments, the formulation includes a dose of resveratrol (approximately 2 g) that is 15 - 25% of the solution.
[00268] In some embodiments, the formulation includes a dose of vitamin C (approximately 1000 mg) that is 15 - 25% of the solution.
[00269] In some embodiments, the formulation includes a dose of vitamin B12 (approximately 2 pg) that is 15 - 25% of the solution.
[00270] In some embodiments, the formulation includes a dose of vitamin B9 (approximately 400 pg) that is 0.5 - 5% of the solution.
[00271] In some embodiments, the formulation includes a dose of vitamin B6 (approximately 100 pg) that is 1 - 10% of the solution.
[00272] In some embodiments, the formulation includes a dose of vitamin E (approximately 15 mg) that is 1 - 10% of the solution.
[00273] In some embodiments, the formulation includes a dose of calcium (approximately 1500 mg) that is 15 - 25% of the solution. [00274] In some embodiments, the formulation includes a dose of potassium (approximately 2.6 g) that is 15 - 25% of the solution (formulated for a female subject).
[00275] In some embodiments, the formulation includes a dose of potassium (approximately 3.4 g) that is 15 - 25% of the solution (formulated for a male subject).
[00276] In some embodiments, the formulation includes a dose of zinc (approximately 20 mg) that is 1 - 10% of the solution.
[00277] In some embodiments, the formulation includes a dose of iron (approximately 18 mg) that is 1 - 10% of the solution (formulated for a female subject).
[00278] In some embodiments, the formulation includes a dose of iron (approximately 8 mg) that is 1 - 10% of the solution (formulated for a male subject).
[00279] In some embodiments, the formulation includes a dose of sodium (approximately 1.5 g) that is 15 - 25% of the solution.
[00280] In some embodiments, the formulation includes a dose of magnesium (approximately 350 mg) that is 5 - 15% of the solution.
[00281] In some embodiments, the formulation includes a dose of chromium (approximately 35 pg) that is 0.5 - 5% of the solution.
[00282] In some embodiments, the formulation includes a dose of capsaicin that is 5 - 15% of the solution.
[00283] In some embodiments, the formulation includes a dose of ginger (approximately 40 mg) that is 1 - 10% of the solution. [00284] In some embodiments, the formulation includes a dose of capsicum (approximately 500 mg) that is 5 - 15% of the solution.
[00285] In some embodiments, the formulation includes a dose of cinnamon (approximately 750 mg) that is 5 - 15% of the solution.
[00286] In some embodiments, the formulation includes a dose of Tetrahydrobiopterin (approximately 2.5 mg) that is approximately 20% of the solution.
[00287] In another aspect disclosed herein is a method to effect transdermal delivery of an active ingredient comprising applying to the skin, nails or hair follicles of a subject an effective amount of the formulation comprising a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 %w/w, further comprises an active agent.
EXAMPLES
[00288] The following non-limiting examples are provided for illustrative purposes only in order to facilitate a more complete understanding of representative embodiments now contemplated. These examples are intended to be a mere subset of all possible contexts in which the components of the formulation may be combined. Thus, these examples should not be construed to limit any of the embodiments described in the present specification, including those pertaining to the type and amounts of components of the formulation and/or methods and uses thereof.
Example 1
Transdermal Administration of Capsicum
[00289] In this example, capsaicin is provided in a transdermal lotion or cream. Capsaicin can be used to relieve nociceptive and neuropathic pain. Capsaicin is thought to work through several mechanisms of action. Transdermal administration allows direct absorption into a specific area. For example, a lotion can be applied to a joint where there is arthritic pain. It can also be applied to a sore, achy muscle or a muscle that is cramping.
[00290] The lotion can include a transdermal delivery formulation and the active agent (collectively referred to as the solution). In this example, the dose of the active agent (i.e. capsicum) is 500 milligrams so that it is 5 - 15 % of the solution. The transdermal delivery formulation can include less than about 60 %w/w of one or more phosphatides, glucose, one or more fatty acids and water.
Example 2
Transdermal Administration of HMB
[00291] P-Hydroxy b-methy!bufyric acid, commonly referred to as “HMB” is often consumed as a nutritional supplement, particularly to help build lean muscle mass, increase strength and endurance, and maximize the results of training. Transdermal administration allows direct absorption into a specific area. For example, a lotion can be applied to one or more areas with muscle soreness. Lotions/creams can be applied to the biceps and triceps of a subject during or after strength training.
[00292] The lotion or cream can include a transdermal delivery formulation and the active agent, HMB. In this example, the dose of the active agent (i.e. HMB) is 3 grams so that it is 15 - 25 % of the solution. The transdermal delivery formulation can include less than about 60 %w/w of one or more phosphatides, glucose, one or more fatty acids and water. The lotion/cream can be used to treat local pain and used, for example, over a 12-hour period.
Example 3
Transdermal Administration of Dietary Supplement
[00293] Transdermal delivery formulations that include dietary supplements offer the benefit of prolonged absorption. For example, vitamin B12 is essential for preventing major birth defects, supporting bone health, improving mood and maintaining healthy skin and hair. Oral administration of vitamin B12 can be ineffective for those who have trouble absorbing it from food. An oral supplement can help but intramuscular injections can be necessary to increase levels. A transdermal formulation offers a more practical option.
[00294] The formulation can include a transdermal lotion and the active agent, vitamin B12. The transdermal delivery formulation can include less than about 60 %w/w of one or more phosphatides, glucose, one or more fatty acids and water. In this example, the dose of the active agent (i.e. vitamin B12) is 250 pg so that it is 0.5 - 5 % of the solution. The lotion can be applied regularly (e.g. daily) to maintain circulating levels of vitamins. Alternatively, a consumer can use a lotion based on needs or circumstances. For example, a user could use apply the lotion to boost her/her immune system. This could be desired when one is feeling susceptible to a cold, flu or infection due to fatigue or exposure to infected individuals.
[00295] Transdermal administration presents a good alternative to oral consumption as well as injections. The consumer does not have to schedule and remember to consume frequent doses or take injections. Administration of supplements across the skin improves bioavailability as the vitamin avoids degradation in the gastrointestinal tract or liver. Transdermal delivery can be particularly useful for molecules with limited systemic bioavailabilities and short half-lives. A transdermal lotion/cream can include vitamin B12 along with a myriad other vitamins such as vitamin C, vitamin B9, vitamin B6, vitamin E, calcium, potassium, zinc, Iron, sodium, magnesium and chromium
[00296] Transdermal administration can also be effective for supplements that are not conducive to oral administration. For example, Vitamin A is important for growth and development, for the maintenance of the immune system and good vision. However, oral administration of vitamin A can result in hypervitaminosis A. The main problems associated with the vitamin A are its half-life, fast absorption (due to lipophilicity) and its toxicity (due to high loading and frequent dosing). Transdermal administration presents a good alternative because it allows for effective control of drug release. [00297] Certain embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the present invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
[00298] Groupings of alternative embodiments, elements, or steps of the present invention are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.
[00299] Unless otherwise indicated, all numbers expressing a characteristic, item, quantity, parameter, property, term, and so forth used in the present specification and claims are to be understood as being modified in all instances by the term “about.” As used herein, the term “about” means that the characteristic, item, quantity, parameter, property, or term so qualified encompasses a range of plus or minus ten percent above and below the value of the stated characteristic, item, quantity, parameter, property, or term. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values setting forth the broad scope of the invention are approximations, the numerical ranges and values set forth in the specific examples are reported as precisely as possible. Any numerical range or value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Recitation of numerical ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate numerical value falling within the range. Unless otherwise indicated herein, each individual value of a numerical range is incorporated into the present specification as if it were individually recited herein.
[00300] The terms “a,” “an,” “the” and similar referents used in the context of describing the present invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the present invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the present specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[00301] Specific embodiments disclosed herein may be further limited in the claims using consisting of or consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of” excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the present invention so claimed are inherently or expressly described and enabled herein.
[00302] All patents, patent publications, and other publications referenced and identified in the present specification are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the compositions and methodologies described in such publications that might be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.

Claims

CLAIMS What is claimed is:
1. A formulation for transdermal delivery of a vitamin, mineral or supplement through the skin of a subject, comprising: a therapeutically effective amount of a vitamin, mineral or supplement; a penetrant portion in an amount between about 44 to 95 %w/w; wherein the formulation further comprises, isopropyl palmitate (1 - 20%w/w), sorbic acid (around 1%w/w), benzyl alcohol (around 1%w/w), polyglyceryl- 4 laurate (1 - 10%w/w), vitamin D3 (around 1%w/w) and poloxamer 407 (5 - 20%w/w).
2. The formulation of claim 1 , wherein the vitamin, mineral or supplement is at least one of creatine, nitrate ion, caffeine, fructose, curcumin, pychnogenol, anthocyanin, phenolic acid, a flavonoid, a flavonol, b-Alanine, b-Hydroxy b- methylbutyric add (HMB), carnosine, an omega-3 fatty acid, leucine, isoleucine, valine, citrulline, a ketone ester, a ketone salt, pyruvate, carnitine, serotonin (5-HTP), arginine, glutamine, berberine, resveratrol, vitamin C, vitamin B12, vitamin B9, vitamin B6, vitamin E, calcium, potassium, zinc, iron, sodium, magnesium, chromium, capsaicin, ginger, capsicum, cinnamon or tetrahydrobiopterin.
3. The formulation of claim 1 , wherein the formulation further comprises 5 - 25% w/w sodium nitrate.
4. The formulation of claim 1 , wherein the penetrant portion comprises water in an amount less than about 85 %w/w.
5. The formulation of claim 1 , wherein the formulation comprises less than about 15 %w/w lecithin.
6. The formulation of claim 1 , wherein the penetrant portion further comprises a sodium lauryl sulfate in an amount between about 1 to 10 %w/w.
7. The formulation of claim 1 , wherein the penetrant portion is in an amount between about 44-80 %w/w of the formulation.
8. The formulation of claim 1 , wherein the water is in an amount between about 15-42 % w/w of the penetrant portion of the formulation.
9. The formulation of claim 1 , wherein the penetrant portion comprises an alcohol in an amount less than 10 % w/w of the formulation.
10. The formulation of claim 7, wherein the penetrant portion comprises lecithin organogel, an alcohol, a surfactant, and a polar solvent.
11. The formulation of claim 1 , wherein the penetrant portion comprises a mixture of xanthan gum, lecithin, sclerotium gum, pullulan, or a combination thereof in an amount less than 5 %w/w of the formulation.
12. The formulation of claim 1 , wherein the penetrant portion comprises a mixture of caprylic triglycerides and capric triglycerides in amount less than 8 %w/w of the formulation.
13. The formulation of claim 1 , wherein the penetrant portion comprises lecithin, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, one or more phosphatides, one or more Inositol phosphatides, or combinations thereof, in amount less than 12 %w/w of the formulation.
14. The formulation of claim 1 , wherein the penetrant portion comprises cetyl alcohol in amount less than 5 %w/w of the formulation.
15. The formulation of claim 1 wherein the penetrant portion comprises stearic acid in an amount less than 5 %w/w of the formulation.
16. The formulation of claim 1 , wherein the formulation comprises a gelling agent in an amount less than 10 %w/w of the formulation.
17. The formulation of claim 1 , further comprising a detergent portion comprised of a nonionic surfactant in an amount between about 2 - 25 %w/w of the penetrant portion; and a polar solvent in an amount less than 5 %w/w of the penetrant portion.
18. The formulation of claim 1 , further comprising a carbonate salt comprised of sodium bicarbonate milled to a particle size less than 70 pm, wherein the sodium bicarbonate is solubilized in the formulation in an amount less than 10 %w/w of the formulation.
19. The formulation of claim 1 , further comprising a polar solvent in an amount less than 5 % w/w of the formulation.
20. The formulation of claim 1 , further comprising a humectant, an emulsifier, an emollient, or a combination thereof.
21. The formulation of claim 1 , wherein the formulation has a pH of 7 - 10.5.
22. A method for transdermal delivery of the formulation of claim 1 , through the skin of a subject.
23. A transdermal delivery formulation for transdermal delivery of a vitamin, mineral or supplement through the skin, nail or hair follicle of a subject, wherein the transdermal delivery formulation comprises: a) a transdermal delivery formulation in an amount less than about 60 %w/w, comprising: i. one or more phosphatides, ii. glucose, iii. one or more fatty acids, and b) water in an amount less than about 50 %w/w.
24. The formulation of claim 23, wherein the vitamin, mineral or supplement is at least one of creatine, nitrate ion, caffeine, fructose, curcumin, pychnogenol, anthocyanin, phenolic acid, a flavonoid, a flavonol, b-Alanine, b-Hydroxy b- methy!butyric add (HMB), carnosine, an omega-3 fatty acid, leucine, isoleucine, valine, citrulline, a ketone ester, a ketone salt, pyruvate, carnitine, serotonin (5-HTP), arginine, glutamine, berberine, resveratrol, vitamin C, vitamin B12, vitamin B9, vitamin B6, vitamin E, calcium, potassium, zinc, iron, sodium, magnesium, chromium, capsaicin, ginger, capsicum, cinnamon or tetrahydrobiopferin.
25. The transdermal delivery formulation of claim 23, further comprising benzyl alcohol in an amount between about 0.5 - 5 %w/w.
26. The transdermal delivery formulation of claim 23 wherein the transdermal delivery formulation comprises benzyl alcohol in an amount less than 5 %w/w of the formulation.
27. The transdermal delivery formulation of claim 23, further comprising isopropyl palmitate in an amount between about 1-15 %w/w.
28. The transdermal delivery formulation of claim 23, wherein the water is deionized water and/or purified water.
29. The transdermal delivery formulation of claim 23, wherein the water is in an amount between about 15 - 40 %w/w of the formulation.
30. The transdermal delivery formulation of claim 23, wherein the one or more phosphatides in an amount between about 0.5 - 55 %w/w of the transdermal delivery formulation.
31. The transdermal delivery formulation of claim 23, wherein the transdermal delivery formulation comprises phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, or a combination thereof in amount less than 30 %w/w of the formulation.
32. The transdermal delivery formulation of claim 23, wherein the one or more phosphatides comprises phosphatidylcholine of the transdermal delivery formulation.
33. The transdermal delivery formulation of claim 23, wherein the one or more fatty acids is an amount between about 1 - 35 %w/w of the transdermal delivery formulation.
34. The transdermal delivery formulation of claim 23, wherein the one or more fatty acids is an amount between about 5 - 35 %w/w of the transdermal delivery formulation.
35. The transdermal delivery formulation of claim 23, wherein the one or more fatty acids comprises Linoleic Acid, Oleic Acid, Stearic Acid, safflower oil, or a combination thereof.
36. The transdermal delivery formulation of claim 23, wherein the one or more phosphatides are derived from a seed oil in an amount between about 0.5 - 55 %w/w of the transdermal delivery formulation.
37. The transdermal delivery formulation of claim 23, wherein the one or more phosphatides are derived from a seed oil in an amount between about 5 - 35 %w/w of the transdermal delivery formulation.
38. The transdermal delivery formulation of claim 23, wherein the one or more phosphatides are derived from a safflower oil in an amount between about 0.5 - 55 %w/w of the transdermal delivery formulation.
39. The transdermal delivery formulation of claim 23, wherein the one or more phosphatides are derived from a safflower oil in an amount between about 5 - 35 %w/w of the transdermal delivery formulation.
40. The transdermal delivery formulation of claim 23, wherein the one or more phosphatides are derived from an almond oil in an amount between about 0.5 - 55 %w/w of the transdermal delivery formulation.
41. The transdermal delivery formulation of claim 23, wherein the one or more phosphatides are derived from an almond oil in an amount between about 5 - 35 %w/w of the transdermal delivery formulation.
42. The transdermal delivery formulation of claim 23, wherein the one or more phosphatides comprises one or more fatty acids derived from soy lecithin.
43. The transdermal delivery formulation of claim 23, wherein the glucose in an amount between about 0.05 - 10 %w/w of the transdermal delivery formulation.
44. The transdermal delivery formulation of claim 23, wherein the glucose is anhydrous dextrose in an amount between about 0.05 - 10 %w/w of the transdermal delivery formulation.
45. The transdermal delivery formulation of claim 23, further comprising a nonionic surfactant in an amount between about 2 - 25 %w/w of the transdermal delivery formulation.
46. The transdermal delivery formulation of claim 45, further comprising a polar solvent at least in an amount in molar excess of the nonionic surfactant.
47. The transdermal delivery formulation of claim 45, wherein the nonionic surfactant is a poloxamer and the polar solvent is water.
48. The transdermal delivery formulation of claim 23, further comprising a polar solvent in an amount less than 5 %w/w of the formulation.
49. The transdermal delivery formulation of claim 23, wherein the transdermal delivery formulation further comprises a detergent portion in an amount between about 1-30 %w/w of the transdermal delivery formulation.
50. The transdermal delivery formulation of claim 49, wherein the detergent portion comprises a nonionic surfactant in an amount between about 2-25 %w/w of the transdermal delivery formulation; and a polar solvent in an amount less than 5 %w/w of the transdermal delivery formulation.
51. The transdermal delivery formulation of claim 23, wherein the transdermal delivery formulation comprises an alcohol in an amount less than 10 %w/w of the transdermal delivery formulation.
52. The transdermal delivery formulation of claim 23, wherein the transdermal delivery formulation further comprises an alcohol, a surfactant, and a polar solvent.
53. The transdermal delivery formulation of claim 23, wherein the transdermal delivery formulation comprises cetyl alcohol in amount less than 5 %w/w of the formulation.
54. The transdermal delivery formulation of claim 23, wherein the transdermal delivery formulation comprises ethanol in an amount less than 5 %w/w of the formulation.
55. The transdermal delivery formulation of claim 23, wherein the transdermal delivery formulation comprises glycerine in an amount less than 5 %w/w of the formulation.
56. The transdermal delivery formulation of claim 23, wherein the transdermal delivery formulation comprises propylene glycol in an amount less than 8 %w/w of the formulation.
57. The transdermal delivery formulation of claim 23, wherein the formulation comprises a gelling agent in an amount less than 20 %w/w of the formulation.
58. The transdermal delivery formulation of claim 23, wherein the formulation comprises menthol in an amount between about 0.05 - 5 %w/w of the formulation.
59. The transdermal delivery formulation of claim 23, further comprising a humectant, an emulsifier, an emollient, or a combination thereof.
60. The transdermal delivery formulation of claim 23, wherein the formulation has a pH of 9 - 11.
61 . The transdermal delivery formulation of claim 23, wherein the formulation has a pH of 7 - 10.5.
62. A method of transdermal delivery an active ingredient comprising a step of applying to the skin, nails or hair follicles of a subject an effective amount of the formulation of claim 23.
63. The transdermal delivery formulation of claim 1 , wherein the formulation includes an active agent to treat a disease.
PCT/US2020/062956 2019-12-02 2020-12-02 Transdermal penetrant formulations for vitamins, minerals and supplements WO2021113411A1 (en)

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