WO2023174433A1 - Compositions solides, semi-solides ou liquides pour augmenter la stabilité, la perméabilité et la biodisponibilité de substances pharmaceutiques actives - Google Patents

Compositions solides, semi-solides ou liquides pour augmenter la stabilité, la perméabilité et la biodisponibilité de substances pharmaceutiques actives Download PDF

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Publication number
WO2023174433A1
WO2023174433A1 PCT/CN2023/082536 CN2023082536W WO2023174433A1 WO 2023174433 A1 WO2023174433 A1 WO 2023174433A1 CN 2023082536 W CN2023082536 W CN 2023082536W WO 2023174433 A1 WO2023174433 A1 WO 2023174433A1
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WO
WIPO (PCT)
Prior art keywords
composition
choline
acid
sodium
capsules
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PCT/CN2023/082536
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English (en)
Inventor
Isa Odidi
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Smart Pharmaceutical (Suzhou) Co., Ltd.
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Publication of WO2023174433A1 publication Critical patent/WO2023174433A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles

Definitions

  • the present invention relates to a novel platform technology for the augmentation of solubility, physiological stability, transmembrane, transmucosal, transcutaneous, intestinal mucosal barrier permeation/penetration into systemic circulation and bioavailability of active pharmaceutical ingredients (API) administered through oral, nasal, buccal, ocular, anal, transdermal and pulmonary routes by the construction and use of a complex multivariate API delivery and targeting system consisting of a plurality of polymeric and or non-polymeric functional materials.
  • API active pharmaceutical ingredients
  • This invention by way of a multivariate approach creates a novel gastrointestinal positioning, protection, perturbation, permeation and penetration system ( or )
  • the multivariate approach of this invention introduces a compounding entourage phenomenon effect wherein the plurality of polymeric and or non-polymeric functional materials within the delivery composition contribute their individual mechanism of action to enhance one another’s possible effects and invariably define the final mechanism of action of the invention.
  • composition (s) capable of 1) more precise control of the physico-chemical and physiological properties of the product environment, such as the internal and external environment within and surrounding the active pharmaceutical ingredient, the delivery system/dosage form and the gastrointestinal environment and mucous membrane and 2) provides for better tolerance, 3) increased gastrointestinal and physiochemical stability, 4) improved membrane perturbation, permeability, penetration, transport, and 5) precise and accurate targeting and maintenance of residency of the API and or dosage form to specific zones in the gastrointestinal tract.
  • This multivariate approach surprisingly allows the effective use of minimal or reduced and less toxic amounts of penetration enhancers, transpoters, contact angle and surface tension modifiers, pH regulators, excipients and enzyme inhibitors in the composition than the very high concentrations which would otherwise be required if they are used separately.
  • the dosage forms made using this multivariate approach can be formulated to modify the surface properties of the API, dosage form or gastrointestinal membrane and or formulated to initially provide one or more pulses of penetration enhancer, contact angle/surface tension modifier and pH regulator release or a protracted release of one or more of these. It can also be formulated to provide a concurrent release of the penetration enhancer, contact angle/surface tension modifier and pH regulator in the composition. All these occurring at same time, or prior to or after release of the API.
  • the release zone, the rate, extent and time of the pulses and release/penetration/permeability are surprisingly controlled precisely using the multivariate approach of this invention. This approach to delivery of poorly bioavailable APIs both small and large molecules is far more superior and represents a paradigm shift from the current practice.
  • compositions, dosage forms and methods of the present invention are particularly suitable for the administration and improvement of solubility, transport, absorption, penetration, permeability, and stability of poorly bioavailable APIs both small and large molecules, their bases, salts, metabolites, pro-drugs, racemates, enantiomers, optical isomers, related substances, or a mixture thereof.
  • the compositions, dosage forms and methods of the present invention are particularly suitable for the precise/accurate targeting and maintenance of the residency of the API and or dosage form to specific zones in the gastrointestinal tract.
  • the oral route remains the preferred route of choice for administration of active pharmaceutical ingredients (API) which are used for their therapeutic effects.
  • API active pharmaceutical ingredients
  • the oral route remains the preferred route of choice for administration of active pharmaceutical ingredients (API) which are used for their therapeutic effects.
  • active pharmaceutical ingredients Unfortunately, not all active pharmaceutical ingredients can be administered by this route.
  • macromolecules, peptides, and proteins, many biopharmaceuticals and even certain small molecules must be used as injectable therapies as they are not stable or absorbed adequately from the different routes of drug administration, particularly the oral one.
  • Microparticles, nanoparticles and liposomes of varying construction have been extensively researched for oral peptide-delivery applications.
  • Formulations prepared with polymeric materials including poly (lactide) co-glycolide, chitosans, as well as polymeric cationic lipids with and without polyethylene glycol (PEG) -ylation, sometimes incorporating targeting motifs have been researched and developed.
  • liposomes as drug delivery systems for insulin and heparin have also been described. See, for instance, U.S. Pat. No. 4,239,754; Patel et al. (1976) FEBS Letters Vol. 62, page 60; and Hashimoto et al. (1979) Endocrinol. Japan, Vol. 26, page 337.
  • microspheres of artificial polymers of mixed amino acids (proteinoids) to protect active agents in drug delivery systems have been disclosed.
  • Modified amino acid carriers for the delivery of active agents are disclosed in U.S. Pat. Nos.
  • Another approach for delivery of vulnerable API by oral route include use of absorption enhancers and enzymatic inhibitors to counterbalance permeation problems and instability caused by proteolytic enzymes respectively.
  • Absorption enhancers and enzymatic inhibitors to counterbalance permeation problems and instability caused by proteolytic enzymes respectively.
  • Human GLP-1 and analogues which have a low oral bioavailability formulated with certain absorption enhancers in a specific amount are disclosed by Steinert et al. (Am J Clin Nutr, October 2010; 92: 810-817) .
  • WO 2010/020978 discloses an oral pharmaceutical composition comprising a protein and N- (8- [2-hydroxybenzoyl) amino) caprylate (SNAC) .
  • a pharmaceutical composition comprising at least one poorly stable, poorly soluble, poorly permeable and or poorly bioavailable active pharmaceutical ingredient, at least one pH regulator or modifier, at least one penetration enhancer and or glycoprotein, dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane or related compounds, optionally one or more enzyme inhibitor and at least one pharmaceutical excipient.
  • a pharmaceutical composition comprising at least one poorly stable, poorly permeable and or poorly bioavailable active pharmaceutical ingredient, at least one pH regulator, at least one penetration enhancer and or glycoprotein, dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane or related compounds, and at least one pharmaceutical excipient.
  • a pharmaceutical composition comprising at least one poorly stable, poorly permeable and or poorly bioavailable active pharmaceutical ingredient, at least one pH regulator, at least one penetration enhancer and or glycoprotein, dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane, polyethylene glycol or related compounds, and at least one pharmaceutical excipient.
  • a pharmaceutical composition comprising at least one poorly stable, poorly permeable and or poorly bioavailable active pharmaceutical ingredient, at least one penetration enhancer and or glycoprotein, simethicone or related compounds, and at least one pharmaceutical excipient.
  • a pharmaceutical composition comprising at least one poorly stable, poorly permeable and or poorly bioavailable active pharmaceutical ingredient and optionally glycoprotein, at least one stabilizer and optionally simethicone or related compounds, and at least one pharmaceutical excipient.
  • a pharmaceutical composition comprising at least o ne penetration enhancer selected from sodium N- (8- (2-hydroxybenzoyl) amino) caprylate (SNAC) ; N- (10- (2-hydroxybenzoyl) amino) capricate; N- (2-methoxybenzoyl) -3- (4-aminophenyl) proprionate; N- (3-dimethylaminobenzoyl) -3- (4-aminophenyl) butyrate; N- (2-methoxybenzoyl) -3- (4-aminophenyl) butyrate; N- (2-aminobenzoyl) -3- (4-aminophenyl) butyrate; N- (4- (3-cycloh exyl-propionyl) amino) butyrate; N- (6- (4-methylcyclohexyl-carbonyl) amino) caproate or a co mbination thereof.
  • SNAC sodium N- (8- (2-hydroxybenzoyl) amino) capry
  • composition or pharmaceutical wherein the penetration enhancer is sodium N- (8- (2-hydroxybenzoyl) amino) caprylate (SNAC) .
  • composition or pharmaceutical wherein the glycoprotein is transferrin.
  • composition or pharmaceutical product from the said composition which when dissolved or mixed with 1mL or more of acidic environment (pH 1-2) alters the pH of the environment to greater than pH 2.
  • said at least one pH regulator comprises at least one alkalinizing or pH modifying agent.
  • said at least one alkalinizing agent is selected from the group consisting of alkaline earth metal salts, alkali metal salts, aluminum salts, amino acids, amino acid derivatives, and combinations thereof.
  • said at least one alkalinizing agent is selected from the group consisting of magnesium hydroxide, magnesium trisilicate, aluminum hydroxide, magnesium oxide, calcium carbonate, sodium bicarbonate, sodium citrate, sodium carbonate, sodium acetate, magnesium carbonate, L-arginine, meglumine, and combinations thereof.
  • said ph modifying agent or penetration enhancer is selected from the group consisting of one or more of the following, sodium caprate, sodium caprylate, salcaprozate sodium, and one or more of the following, copolymer of methyl acrylate with different acidic or alkaline end groups; copolymers of methyl acrylate; methacrylic acid and methyl methacrylate; methyl methacrylate and methacrylic acid; methacrylic acid and ethyl acrylate copolymer; ethylacrylate methy lmethacrylate; cationic copolymer based on dimethylaminoethyl methacrylate; butyl methacrylate, and methyl methacrylate; copolymer of ethyl acrylate, methyl methacrylate and methacrylic acid ester with quaternary ammonium groups; Poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl me
  • choline oleate choline propionate
  • choline stearate choline linoleate
  • choline fatty acids choline amino acids
  • ionic liquids Deep Eutectic Solvents
  • choline based ionic liquids or related compounds derivatives or their combinations.
  • the ionic liquid at least one anionic and at least one cationic component in any molar ratio which may include but are limited to molar ratios (cation: anion) 1: 1, 1: 2, 2: 1, 1: 3, 3: 1, 2: 3, 3: 2, and ranges between these ratios or 100: 1 and 1: 100.
  • composition or pharmaceutical product wherein when the composition is exposed or dissolved in water or gastric fluid medium the contact angle and or surface tension is reduced.
  • composition or pharmaceutical product which when exposed or dissolved in the gastrointestinal tract the contact angle and or surface tension of the fluid surrounding the product, external or interior environment of the gastrointestinal tract and or dosage form is reduced.
  • composition or pharmaceutical product which imparts hydrophobicity to the surroundings, external or interior environment of the gastrointestinal tract, intestinal mucosal barrier and or dosage form and its constituents.
  • the pharmaceutical composition is a solid, semisolid, or liquid form
  • the poorly stable, poorly permeable and poorly bioavailable active pharmaceutical ingredient is a macromolecule.
  • the poorly stable, poorly bioavailable active pharmaceutical ingredient is a small molecule.
  • the poorly stable, poorly permeable and poorly bioavailable active pharmaceutical ingredient is a peptide.
  • the poorly stable, poorly permeable and poorly bioavailable active pharmaceutical ingredient is a protein.
  • the hormone, peptide or protein is Ipamorelin, hexarelin, examorelin, pralmorelin, sermorelin, acyline, human growth hormone, teriparatide, somatostatin, encephalin, incretin mimetics, cyclosporine, insulin, salmon calcitonin, teragastrin, thyrotropin releasing hormone, phenyl alanine, glycine, glatiramer, interferon beta-1b, albumin, G-CSF, EPO, LHRH and analogues, DP3, dextran nanoparticles, desmopressin, vasopressin, leucine encephalin, d-Ala2, d-Leu5 enkephalin (DADLE) , met-kephamid, Pramlintide, Tesamorelin, Ancestim and buserelin.
  • DADLE d-Leu5 enkephalin
  • said penetration enhancer is one or more of lysine, histidine, glutamic acid, aspartic acid, menthol, hexylamine, chembetaine, decyltrimethyl ammonium bromide, sorbitan esters, ethoxylated sorbitan esters, sodium dodecyl sulphate, sodium glycocholate, sodium deoxycholate, sodium tauroglycocholate, and oleic acid, simethicone, dimethicone, silica, poly (dimethylsiloxane) , sodium caprate, sodium caprylate, salcaprozate sodium, chitosans, lectins, zonula occludens toxin, cell-penetrating peptides, bile salts and n-lauryl-beta-D-maltopyranoside or related compounds, copolymer of methyl acrylate with different acidic or alkaline end groups; copolymer of methyl acrylate with
  • composition ionic liquids used may include organic cations that contain independently for each occurrence a heterocycle selected from the group consisting of azathiozoles, pyrazoles, thiazoles, isothiazoles, oxothiazoles, oxazines, oxazo lines, oxazoboroles, dithioazoles, triazoles, selenozoles, oxaphopholes, pyrroles, boroles, furans, thiophenes, phospholes, pentazoles, indoles, indolines, oxazoles, isoozazoles, isotriazoles, tetrazoles, benzofurans, dibenzofurans, benzothiophenes, dibenzothiophenes, thiadiazoles, pyrimidines, pyrazines, pyridazines, piperazines, pipidines, morpholenes, pyrans, annolines
  • said penetration enhancer is taken from surfactants, fatty acids, medium chain glycerides, steroidal detergents, acyl carnitine and alkanoylcholines, N ⁇ acetylated ⁇ amino acids and N ⁇ acetylated non ⁇ amino acids, and chitosans.
  • the active pharmaceutical ingredient (s) is insulin, zoledronic acid, alendronate, glucagon, Glucose-dependent insulinotropic polypeptide (GIP) , a glucagon-like peptide-1 receptor agonist (GLP-1) , a glucagon-like peptide-2 receptor agonist (GLP-2) , GLP-1/glucagon dual agonist, GLP-1/GIP dual agonist, GLP-1/Peptide YY dual agonist, oxyntomodulin/Peptide YY dual agonist, GLP-1/oxyntomodulin/Peptide YY (GOP) tri-agonist, GLP-1/GIP/glucagon tri-agonist or their analogues.
  • GIP Glucose-dependent insulinotropic polypeptide
  • GLP-1 receptor agonist GLP-1 receptor agonist
  • GLP-2 glucagon-like peptide-2 receptor agonist
  • GLP-1/glucagon dual agonist GLP-1/GIP
  • the glucagon-like peptide-1 receptor or glucagon-like peptide-2 receptor agonist is exenatide, efpeglenatide, Liraglutide, lixisenatide, albiglutide, dulaglutide, oxyntomodulin, cotadutide, peptide YY, semaglutide, tirzepatide, teduglutide or combination thereof.
  • composition wherein the active pharmaceutical ingredient is derived from plant, animal, microorganisms or synthetic origin.
  • composition wherein when exposed to or dissolved or mixed with 1mL to 5mL or more of acidic environment (pH 1-2) it alters the pH of the environment to between pH 3 and pH 10.
  • composition wherein when exposed to or dissolved or mixed with 1mL to 5mL or more of acidic environment (pH 1-2) it alters the pH of the environment to greater than pH 6.8.
  • the composition wherein the enzyme inhibitor (s) is pepstatin, soybean trypsin inhibitor, Aprotinin, Puromycin, N-acetylcysteine, Sodium glycocholate, sodium tauroglycocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, sodium glycodihydrofusidate, camostat mesylate, Bacitracin or combinations thereof.
  • composition wherein there is present transporters, protein stabilizers or anti protein aggregation agents.
  • composition wherein the protein stabilizers or anti-protein aggregation agent is selected from trehalose, trehalose phenylalaninate, sodium 4-phenylbutyrate, polyQ-binding peptide. Resveratrol, Tannic acid and baicalin.
  • the composition wherein the pH regulator is from the group consisting of magnesium hydroxide, magnesium trisilicate, aluminum hydroxide, magnesium oxide, calcium carbonate, sodium bicarbonate, sodium citrate, sodium carbonate, sodium acetate, magnesium carbonate, L-arginine, meglumine, and combinations thereof.
  • the composition wherein the pH regulator is capable of modifying, controlling and/or adjusting the pH of the external or interior environment of a dosage form typically by making the environment have or maintain a basic pH or increase the pH.
  • composition in the form of powder, crystals, granules, tablets, beads, spheres, pellets, capsule, sachet, etc. or combinations thereof.
  • the composition contains at least one pharmaceutical excipients
  • the composition wherein when said excipient is microcrystalline cellulose, polyethylene glycol, tween 80, sodium lauryl sulphate, silicone dioxide, colloidal silica, silica, magnesium stearate, stearic acid, and sodium stearyl fumarate, dibasic calcium phosphate, lactose, lecithin, mannitol, sorbitol, calcium carbonate, talc, Pregelatinized starch, sodium starch glycollate, crospovidone, croscarmellose sodium, carboxymethyl cellulose sodium, or more of Diluents, granulating aid, solubility enhancer, lubricant, glidant, filler, binder, humectant, surface active agent, solubuliser, antioxidant, sweetening agent, flavouring agent, non-polar solvents, buffering agents, mucoadhesive agents, super disintegrant.
  • said excipient is microcrystalline cellulose, polyethylene glycol, tween 80, sodium
  • composition wherein the tablet is manufactured by direct compression of a homogeneous blend of the composition and pharmaceutical excipients.
  • the composition wherein the homogeneous blend is made in a two-step process involving i) Spray drying process and or dry granulating active pharmaceutical ingredient and one or more excipients/penetration enhancers/enzyme inhibitors/pH regulators to yield homogenous granules and ii) blending the dry granulated granules with a lubricant magnesium stearate, stearic acid, and sodium stearyl fumarate or mixture thereof.
  • the composition wherein when wherein the homogeneous blend is made in a three-step process involving dry granulating active pharmaceutical ingredient and one or more excipients to yield homogenous granules, passing the granules through a mill and blending the dry granulated milled granules with a lubricant such as magnesium stearate, stearic acid, and sodium stearyl fumarate or mixture thereof.
  • a lubricant such as magnesium stearate, stearic acid, and sodium stearyl fumarate or mixture thereof.
  • composition in form of a multilayer tablet.
  • composition wherein at least one layer contains the pH regulator or modifier.
  • composition wherein the dosage form is presented as a multiple population of units having same or different compositions wherein at least one-unit population contains the pH regulator or modifier.
  • composition wherein the dosage form is presented as multiple population of drug (s) containing core (s) e.g., beads, pellets, granules, tablets or capsules wherein inside or outside the core is contained one or more of, penetration enhancer, pH regulator or modifier, enzyme inhibitor, contact angle/surface tension modifier.
  • core e.g., beads, pellets, granules, tablets or capsules wherein inside or outside the core is contained one or more of, penetration enhancer, pH regulator or modifier, enzyme inhibitor, contact angle/surface tension modifier.
  • composition wherein the dosage form is a multiple population of cores in which some or all of the population contain API and some do not.
  • composition presented as a tablet, bead, sphere, granule or capsule having one or more layers of a pH sensitive coat completely or partially surrounding it.
  • composition wherein the pH regulator or modifier is less than 500 mg.
  • composition wherein the pH regulator or modifier is less than 1000 mg.
  • the composition wherein the penetration enhancer or enzyme inhibitor is less than 750 mg.
  • composition wherein the penetration enhancer or enzyme inhibitor is less than 1500 mg.
  • the composition the enzyme inhibitor is less than 2500 mg.
  • composition wherein the active pharmaceutical ingredient is less than 2000 mg.
  • composition wherein silicone dioxide (silica) is present.
  • composition wherein simethicone is present.
  • the composition is a self-emulsifying formulation containing at least one surfactant selected from nonionic, anionic, cationic, amphotheric and zwitterionic surfactants and combinations thereof.
  • composition wherein is present one or more stabilizers selected from fatty acids, fatty alcohols, alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidones, polyvinyl ethers, polyvinyl alcohols, hydrocarbons, hydrophobic polymers, moisture-absorbing polymers, and antioxidants
  • stabilizers selected from fatty acids, fatty alcohols, alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidones, polyvinyl ethers, polyvinyl alcohols, hydrocarbons, hydrophobic polymers, moisture-absorbing polymers, and antioxidants
  • composition wherein the active ingredient is an herbal medicine, Chinese herbal medicine, or Ayurvedic medicine.
  • composition and method of treating the condition, disease or disorder such as pain, an age-associated disorder, a geriatric disorder, a disorder having an age-associated susceptibility factor, a neoplastic disorder, a non-neoplastic disorder, a neurological disorder, a cardiovascular disorder, a metabolic disorder, a dermatological disorder, or a dermatological tissue condition.
  • Examples include hypertension, angina, diabetes, HIV AIDS, pain, depression, psychosis, microbial infections, gastro oesophageal reflux disease, impotence, cancer, cardiovascular diseases, gastric/stomach ulcers, blood disorders, nausea, epilepsy, Parkinson's disease, obesity, malaria, gout, asthma, erectile dysfunction, impotence, urinary incontinence, irritable bowel syndrome, ulcerative colitis, smoking, arthritis, rhinitis, Alzheimer's disease, attention deficit disorder, cystic fibrosis, anxiety, insomnia, headache, fungal infection, herpes, hyperglycemia, hyperlipidemia, hypotension, high cholesterol, hypothyroidism, infection, inflammation, mania, menopause, multiple sclerosis, osteoporosis, transplant rejection, schizophrenia, neurological disorders.
  • Inflammatory conditions include, but are not limited to, chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, multiple sclerosis, and type I and II diabetes, asthma, and inflammatory diseases of the central nervous system such as multiple sclerosis, abscess, meningitis, encephalitis and vasculitis.
  • cardiovascular conditions include, but are not limited to, angina, arrhythmia, high blood pressure, stroke, congestive heart failure, atherosclerosis, peripheral artery diseases, high cholesterol levels, and heart attacks.
  • Other disorders/conditions include Neurological or neurodegenerative condition or a mental or behavioural disorder.
  • neurological conditions include, but are not limited to, Alzheimer's disease, amnesia, Aicardi syndrome, amyotrophic lateral sclerosis (Lou Gehrig's disease) , anencephaly, anxiety, aphasia, arachnoiditis, Arnold Chiari malformation, attention deficit syndrome, autism, Batten disease, Bell's Palsy, bipolar syndrome, brachial plexus injury, brain injury, brain tumours, childhood depresses ion, Charcol-Marie tooth disease, depression, dystonia, dyslexia, encephalitis, epilepsy, essential tremor, Guillain-Barre syndrome, hydrocephalus, hyperhidrosis, Krabbes disease, learning disabilities, leukodystrophy, meningitis, Moebius syndrome, multiple sclerosis, muscular dystrophy, Parkinson's disease, peripheral neuropathy, obsessive compulsive disorder, postural orthostatic tachycardia syndrome, progressive supranuclear palsy, prosopagnos
  • Examples of mental and behavioural disorders include, but are not limited to, anxiety disorder, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, social phobia (or social anxiety disorder) , specific phobias, and generalized anxiety disorder.
  • Examples of neoplastic growth include, but are not limited to, breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, brain cancer, cancer of the larynx, gallbladder, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, kidneys, basal cell carcinoma, squamous cell carcinoma of both ulcerating and papillary type, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma, reticulum cell sarcoma, myeloma, giant cell tumor, small-cell lung tumor, gallstones, islet cell tumor, primary brain tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-
  • compositions and a method of stimulating insulin secretion, decreasing gastric emptying, inhibiting food intake, the treatment of obesity and metabolic syndrome, increasing natriuresis and diuresis, treatment of type-2 diabetes and modulation of ⁇ -cell proliferation are provided.
  • compositions and a method for cardio-and neuroprotective effects, decreasing inflammation and apoptosis, for treating depression and improving learning and memory are provided.
  • compositions and a method of improving transmucosal permeability of active pharmaceutical ingredients via oral, nasal, buccal, ocular and pulmonary routes are provided.
  • a composition and a method wherein the manufacturing process include at least one of the following steps, emulsification, encapsulation, solubilization, wet granulation, extrusion spheronization, encapsulation, tableting, hot melt extrusion, coating, drying, spray drying, freeze drying, 3-D printing and curing step.
  • composition containing surfactants, chelating agents, bile salts, nonionic, cationic and anionic polymers, thiomers, acylcarnitines, fatty acids and their derivatives.
  • the present invention relates to a composition and method of medical treatment wherein a) said composition is administered multiple times day; or b) said composition is administered once a day; or c) said composition is administered once a week; or d) said composition is administered once a month.
  • the present invention when the composition or pharmaceutical product from the composition is exposed to or dissolved in gastric fluid or in the gastrointestinal tract, the contact angle and or surface tension of the fluid or the interior environment of the gastrointestinal tract, mucus/mucus membrane and or external surrounding, dosage form is reduced.
  • composition or pharmaceutical product imparts hydrophobicity to the surroundings, external or interior environment of the gastrointestinal tract and or dosage form and its constituents.
  • a composition wherein, drug release targets the stomach.
  • composition wherein, drug release targets the duodenum.
  • composition wherein, drug release targets the mid-jejunum.
  • a composition wherein, drug release targets the small intestine.
  • a composition wherein, drug release targets the large intestine.
  • a composition wherein, the active pharmaceutical ingredient is a charged molecule and or the composition contain excipients to render the active pharmaceutical ingredient charged or modify the charge on the active pharmaceutical ingredient or gastrointestinal membrane.
  • the composition wherein, present is one or more of the following choline, choline hydroxide, choline chloride, choline bicarbonate, geranic acid, choline geranate, stearic acid, propionic acid, linoleic acid, oleic acid, Urea, adipic acid, succinic acid, glutaric acid, choline oleate, choline propionate, choline stearate, choline linoleate, choline succinate, choline adipate, choline glutarate choline fatty acids, choline amino acids, ionic liquids, Deep Eutectic Solvents, choline based ionic liquids or related compounds, derivatives or their combinations.
  • the composition wherein, present is one or more of the following, sodium hydrogen carbonate (NaHCO 3 ) , barium chloride dehydrate (BaCl 2 ) , sodium sulfite (Na 2 SO 3 ) , sodium sulfate (Na 2 SO 4 ) , barium sulfate (BaSO 4 ) , barium sulfite (BaSO 3 ) , and barium carbonate (BaCO 3 ) or a combination or their derivatives.
  • the composition wherein, present is one or more of the following, copolymer of methyl acrylate with different acidic or alkaline end groups; copolymers of methyl acrylate; methacrylic acid and methyl methacrylate; methyl methacrylate and methacrylic acid; methacrylic acid and ethyl acrylate copolymer; ethylacrylate methylmethacrylate; cationic copolymer based on dimethylaminoethyl methacrylate; butyl methacrylate, and methyl methacrylate; copolymer of ethyl acrylate, methyl methacrylate and methacrylic acid ester with quaternary ammonium groups; Poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) ; cellulose esters or a combination or their derivatives.
  • the composition wherein, present is one or more of the following, sodium hydrogen carbonate (NaHCO 3 ) , barium chloride dehydrate (BaCl 2 ) , sodium sulfite (Na 2 SO 3 ) , sodium sulfate (Na 2 SO 4 ) , barium sulfate (BaSO 4 ) , barium sulfite (BaSO 3 ) , and barium carbonate (BaCO 3 ) , choline, choline hydroxide, choline chloride, choline bicarbonate, geranic acid, choline geranate, stearic acid, propionic acid, linoleic acid, oleic acid, Urea, adipic acid, succinic acid, glutaric acid, choline oleate, choline propionate, choline stearate, choline linoleate, choline succinate, choline adipate,
  • composition used in stimulating insulin secretion, decreasing gastric emptying, inhibiting food intake, inducing weight loss, the treatment of obesity, and metabolic syndrome, increasing natriuresis and diuresis, treatment of type-1 or type-2 diabetes and modulation of ⁇ -cell proliferation is not limited to, but not limited to, obesity, and metabolic syndrome, increasing natriuresis and diuresis, treatment of type-1 or type-2 diabetes and modulation of ⁇ -cell proliferation.
  • the composition wherein, present is one or more of the following, lysine, histidine, glutamic acid, aspartic acid, sodium caprate, sodium caprylate, salcaprozate sodium, and one or more of the following, copolymer of methyl acrylate with different acidic or alkaline end groups; copolymers of methyl acrylate; methacrylic acid and methyl methacrylate; methyl methacrylate and methacrylic acid; methacrylic acid and ethyl acrylate copolymer; ethylacrylate methylmethacrylate; cationic copolymer based on dimethylaminoethyl methacrylate; butyl methacrylate, and methyl methacrylate; copolymer of ethyl acrylate, methyl methacrylate and methacrylic acid ester with quaternary ammonium groups; Poly (ethyl acrylate-co-methyl methacrylate-co-trimethylammonioe
  • surfactants examples include, but are not limited to, medium chain transesterification products of oils and alcohols, monoglycerides or diglycerides or mixtures thereof, polyethylene glycol fatty acid monoesters or diesters or mixtures thereof, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol alkyl ethers, propylene glycol fatty acid monoesters or diesters or mixtures thereof, POE-POP block copolymer fatty acid monoesters or diesters or mixtures thereof, sugar esters, bile salts, fatty acid salts, bisalkyl sulfosuccinate salts, phospholipids, hydrophilic derivatives of phospholipids, fatty acid derivatives of polyamines or polyimines or aminoalcohols or aminosugars or peptides or polypeptides; or mixtures of the above surfactants thereof.
  • Surfactants may be selected from sodium lauryl sulfate, sodium taurocholate, lecithin, lyso-lecithin, phosphatidyl glycerol, polyethylene glycol-phosphatidyl ethanolamine, cetyl trimethyl ammonium bromide, lauryl betaine, sucrose esters, polysorbates, sorbitan fatty acid esters, polyethylene glycosylated glycerides, PEGylated glycerides and combinations thereof.
  • non-ionic surfactant may include mixtures of monoglycerides, diglycerides, and triglycerides and monoesters and diesters of polyethylene glycol, polyethylene glycosylated almond glycerides, polyethylene glycosylated corn glycerides, polyethylene glycosylated caprylic/capric triglyceride, polysorbate 20, polysorbate 60, polysorbate 80, Polyoxyl 20 Cetostearyl Ether, Polyoxyl 10 Oleyl Ether and combinations thereof.
  • non-ionic surfactants include PEG stearate, PEG hydrogenated castor oil, PEG laurate, PEG apricot kernel oil esters, PEG caprylate, PEG caprate, PEG myristate, PEG palmitate, and PEG oleate and combinations thereof.
  • Surfactants that may be part of the composition include phospholipids, sorbitan tristearate, sorbitan sesquioleate, glyceryl monostearate, sorbitan monooleate, sorbitan monostearate, sorbitan distearate, propylene glycol monostearate, glyceryl monooleate, glyceryl stearate mono, propylene glycol monolaurate, glyceryl monolaurate, diethylene glycol monoethyl ether and combinations thereof.
  • surfactants also include but in no way do they serve as any limitations on the scope of the surfactants: PEG-8 caprylic/capric glycerides (Labrasol, Acconon MC-8) , PEG-6 caprylic/capric glycerides (Softgen 767, Acconon CC-6) , PEG-12 caprylic/capric glycerides (Acconon CC-1 2) , PEG-35 castor oil (Cremophor EL) , PEG-60 corn glycerides (Crovol M70) , PEG-23 lauryl ether (Brij 35) , PEG-8 laurate (MAPEG 400 ML) , CTAB, DODAB, sodium bis (2-ethylhexyl) sulfosuccinate, glyceryl fatty acids, glyceryl fatty acid esters, propylene glycol laureate, glyceryl glycol esters, polyglycolyzed glycer
  • compositions of the present invention may comprise further additives or ingredients, for example thickening agents, suspending agents, solidifying agents, as well as antioxidants, e.g., tocopherols, ascorbyl palmitate, butyl hydroxy anisole (BHA) , butyl hydroxy toluene (BHT) , antimicrobial agents, enzyme inhibitors, stabilizers, preserving agents, and the like.
  • thickening agents e.g., tocopherols, ascorbyl palmitate, butyl hydroxy anisole (BHA) , butyl hydroxy toluene (BHT)
  • antioxidants e.g., tocopherols, ascorbyl palmitate, butyl hydroxy anisole (BHA) , butyl hydroxy toluene (BHT)
  • antioxidants e.g., tocopherols, ascorbyl palmitate, butyl hydroxy anisole (BHA) , butyl hydroxy toluene (B
  • compositions of the present invention may also contain calcium silicate, magnesium aluminometasilicate, silicon dioxide or carbon nanotubes, 888 ATO or Glyceryl Behenate or ATO 5.
  • additives that may be present in the invention, are gelling agents, mucoadhesives, amino acids, hydrophilic and hydrophobic polymers, water-soluble and water insoluble polymers, including but are not limited thereto: Polycarbophil (Noveon) and Carbomers (Carbopol) , homopolymers and copolymers of N-vinyl lactams, especially homopolymers and copolymers of N-vinyl pyrrolidone, e.g.
  • polyvinylpyrrolidone PVP
  • copolymers of N-vinyl pyrrolidone and vinyl acetate or vinyl propionate cellulose esters and cellulose ethers, in particular sodium carboxymethylcellulose, methylcellulose and ethylcellulose, hydroxyalkylcelluloses, in particular hydroxypropylcellulose, hydroxyalkylalkylcelluloses, in particular hydroxypropylmethylcellulose, cellulose phthalates or succinates, in particular cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate or hydroxypropylmethylcellulose acetate succinate; high molecular polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, polyacrylates and polymethacrylates such as methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl methacrylate copolymers, butyl methacrylate/2-
  • the dosage forms of the invention may contain at least one of the following lysine, histidine, glutamic acid, aspartic acid, sodium hydrogen carbonate (NaHCO3) , barium chloride dehydrate (BaCl2) , sodium sulfite (Na2SO3) , sodium sulfate (Na2SO4) , barium sulfate (BaSO4) , barium sulfite (BaSO3) , barium carbonate (BaCO3) , copolymer of methyl acrylate with different acidic or alkaline end groups, ethyacrylate methylmethacrylate, choline, choline hydroxide, choline chloride, choline bicarbonate, geranic acid, choline geranate, stearic acid, propionic acid, linoleic acid, oleic acid, Urea, adipic acid, succinic acid, glutaric acid, choline oleate, choline prop
  • the dosage forms of the invention may contain at least one conventional additive, such as flow regulators such as colloidal silica; lubricants, fillers, plasticizers, stabilizers such as antioxidants, light stabilizers, radical scavengers, stabilizers against microbial attack, bulking agents (fillers) and disintegrants.
  • flow regulators such as colloidal silica
  • lubricants such as colloidal silica
  • fillers such as colloidal silica
  • plasticizers such as antioxidants, light stabilizers, radical scavengers, stabilizers against microbial attack
  • stabilizers such as antioxidants, light stabilizers, radical scavengers, stabilizers against microbial attack
  • bulking agents fillers
  • Suitable disintegrants used in this invention are crosslinked polymers such as crosslinked polyvinyl pyrrolidone and crosslinked sodium carboxymethylcellulose.
  • Suitable bulking agents are selected from lactose, mannitol, sorbitol, calcium hydrogenphosphate, microcrystalline cellulose (Avicell. RTM. ) , silicates, in particular silicium dioxide, magnesium oxide, talc, potato or corn starch, isomalt, polyvinyl alcohol.
  • any desired amounts of the active substance may be used in the formulation described herein.
  • a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.01 ng/ml to about 50-250 ⁇ g/ml.
  • the pharmaceutical compositions typically should provide a dosage of from about 0.0001 mg to about 3000 mg of active pharmaceutical ingredient per kilogram of body weight per day.
  • Pharmaceutical dosage unit forms are prepared to provide from about 0.001 mg to about 2000 mg and preferably from about 0.5 to about 1200 mg of one or more active ingredients per dosage unit form.
  • the invention by way of a multivariate approach that creates a gastrointestinal positioning, protection, perturbation, permeation and penetration system.
  • composition wherein the multivariate approach of this invention introduces a compounding entourage phenomenon effect wherein the plurality of polymeric and or non-polymeric functional materials within the delivery composition contribute their individual mechanism of action to enhance one another’s possible effects and invariably define the final mechanism of action of the invention.
  • composition capable of 1) more precise control of the physico-chemical and physiological properties of the product environment, such as the internal and external environment within and surrounding the active pharmaceutical ingredient, the delivery system/dosage form and the gastrointestinal environment and mucous membrane and 2) provides for better tolerance, 3) increased gastrointestinal and physiochemical stability, 4) improved membrane perturbation, permeability, penetration, transport, and 5) precise and accurate targeting and maintenance of residency of the API and or dosage form to specific zones in the gastrointestinal tract.
  • composition wherein the multivariate approach surprisingly allows the effective use of minimal or reduced and less toxic amounts of penetration enhancers, contact angle and surface tension modifiers, pH regulators, excipients and enzyme inhibitors in the composition than the very high concentrations which would otherwise be required if they are used separately.
  • composition wherein the dosage forms made using this multivariate approach can be formulated to modify the surface properties of the API, dosage form or gastrointestinal membrane and or formulated to initially provide one or more pulses of penetration enhancer, contact angle/surface tension modifier and pH regulator release or a protracted release of one or more of these. It can also be formulated to provide a concurrent release of the penetration enhancer, contact angle/surface tension modifier and pH regulator in the composition. All these occurring at same time, or prior to or after release of the API.
  • composition wherein the release zone, the rate, extent and time of the pulses and release/penetration/permeability are surprisingly controlled precisely using the multivariate approach of this invention.
  • composition and method wherein active pharmaceutical ingredients loaded particles are made by spray drying process using ionic liquids as a spray drying feed medium.
  • composition and method wherein active pharmaceutical ingredients loaded particles are made by spray drying process using Methacrylic acid -methyl methacrylate copolymer (s) and or Ammonio methacrylate copolymer (s) dispersions, suspensions or solutions as a spray drying feed medium.
  • composition and method wherein active pharmaceutical ingredients loaded particles are made by spray drying process using microemulsions or nano-emulsions as a spray drying feed medium.
  • composition and method wherein the pharmaceutical ingredients loaded spray particles contain macromolecules such as proteins, peptides, hormones, their derivatives or combinations.
  • composition and method wherein the pharmaceutical ingredients loaded spray particles contains or is combined with any of the following; pH regulator, penetration enhancer, glycoprotein, dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane, tween 80, span 20, span 60, polyethylene glycol or related compounds, and pharmaceutical excipient.
  • the invention may also solve further problems that will be apparent from the disclosure of the exemplary embodiments.
  • the particle size of the microsphere plays an important role in determining release of the active agent in the targeted area of the gastro-intestinal tract.
  • the microspheres provided have diameters between about ⁇ 0.1 microns and about 100 microns. In some embodiments, the microspheres provided have diameters between about 0.5 microns and about 50 microns. The microspheres are sufficiently small to release effectively the active agent at the targeted area within the gastro-intestinal tract such as, for example, between the stomach and the jejunum.
  • the active pharmaceutical ingredient e.g., insulin, Semaglutide
  • the active pharmaceutical ingredient becomes more amorphous than crystalline or becomes completely amorphous or yield an amorphous form in the microcapsules or microspheres.
  • Figure 1 shows the Scanning electron microscopy example of Smart Pharmaceutical large molecules delivery technology platform–autonomous novel Gastrointestinal Propulsion System (nGPS or onGPS) showing non drug loaded microspheres prepared by Method 1 in Example 72.
  • Figure 2A shows Scanning electron microscopy example of Smart Pharmaceutical large molecules delivery technology platform–autonomous novel Gastrointestinal Propulsion System (nGPS or onGPS) showing non drug loaded microspheres prepared by Method 2 in Example 72.
  • FIG. 2B Scanning electron microscopy example of Smart Pharmaceutical large molecules delivery technology platform–autonomous novel Gastrointestinal Propulsion System (nGPS or onGPS) showing non drug loaded microspheres prepared by Method 3 in Example 72.
  • Figure 3 shows the Scanning electron microscopy of insulin drug loaded microcapsules prepared by Method 1 in Example 72.
  • Figure 4 shows the Scanning electron microscopy of insulin drug loaded microcapsules prepared by Method 2 in Example 72.
  • Figure 5 shows the Scanning electron microscopy of insulin drug loaded microcapsules prepared by Method 3 in Example 72.
  • Figure 6 shows X-Ray Defractometry (XRD) Data for Placebo Microspheres, Insulin API and Insulin loaded Microspheres by Example 72.
  • Figure 7 shows X-Ray Diffractometry (XRD) Data for Placebo Microspheres, Semaglutide API and Semaglutide Loaded Microspheres by Example 75.
  • Figure 8 shows dissolution profile of insulin 10mg tablets (insulin microspheres compressed into tablets) by Example 72.
  • Figure 9A shows dissolution profile of insulin controlled (targeted) release tablet 10mg (insulin microspheres compressed into tablets) by Example 73.
  • Figure 9B shows dissolution profile of insulin controlled (targeted) release tablet 10mg (insulin microspheres compressed into tablets) by Example 73.
  • dosage forms or dosage forms come in several types. Common dosage forms may be described on the basis of their physico-chemical forms. These include many kinds of liquid, solid, and semisolid dosage forms as well as pills, tablets, capsules, granules, beads, soft gels, films and powders among many others. Various dosage forms may exist for a single or a particular drug, since different medical conditions can warrant different routes of administration and can be described on the basis of route of administration. For example, oral, inhalational, buccal, sublingual, nasal, suppository, pessaries or parenteral dosage forms and others as defined by the United States Food and Drug Administration.
  • pH regulator or pH modifier refers to "alkalinizing agent, " "alkaline pH adjuster, “ and “alkaline pH control agent” which may be used interchangeably and refer to substances that are capable of modifying, controlling and/or adjusting the pH of the external or interior environment of a dosage form or the gastrointestinal tract/membrane, typically by making the environment have or maintain a basic pH or increase the pH. It also refers to basic substances and substances that can convert an acidic environment to a less acidic or more basic environment. Typically, these agents, when present in a sufficient amount, are able to raise the pH of the stomach to beyond physiological levels and thereby 1) protect the API and 2) prevent, reduce, or inhibit dissolution of an acid labile substance described above.
  • pH regulator is also understood to include any pharmaceutically acceptable additive that is capable of reacting with fluid media or gastrointestinal tract environment to adjust/regulate the pH of a fluid media or gastrointestinal tract environment or immediate environment around the API or dosage form.
  • pH regulators or alkalinizing agents include basic salts, for example, alkaline earth metal and/or alkali metal salts such as magnesium hydroxide, magnesium trisilicate magnesium oxide, calcium carbonate, sodium bicarbonate, sodium citrate, sodium carbonate, sodium acetate, magnesium carbonate, etc.
  • alkali metal salts such as magnesium hydroxide, magnesium trisilicate magnesium oxide, calcium carbonate, sodium bicarbonate, sodium citrate, sodium carbonate, sodium acetate, magnesium carbonate, etc.
  • Other examples include aluminum salts, such as aluminum oxide/hydroxides, any suitable amino acids or amino acid derivatives such as L-arginine or meglumine.
  • Combinations of the alkalinizing agents may be used, including combinations of the examples listed. However, it will be understood that any agent capable of dissolving and/or degrading and raising the pH of an acidic solution can be used.
  • any of the following or their combination or derivatives can also act as pH regulators or alkalinizing agents; sodium caprate, Sodium caprylate, Salcaprozate Sodium, copolymer of methyl acrylate with different acidic or alkaline end groups, ethyacrylate methylmethacrylate, cellulose esters, sodium hydrogen carbonate (NaHCO 3 ) , barium chloride dehydrate (BaCl 2 ) , sodium sulfite (Na 2 SO 3 ) , sodium sulfate (Na 2 SO 4 ) , barium sulfate (BaSO 4 ) , barium sulfite (BaSO 3 ) , barium carbonate (BaCO 3 ) , choline, choline hydroxide, choline chloride, choline bicarbonate, geranic acid, choline geranate, stearic acid, , propionic acid, linoleic acid, oleic acid, cho
  • Penetration or absorption enhancers when present act by several mechanisms: a) temporarily disrupting the structural integrity of the intestinal barrier, b) decreasing the mucus viscosity, c) opening the tight junctions, d) increasing the membrane fluidity and e) altering surface tension, contact angle and wettability of gastrointestinal fluid, mucus membrane, biologic membranes and intestinal mucosal barrier.
  • the term “poorly permeable active pharmaceutical ingredients” as used herein refers to APIs that require external or internal intervention to increase or facilitate their permeability and diffusion across the mucosal barrier by one or more mechanism. These include disrupting the mucosal barrier either by the opening of the tight-junctions between adjacent epithelial cells (paracellular pathway) or by the fluidization of phospholipid membranes to allow better diffusion of the active drug across the bilayer (transcellular pathway) or by hindering their active transport from the enterocyte back into the intestinal lumen via secretory transporters such as P-glycoprotein (Pgp) and the family of multidrug resistance-associated proteins (MRP) .
  • Pgp P-glycoprotein
  • MRP multidrug resistance-associated proteins
  • auxiliary excipients refers to excipients which help to enhance, support or assist the preferred properties of the composition such as without limitation solubility, permeability, penetration, stability.
  • examples without limitation include Tween 80, Span 20, span 60, polyethylene glycol, glycoprotein, transferrin, silicone dioxide, dioxosilane, methoxy-dimethyl-trimethylsilyloxysilane and lysine, polyvinyl alcohol, polyvinylpyrrolidone, magnesium stearate, hydroxypropyl methyl cellulose.
  • pharmaceutical active ingredient means any compound which has biological, chemical, or physiological utility including, without limitation, active pharmaceutical ingredient, drug, naturally occurring compound, nucleic acid compound, peptide compound, protein, hormones, biologics, nutraceutical, agricultural or nutritional ingredient or synthetic drug.
  • compositions of the following invention depends on the particular condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art.
  • Insulin-Complex particles composition 1, 2, 3 and 4
  • Insulin tablets/Capsules composition 1, 2, 3 and 4
  • wet granulation the granulating liquid is 5-15%PVP alcoholic solution or alcohol and or water without PVP
  • Insulin-Complex particles and or the Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.
  • Insulin Tablets/Capsules Type 2 were prepared by coating Insulin Tablets/Capsules Type 1 from example 1 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.
  • Semaglutide Tablets/Capsules Type 2 were prepared by coating Semaglutide Type 1 from example 3 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Step 1.4 Preparation of Semaglutide-Insulin-Complex particles Composition 1, 2, 3 and 4 Carry out the following to obtain the different types of Insulin-Complex particles (composition 1, 2, 3 and 4)
  • Insulin tablets/Capsules composition 1, 2, 3 and 4
  • Semaglutide-Insulin Tablets/Capsules Type 2 was made by coating Semaglutide-Insulin Tablets/Capsules Type 1 from example 5 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Step 1 Preparation of Insulin Loaded Granulation liquid
  • Insulin may be added at Step (b) or Step (c) .
  • Insulin tablets/Capsules Type 3 composition 1, 2, 3 and 4
  • Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.
  • Insulin Tablets/Capsules Type 4 was made by coating Insulin Tablets/Capsules Type 3 from example 7 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Insulin Tablets/Capsules Type 5 was made by coating Insulin Tablets/Capsules Type 3 from example 7 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted.
  • Type A aqueous suspension was prepared according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Step 1 Preparation of Somatropin Loaded Granulation liquid
  • Somatropin may be added at Step (b) or Step (c) .
  • Step 2 Preparation of Somatropin Granules and Tablets/Capsules Type 1
  • somatropin tablets/Capsules Type 1 composition 1, 2, 3 and 4
  • Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.
  • Somatropin Tablets/Capsules Type 2 was made by coating Somatropin Tablets/Capsules Type 1 from example 10 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Semaglutide and or Insulin may be added at Step (b) or Step (c) .
  • Step 2 Preparation of Semaglutide-Insulin Granules and Tablets/Capsules Type 4
  • Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.
  • Semaglutide-Insulin Tablets/Capsules Type 5 was made by coating Semaglutide-Insulin Tablets/Capsules Type 4 from example 10 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Semaglutide-Insulin Tablets/Capsules Type 6 was made by coating Semaglutide-Insulin Tablets/Capsules Type 4 from example 12 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted.
  • Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension was prepared according to the compositions 1, 2, 3, and 4 above. The coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Semaglutide and or Insulin may be added at Step 1.1 or Step 1.2.
  • Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.
  • Semaglutide-Insulin Tablets/Capsules Type 8 was made by coating Semaglutide-Insulin Tablets/Capsules Type 7 from example 15 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Semaglutide-Insulin Tablets/Capsules Type 9 was made by coating Semaglutide-Insulin Tablets/Capsules Type 7 from example 15 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted.
  • Type A aqueous suspension was prepared according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Insulin may be added at Step (b) or Step (c) .
  • Insulin granules/microcapsules/nanocapsules are prepared by spray drying the insulin loaded spray drying feed liquid in a spray dryer.
  • Insulin tablets/Capsules Type 3 composition 1, 2, 3 and 4
  • the insulin spray dried granules Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending and lubrication step.
  • Insulin Tablets/Capsules Type 7 was made by coating Insulin Tablets/Capsules Type 6 from example 20 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Insulin Tablets/Capsules Type 8 was made by coating Insulin Tablets/Capsules Type 6 from example 20 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted.
  • Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension was prepared according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Step 1 Preparation of Insulin Loaded Spray Drying Feed Liquid
  • Insulin may be added at Step (b) or Step (c) .
  • Insulin granules/microcapsules/nanocapsules are prepared by spray drying the insulin loaded spray drying feed liquid in a spray dryer.
  • Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending and lubrication step.
  • Semaglutide-Insulin Tablets/Capsules Type 12 was made by coating Semaglutide-Insulin Tablets/Capsules Type 11 from example 23 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Semaglutide-Insulin Tablets/Capsules Type 13 was made by coating Insulin Tablets/Capsules Type 11 from example 23 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted.
  • Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension was prepared according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Step 1 Preparation of Semaglutide-Insulin Loaded Spray Drying Feed Liquid
  • Semaglutide and or Insulin may be added at Step (b) or Step (c) .
  • Semaglutide-Insulin granules/microcapsules/nanocapsules are prepared by spray drying the semaglutide-insulin loaded spray drying feed liquid in a spray dryer.
  • Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending and lubrication step.
  • Semaglutide-Insulin Tablets/Capsules Type 15 was made by coating Semaglutide-Insulin Tablets/Capsules Type 14 from example 26 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Semaglutide-Insulin Tablets/Capsules Type 16 was made by coating Semaglutide-Insulin Tablets/Capsules Type 14 from example 26 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted.
  • Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension was prepared according to the compositions 1, 2, 3, and 4 above. The coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Semaglutide may be added at Step (b) or Step (c) .
  • Semaglutide granules/microcapsules/nanocapsules are prepared by spray drying the Semaglutide loaded spray drying feed liquid in a spray dryer.
  • Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending and lubrication step.
  • Semaglutide Tablets/Capsules Type 4 was made by coating Semaglutide Tablets/Capsules Type 3 from example 28 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Semaglutide Tablets/Capsules Type 5 was made by coating Semaglutide Tablets/Capsules Type 3 from example 28 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted.
  • Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension was prepared according to the compositions 1, 2, 3, and 4 above. The coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Semaglutide may be added at Step 1.1 or Step 1.3.
  • Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.
  • Semaglutide Tablets/Capsules Type 8 was made by coating Semaglutide Tablets/Capsules Type 6 from example 31 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Semaglutide Tablets/Capsules Type 9 was made by coating Semaglutide Tablets/Capsules Type 6 from example 31 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted.
  • Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension was prepared according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Step 1a Add geranic acid to Ammonium bicarbonate while stirring followed by insulin.
  • Step 1b Add Tween and or polyethylene glycol followed by dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane to water and or ethanol while stirring.
  • Step 1c Add the mixture from Step 1b to that from Step 1a while stirring vigorously. Continue stirring for 30 minutes.
  • Semaglutide may be added at Step 1b or Step 1c.
  • Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.
  • Semaglutide Tablets/Capsules Type 10 was made by coating Semaglutide Tablets/Capsules Type 9 from example 34 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Semaglutide Tablets/Capsules Type 11 was made by coating Semaglutide Tablets/Capsules Type 9 from example 34 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted.
  • Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension was prepared according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Insulin may be added at Step 1a.
  • Insulin tablets/Capsules Type 9 composition 1, 2, 3 and 4
  • Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.
  • Insulin Tablets/Capsules Type 10 was made by coating Insulin Tablets/Capsules Type 9 from example 37 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Insulin Tablets/Capsules Type 11 was made by coating Insulin Tablets/Capsules Type 9 from example 37 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted.
  • Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension was prepared according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Insulin may be added at Step 1a.
  • Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.
  • Semaglutide Tablets/Capsules Type 13 was made by coating Semaglutide Tablets/Capsules Type 12 from example 40 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Semaglutide Tablets/Capsules Type 14 was made by coating Semaglutide Tablets/Capsules Type 12 from example 40 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted.
  • Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension was prepared according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Step 1b Preparation of Semaglutide Loaded Spray Drying Feed Suspension
  • Semaglutide may be added at Step 1a.
  • Semaglutide particles/microcapsules/nanocapsules are prepared by spray drying the semaglutide loaded spray drying feed liquid in a spray dryer.
  • the semaglutide loaded spray dried particles Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.
  • Semaglutide Tablets/Capsules Type 16 was made by coating Semaglutide Tablets/Capsules Type 15 from example 43 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Semaglutide Tablets/Capsules Type 17 was made by coating Semaglutide Tablets/Capsules Type 15 from example 43 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted.
  • Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension was prepared according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Step 1b Preparation of Insulin Loaded Spray Drying Feed Suspension
  • Insulin may be added at Step 1a.
  • Insulin particles/microcapsules/nanocapsules are prepared by spray drying the insulin loaded spray drying feed suspension in a spray dryer.
  • Insulin tablets/Capsules Type 12 composition 1, 2, 3 and 4
  • Insulin spray dried particles Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.
  • Insulin Tablets/Capsules Type 13 was made by coating Insulin Tablets/Capsules Type 12 from example 46 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Insulin Tablets/Capsules Type 14 was made by coating Insulin Tablets/Capsules Type 12 from example 46 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted.
  • Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A aqueous suspension was prepared according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Step 1b Preparation of Methacrylic acid –methyl methacrylate copolymer Solution Gradually, add Methacrylic acid –methyl methacrylate copolymer to 50%of the Ethanol/water solution and stir until the polymer is completely dissolved.
  • Insulin may be added at Step 1a or step 1b
  • Insulin particles/microcapsules/nanocapsules are prepared by spray drying the Insulin loaded spray drying feed suspension in a spray dryer.
  • Insulin tablets/Capsules Type 15 composition 1, 2, 3 and 4
  • Insulin loaded spray dried particles Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.
  • Insulin Tablets/Capsules Type 16 was made by coating Insulin Tablets/Capsules Type 15 from example 49 with Methacrylic acid -methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid -methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid -methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid -methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Insulin Tablets/Capsules Type 17 was made by coating Insulin Tablets/Capsules Type 15 from example 49 with Methacrylic acid -methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted.
  • Methacrylic acid -methyl methacrylate copolymer (1: 1) Type A suspension was prepared according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Insulin loaded spray dried particles from Examples 20, 40 or 43 is incorporated with or without pharmaceutical excipients, into tablets or encapsulated into either hard gelatin capsules, soft gelatin capsules, HPMC capsules, pullulan capsules or other delivery device and optionally coated with pH sensitive coat or non pH sensitive coat or a combination.
  • Example 54 Insulin-Transferrin Tablets/Capsules Type 1
  • Step 1b Preparation of Insulin Loaded Spray Drying Feed Suspension
  • Insulin may be added at Step 1a.
  • Step 1c Preparation of Insulin-Transferrin Spray Drying Feed Suspension
  • Insulin-Transferrin particles/microcapsules/nanocapsules are prepared by spray drying the insulin-Transferrin loaded spray drying feed suspension in a spray dryer.
  • Insulin-Transferin tablets/Capsules Type 1 composition 1, 2, 3 and 4
  • Insulin spray-Transferrin dried particles Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.
  • Insulin-Transferrin Tablets/Capsules Type 2 was made by coating Insulin-Transferrin Tablets/Capsules Type 1 from example 53 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Insulin-Transferrin Tablets/Capsules Type 3 was made by coating Insulin-Transferrin Tablets/Capsules Type 1 from example 53 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted.
  • Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension was prepared according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Step 1b Preparation of Methacrylic acid –methyl methacrylate copolymer Solution Gradually, add Methacrylic acid –methyl methacrylate copolymer to 50%of the Ethanol/water solution and stir until the polymer is completely dissolved
  • Step 1c Preparation of Insulin-Transferrin Loaded Spray Drying Feed Suspension
  • Insulin and or Transferrin may be added at Step 1a or step 1b
  • Insulin-Transferrin particles/microcapsules/nanocapsules are prepared by spray drying the Insulin-Transferrin loaded spray drying feed suspension in a spray dryer.
  • Insulin-Transferrin tablets/Capsules Type 4 composition 1, 2, 3 and 4
  • Insulin-Transferrin loaded spray dried particles Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.
  • Example 58 Insulin-Transferrin Tablets/Capsules Type 5
  • Insulin Tablets/Capsules Type 5 was made by coating Insulin Tablets/Capsules Type 4 from example 56 with Methacrylic acid -methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid -methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid -methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid -methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Insulin-Transferrin Tablets/Capsules Type 6 was made by coating Insulin-Transferrin Tablets/Capsules Type 4 from example 56 with Methacrylic acid -methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted.
  • Methacrylic acid -methyl methacrylate copolymer (1: 1) Type A suspension was prepared according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Step 1a Add geranic acid to Ammonium bicarbonate while stirring followed by insulin and
  • Step 1b Add Tween and or polyethylene glycol and lysine followed by dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane to water and or ethanol while stirring
  • Step 1c Add the mixture from Step 1b to that from Step 1a while stirring vigorously. Continue stirring for 30 minutes.
  • Insulin and or Transferrin may be added at Step 1b or Step 1c.
  • Insulin-Transferrin granules/microcapsules/nanocapsules are prepared by spray drying the insulin-Transferrin loaded spray drying feed liquid in a spray dryer.
  • Insulin-Transferrin tablets/Capsules Type 7 composition 1, 2, 3 and 4
  • the insulin-Transferrin spray dried granules Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending and lubrication step.
  • Insulin Tablets/Capsules Type 8 was made by coating Insulin Tablets/Capsules Type 7 from example 59 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Insulin-Transferrin Tablets/Capsules Type 9 was made by coating Insulin-Transferrin Tablets/Capsules Type 7 from example 59 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted. Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A Type A aqueous suspension was prepared according to the compositions 1, 2, 3, and 4 above. The coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Step 1b Preparation of Insulin Loaded Spray Drying Feed Suspension
  • Insulin may be added at Step (a)
  • Step 1c Preparation of Insulin-Transferrin Spray Drying Feed Suspension
  • Insulin-Transferrin particles/microcapsules/nanocapsules are prepared by spray drying the insulin-Transferrin loaded spray drying feed suspension in a spray dryer.
  • Semaglutide and or Insulin spray-Transferrin dried particles Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.
  • Semaglutide-Insulin-Transferrin Tablets/Capsules Type 2 was made by coating Semaglutide-Insulin-Transferrin Tablets/Capsules Type 1 from example 62 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Example 65 Semaglutide-Insulin-Transferrin Tablets/Capsules Type 3
  • Insulin-Transferrin Tablets/Capsules Type 3 was made by coating Insulin-Transferrin Tablets/Capsules Type 1 from example 62 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted.
  • Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A aqueous suspension was prepared according to the compositions 1, 2, 3, and 4 above. The coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Step 1c Preparation of Insulin-Transferrin Loaded Spray Drying Feed Suspension
  • Insulin and or Transferrin may be added at Step 1a or step 1b.
  • Insulin-Transferrin particles/microcapsules/nanocapsules are prepared by spray drying the Insulin-Transferrin loaded spray drying feed suspension in a spray dryer.
  • Semaglutide and or Insulin-Transferrin loaded spray dried particles Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.
  • Insulin Tablets/Capsules Type 5 was made by coating Insulin Tablets/Capsules Type 4 from example 65 with Methacrylic acid -methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid -methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid -methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid -methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Insulin-Transferrin Tablets/Capsules Type 6 was made by coating Insulin-Transferrin Tablets/Capsules Type 4 from example 65 with Methacrylic acid -methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted.
  • Methacrylic acid -methyl methacrylate copolymer (1: 1) Type A suspension was prepared according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Step 1a Add geranic acid to Ammonium bicarbonate while stirring followed by insulin and Transferrin.
  • Step 1b Add Tween and or polyethylene glycol and lysine followed by dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane to water and or ethanol while stirring.
  • Step 1c Add the mixture from Step 1b to that from Step 1a while stirring vigorously. Continue stirring for 30 minutes.
  • Insulin and or Transferrin may be added at Step 1b or Step 1c.
  • Insulin-Transferrin granules/microcapsules/nanocapsules are prepared by spray drying the insulin-Transferrin loaded spray drying feed liquid in a spray dryer.
  • the insulin-Transferrin spray dried granules Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending and lubrication step.
  • Example 70 Semaglutide-Insulin-Transferrin Tablets/Capsules Type 8
  • Insulin Tablets/Capsules Type 8 was made by coating Insulin Tablets/Capsules Type 7 from example 68 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Insulin-Transferrin Tablets/Capsules Type 9 was made by coating Insulin-Transferrin Tablets/Capsules Type 7 from example 68 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted. Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A Type A aqueous suspension was prepared according to the compositions 1, 2, 3, and 4 above. The coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Step (c) Add the mixture from Step (a) to that from Step (b) while stirring vigorously. Continue stirring for greater than 10 minutes.
  • insulin also could be added at Step (b) or Step (c) .
  • Step 2 Preparation of Insulin Granules/Microspheres/Nanospheres
  • Insulin granules/microcapsules/nanocapsules are prepared by spray drying the insulin loaded spray drying feed liquid in a spray dryer.
  • Insulin tablets/Capsules Type 19 composition 1, 2, 3 and 4
  • the insulin spray dried granules, Crospovidone and or microcrystalline and or Magnesium stearate is incorporated during the blending and lubrication step.
  • Insulin Tablets/Capsules Type 20 (composition 1, 2, 3 and 4) was made by coating Insulin Tablets/Capsules Type 19 from example 71 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B solution to a weight gain of 1 to 30%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A and or Methacrylic acid –methyl methacrylate copolymer (1: 2) Type B were prepared in a mixture of ethanol water according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Insulin Tablets/Capsules Type 21 (composition 1, 2, 3 and 4) was made by coating Insulin Tablets/Capsules Type 19 from example 71 with Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A suspension to a weight gain of 1 to 50%depending on where in the gastrointestinal tract the drug release was targeted.
  • Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A Type A aqueous suspension was prepared according to the compositions 1, 2, 3, and 4 above.
  • the coating of the tablets or capsules was performed by coating in a perforated coating pan in a side vented tablet coater at temperatures equal to or less than 61 degrees centigrade.
  • Figure 1 Figure 2A, Figure 2B, and Figures 3-5 showed the Scanning electron microscopy of microcapsules loaded or not loaded insulin.
  • the particle size of the microsphere was between about 0.5 microns and about 50 microns. Meanwhile, microcapsules cross section show that it can incorporate microdomains and nanodomains.
  • Figures1-5 support that the novel composition and process of the invention yield robust microspheres with particle size range and distribution adequate for release of the active agent in targeted areas of the gastro-intestinal tract.
  • Figures 1-5 also show that the novel compositions and processes of the invention can produce hollow microspheres and is capable of microencapsulating active pharmaceutical ingredients.
  • Figure 6 shows X-Ray Defractometry (XRD) Data for Placebo Microspheres, Insulin API and Insulin loaded Microspheres.
  • Figure 7 shows X-Ray Diffractometry (XRD) Data for Placebo Microspheres, Semaglutide API and Semaglutide Loaded Microspheres.
  • Figures 6 and 7 show X-ray diffraction (XRD) studies that were performed to investigate the crystalline and amorphous structure of empty microspheres, API and API loaded microspheres.
  • XRD X-ray diffraction
  • the onGPS platform (Placebo) and Insulin remain intact without any chemical reaction.
  • Figure 8 Figure 9A (from Example 72)
  • Figure 9B shows dissolution profile of insulin tablets. About 100%of insulin is released in 30 minutes which shows that the insulin microspheres made from the composition and process of the invention are stable and can be incorporated into a tablet without loss of potency (Figure 9A) .
  • the composition and process allow for finished dosage forms such as tablets/Capsules that can be targeted to release Insulin at specific sites in gastrointestinal tract ( Figure 9B) .
  • the drug loading efficiency of insulin microspheres were detected by HPLC method. From Example 72 (Methods 1-3 ) the drug loading efficiency were calculated by the following formula:

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Abstract

Une composition solide, semi-solide ou liquide pour le positionnement et l'augmentation de la stabilité, de la perméabilité et de la biodisponibilité d'ingrédients pharmaceutiques actifs peu perméables et/ou peu biodisponibles tels que des macromolécules ou de petites molécules peu perméables. La composition pharmaceutique comprend : i) au moins un ingrédient pharmaceutique actif peu stable, peu soluble, peu perméable et/ou peu biodisponible, ii) au moins un régulateur de pH, iii) au moins un activateur de pénétration et/ou une glycoprotéine, iv) du dioxosilane ; méthoxy-diméthyl-triméthylsilyloxysilane ou des composés apparentés, v) éventuellement un ou plusieurs inhibiteurs d'enzyme, vi) au moins un excipient pharmaceutique, lorsque la composition ou le produit pharmaceutique de la composition est exposé ou dissous ou mélangé avec 1 mL ou plus d'environnement acide (pH 1-2), il modifie le pH de l'environnement à plus de pH 2.
PCT/CN2023/082536 2022-03-18 2023-03-20 Compositions solides, semi-solides ou liquides pour augmenter la stabilité, la perméabilité et la biodisponibilité de substances pharmaceutiques actives WO2023174433A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1579546A (zh) * 2003-08-12 2005-02-16 中国医学科学院生物医学工程研究所 胰岛素固体粒子及其制备方法和该固体粒子在制备治疗糖尿病药物中的应用
CN102119025A (zh) * 2008-04-22 2011-07-06 雅培产品有限公司 渗透不良的活性药物成分的改进制剂
US20150072926A1 (en) * 2012-03-22 2015-03-12 Novo Nordisk A/S Compositions of glp-1 peptides and preparation thereof
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CN1579546A (zh) * 2003-08-12 2005-02-16 中国医学科学院生物医学工程研究所 胰岛素固体粒子及其制备方法和该固体粒子在制备治疗糖尿病药物中的应用
CN102119025A (zh) * 2008-04-22 2011-07-06 雅培产品有限公司 渗透不良的活性药物成分的改进制剂
US20150072926A1 (en) * 2012-03-22 2015-03-12 Novo Nordisk A/S Compositions of glp-1 peptides and preparation thereof
US20210087250A1 (en) * 2018-04-06 2021-03-25 Cyprumed Gmbh Pharmaceutical compositions for the transmucosal delivery of therapeutic peptides and proteins

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SONGWEI XU, JIE ZHANG, ZHANPING YANG, JIANHUA CAO, XIAOLONG MA, ZHONGYI JIANG: "Analyzing the Effect of Carrier on the Microenvironment of Encapsulated Enzyme", PROGRESS IN CHEMISTRY, vol. 20, no. 1, 24 January 2008 (2008-01-24), pages 163 - 170, XP093092810 *

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