WO2023174433A1

WO2023174433A1 - Solid, semisolid, or liquid compositions for augmenting the stability, permeability and bioavailability of active pharmaceutical substances

Info

Publication number: WO2023174433A1
Application number: PCT/CN2023/082536
Authority: WO
Inventors: Isa Odidi
Original assignee: Smart Pharmaceutical (Suzhou) Co., Ltd.
Priority date: 2022-03-18
Filing date: 2023-03-20
Publication date: 2023-09-21

Abstract

A solid, semisolid, or liquid composition for positioning and augmenting the stability, permeability and bioavailability of poorly permeable and/or poorly bioavailable active pharmaceutical ingredients such as macromolecules or poorly permeable small molecules. The pharmaceutical composition comprises: i) at least one poorly stable, poorly soluble, poorly permeable and/or poorly bioavailable active pharmaceutical ingredient, ii) at least one pH regulator, iii) at least one penetration enhancer and/or glycoprotein, iv) dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane or related compounds, v) optionally one or more enzyme inhibitors, vi) at least one pharmaceutical excipient, wherein when the composition or pharmaceutical product from the composition is exposed or dissolved or mixed with 1mL or more of acidic environment (pH 1-2), it alters the pH of the environment to greater than pH 2.

Description

SOLID, SEMISOLID, OR LIQUID COMPOSITIONS FOR AUGMENTING THE STABILITY, PERMEABILITY AND BIOAVAILABILITY OF ACTIVE PHARMACEUTICAL SUBSTANCES

FIELD OF THE INVENTION

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.

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.

This multivariate approach uses novel construction techniques in which materials having differing perturbation, penetration/permeability/stability enhancing mechanisms are combined together, to surprisingly produce a compounding entourage phenomenon, which surprisingly yields 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.

The 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.

BACKGROUND

The oral route remains the preferred route of choice for administration of active pharmaceutical ingredients (API) which are used for their therapeutic effects. Unfortunately, not all active pharmaceutical ingredients can be administered by this route. At present, 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.

There have been numerous attempts to address the problem by creating oral delivery technologies for macromolecules, peptides and proteins. Unfortunately, these have resulted in a series of clinical disappointments as many supposed ‘platform technologies’ failed for a variety of reasons: very low oral bioavailability, toxicity and lack of study reproducibility. Other factors that were implicated in the demise of these programs included formulation and scale-up issues, which prevented the required translation to commercialization and approved use in man. Furthermore, none of these approaches provided a solution or sufficiently and efficiently addressed the issue of the physico-chemical or physiological environment and its impact on API stability and permeation.

Thus, oral administration of therapeutically active macromolecules, peptides, peptidomimetics, hormones and proteins continue to remain a challenge. Major obstacles preventing efficient utilization of the oral route for these poorly permeable active pharmaceutical ingredients class of therapeutics are their lack of oral bioavailability and low gastrointestinal and physiochemical instability under physiological conditions. The cause of these obstacles includes enzymatic degradation in the gastrointestinal tract and intestinal mucosa, insufficient absorption from the intestinal mucosa, as well as first pass metabolism in the liver. Their insufficient absorption is attributed to their high molecular weight, high hydrophilicity and rigidity of the absorptive tissues. In the case of API that are poorly permeable, degradation is highest in the stomach and duodenum decreasing significantly in the ileum and colon.

There are many examples of delivery systems such as delayed or targeted release devices designed to target absorption from the colon and ileum while minimizing exposure of the API to proteolytic enzymes. However, these are not without its drawbacks such as potential changes in colon microflora, delay API absorption and risk of co-absorption of API along with endotoxins and other potentially harmful compounds residing in this intestinal region (Rubinstein, 1995; Van den and Kinget, 1995) .

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.

While these platforms may have shown promising in vitro results, they have not worked very well in vivo. This lack of in vivo success can be attributed to poor loading efficiency for the delivered bioactive, difficulty in their synthesis resulting in lack of batch-to-batch consistency during scale-up, and lack of significant intestinal particle uptake by enterocytes.

The use of 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. Use of 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 and are disclosed in U.S. Pat. Nos. 5,650,386, 5,866,536, 5,965,121, 5,989,539, 6,001,347, 6,344,213, 6,346,242, 6,623,731, and 6,699,467. Other delivery agents have been disclosed in U.S. Pat. Nos. 5,451,410, 5,766,633, 5,792,451, and 6,099,856.

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. For example, 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) .

These methods have their drawbacks. One major drawback is that they are based on the use of single penetration enhancement mechanism involving the use of medium-to-long-chain fatty acid mostly alone or in combination with an enzyme inhibitor. Other drawbacks include for example, 1) very high concentrations of enzymatic inhibitors required in these systems can result in the deficiency of these enzymes in humans when administered for long duration, raising concerns regarding severe side effects that may occur in the treatment of chronic diseases; 2) large quantities of the type of penetration enhancers used in these systems which are intended for long-term usage they may damage or even dissolve the biomembrane, leading to local inflammation; 3) these systems are difficult and uneconomical to manufacture; 4) the systems are not well designed to adequately protect the API or augment its absorption; and 5) these systems display poor stability and inadequate shelf life.

There is a dearth of commercially available oral macromolecules such as peptides, peptidomimetics, hormones and proteins.

There therefore exists a need for a simple, inexpensive, easy to prepare improved drug delivery device, composition and construction method for augmenting the stability, absorption and bioavailability of therapeutically active macromolecules and small molecules by the oral route that is easy to commercialize. There is also a need for an improved method for administering or use of poorly stable, poorly permeable and or poorly bioavailable active pharmaceutical ingredients such as macromolecules or small molecules by the oral route.

SUMMARY

According to an aspect, there is provided 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.

In an aspect there, is provided 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.

In an aspect there, is provided 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.

In an aspect, there is provided 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.

In an aspect, there is provided 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.

In an aspect, there is provided 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.

In an aspect, the composition or pharmaceutical wherein the penetration enhancer is sodium N- (8- (2-hydroxybenzoyl) amino) caprylate (SNAC) .

In an aspect, the composition or pharmaceutical wherein the glycoprotein is transferrin.

In an aspect, the 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.

In an aspect, said at least one pH regulator comprises at least one alkalinizing or pH modifying agent.

In an aspect, 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.

In an aspect, 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.

In an aspect, 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 methacrylate chloride) ; cellulose esters; 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, ethylacrylate methylmethacrylate, choline, choline hydroxide, choline chloride, choline bicarbonate, geranic acid, choline geranate, stearic acid, , propionic acid, linoleic acid, oleic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, geranic acid, vaccenic acid, linoleic acid, linoelaidic acid, . alpha. -linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecyclic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, nonadecylic acid, arachidic acid, heneicosylic acid, behenic acid, tricosylic acid, lignoceric acid, pentacosylic acid, cerotic acid, heptacosylic acid, montanic acid, nonacosylic acid, melissic acid, henatriacontylic acid, lacceroic acid, psyllic acid, geddic acid, ceroplastic acid, or hexatriacontylic acid, fatty acid salts such as sodium oleate, sodium geranate, or sodium hexanoate. 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.

In an aspect there is present in 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.

In an aspect, the 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.

In an aspect, the 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.

In an aspect, the 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.

In an aspect, wherein the pharmaceutical composition is a solid, semisolid, or liquid form

In an aspect, wherein in the composition, the poorly stable, poorly permeable and poorly bioavailable active pharmaceutical ingredient is a macromolecule.

In an aspect, wherein in the composition, the poorly stable, poorly bioavailable active pharmaceutical ingredient is a small molecule.

In an aspect, wherein in the composition, the poorly stable, poorly permeable and poorly bioavailable active pharmaceutical ingredient is a peptide.

In an aspect, wherein in the composition, the poorly stable, poorly permeable and poorly bioavailable active pharmaceutical ingredient is a protein.

In an aspect, wherein in the composition, 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.

In an aspect, wherein in the composition, 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; copolymers of methyl acrylate; methacrylic acid and methyl methacrylate; methyl methacrylate and methacrylic acid; methacrylic acid and ethyl acrylate copolymer; ethyacrylate 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, sodium hydrogen carbonate (NaHCO₃) , barium chloride dehydrate (BaCl₂) , sodium sulfite (Na₂SO₃) , sodium sulfate (Na₂SO₄) , barium sulfate (BaSO₄) , barium sulfite (BaSO₃) , and barium carbonate (BaCO₃) , choline, choline hydroxide, choline chloride, choline bicarbonate, geranic acid, choline geranate, stearic acid, propionic acid, linoleic acid, oleic acid, 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 or their combinations.

In an aspect, wherein in the 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, phthalzines, quinazolines, quinoxalines, quino lines, isoquinolines, thazines, oxazines, and azaannulenes, acyclic organic cations, such as amines such as amidines, imines, guanidines, phosphines such as phosphinimines, arsines, stibines, ethers, thioethers, and selenoethers.

In an aspect, wherein in the composition, said penetration enhancer is taken from surfactants, fatty acids, medium chain glycerides, steroidal detergents, acyl carnitine and alkanoylcholines, N‐acetylated α‐amino acids and N‐acetylated non‐α‐amino acids, and chitosans.

In an aspect, wherein in the composition, 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.

In an aspect, wherein in the composition, 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.

In an aspect, the composition wherein the active pharmaceutical ingredient is derived from plant, animal, microorganisms or synthetic origin.

In an aspect, the 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.

In an aspect, the 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.

In an aspect, 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.

In an aspect, the composition wherein there is present transporters, protein stabilizers or anti protein aggregation agents.

In an aspect, the 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.

In an aspect, 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.

In an aspect, 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.

In an aspect, the composition in the form of powder, crystals, granules, tablets, beads, spheres, pellets, capsule, sachet, etc. or combinations thereof.

In an aspect, the composition contains at least one pharmaceutical excipients

In an aspect, 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.

In an aspect, the composition wherein the tablet is manufactured by direct compression of a homogeneous blend of the composition and pharmaceutical excipients.

In an aspect, 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.

In an aspect, 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.

In an aspect, the composition in form of a multilayer tablet.

In an aspect, the composition wherein at least one layer contains the pH regulator or modifier.

In an aspect, the 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.

In an aspect, the 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.

In an aspect, the 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.

In an aspect, the composition presented as a tablet, bead, sphere, granule or capsule having the pH regulator coated onto it.

In an aspect, the 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.

In an aspect, the composition wherein the pH regulator or modifier is less than 500 mg.

In an aspect, the composition wherein the pH regulator or modifier is less than 1000 mg.

In an aspect, the composition wherein the penetration enhancer or enzyme inhibitor is less than 750 mg.

In an aspect, the composition wherein the penetration enhancer or enzyme inhibitor is less than 1500 mg.

In an aspect, the composition the enzyme inhibitor is less than 2500 mg.

In an aspect, the composition wherein the active pharmaceutical ingredient is less than 2000 mg.

In an aspect, the composition wherein silicone dioxide (silica) is present.

In an aspect, the composition wherein simethicone is present.

In an aspect, the composition is a self-emulsifying formulation containing at least one surfactant selected from nonionic, anionic, cationic, amphotheric and zwitterionic surfactants and combinations thereof.

In an aspect, the 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

In an aspect, the composition wherein the active ingredient is an herbal medicine, Chinese herbal medicine, or Ayurvedic medicine.

In an aspect, the 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. Examples of 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. Examples of 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, prosopagnosia, schizophrenia, shingles, Shy-Drager syndrome, spasmodic torticollis, spina bifida, spinal muscular atrophy, stiff man syndrome, synesthesia, syringomyelia, thoracic outlet syndrome, tourette syndrome, toxoplasmosis, and trigeminal neuralgia. 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-cell leukemia, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuronms, intestinal ganglioneuromas, hyperplastic corneal nerve tumor, marfanoid habitus tumor, Wilm's tumor, seminoma, ovarian tumor, leiomyomater tumor, cervical dysplasia and in situ carcinoma, neuroblastoma, retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical skin lesion, mycosis fungoide, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic and other sarcoma, malignant hypercalcemia, renal cell tumor, polycythermia vera, adenocarcinoma, glioblastoma multiforme, leukaemia’s , lymphomas, malignant melanomas, epidermoid carcinomas, and other carcinomas and sarcomas.

According to an aspect, a composition 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 β-cell proliferation.

According to an aspect, a composition and a method for cardio-and neuroprotective effects, decreasing inflammation and apoptosis, for treating depression and improving learning and memory.

According to an aspect, a composition and a method of improving transmucosal permeability of active pharmaceutical ingredients via oral, nasal, buccal, ocular and pulmonary routes.

According to an aspect, 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.

According to an aspect, a composition containing surfactants, chelating agents, bile salts, nonionic, cationic and anionic polymers, thiomers, acylcarnitines, fatty acids and their derivatives.

In some embodiments 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.

In some embodiments 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.

In some embodiments the present invention the composition or pharmaceutical product imparts hydrophobicity to the surroundings, external or interior environment of the gastrointestinal tract and or dosage form and its constituents.

According to an aspect, a composition wherein, drug release targets the stomach.

According to an aspect, a composition wherein, drug release targets the duodenum.

According to an aspect, a composition wherein, drug release targets the mid-jejunum.

According to an aspect, a composition wherein, drug release targets the small intestine.

According to an aspect, a composition wherein, drug release targets the large intestine.

According to an aspect, 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.

In an aspect, 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.

In an aspect, the composition wherein, present is one or more of the following, sodium hydrogen carbonate (NaHCO₃) , barium chloride dehydrate (BaCl₂) , sodium sulfite (Na₂SO₃) , sodium sulfate (Na₂SO₄) , barium sulfate (BaSO₄) , barium sulfite (BaSO₃) , and barium carbonate (BaCO₃) or a combination or their derivatives.

In an aspect, 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.

In an aspect, the composition wherein, present is one or more of the following, sodium hydrogen carbonate (NaHCO₃) , barium chloride dehydrate (BaCl₂) , sodium sulfite (Na₂SO₃) , sodium sulfate (Na₂SO₄) , barium sulfate (BaSO₄) , barium sulfite (BaSO₃) , and barium carbonate (BaCO₃) , 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 when present are less than 97%weight by weight.

In an aspect, the 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 β-cell proliferation.

In an aspect, 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-trimethylammonioethyl methacrylate chloride) ; cellulose esters; 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, ethylacrylate 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 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.

Examples of the surfactants that may be used in this invention 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. These 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. Additionally suitable 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.

Specific examples of 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 glycerides, propylene glycol esters or partial esters and polyoxyethyl steryl ethers, or combinations thereof.

Pharmaceutical 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.

Pharmaceutical compositions of the present invention may also contain calcium silicate, magnesium aluminometasilicate, silicon dioxide or carbon nanotubes, 888 ATO or Glyceryl Behenate orATO 5.

Other 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-dimethylaminoethyl methacrylate copolymers, poly (hydroxyalkyl acrylates) , poly (hydroxyalkyl methacrylates) , polyacrylamides, vinyl acetate polymers such as copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate (also referred to as partially saponified "polyvinyl alcohol" ) , polyvinyl alcohol, oligo-and polysaccharides such as acacia gum, carrageenans, galactomannans and xanthan gum, lectins, pectins, alginates, chitosans, polyacrilates, cellulose derivatives or mixtures of one or more thereof.

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 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 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.

Suitable disintegrants used in this invention are crosslinked polymers such as crosslinked polyvinyl pyrrolidone and crosslinked sodium carboxymethylcellulose. Suitable bulking agents (also referred to as "fillers" ) 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.

For example, a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.01 ng/ml to about 50-250 μg/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.

In an aspect the 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.

In an aspect the composition wherein the multivariate approach uses novel construction techniques in which materials having differing perturbation, penetration/permeability/stability enhancing mechanisms are combined together, to surprisingly produce a compounding entourage phenomenon, which surprisingly yields 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.

In an aspect the 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.

In an aspect the 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.

In an aspect the 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.

In another aspect the composition and method wherein active pharmaceutical ingredients loaded particles are made by spray drying process using ionic liquids as a spray drying feed medium.

In yet another aspect the 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.

In a further aspect the 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.

In an aspect the composition and method wherein the pharmaceutical ingredients loaded spray particles contain macromolecules such as proteins, peptides, hormones, their derivatives or combinations.

In an aspect the 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. In some embodiments, 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.

In some embodiments, the active pharmaceutical ingredient (API) , e.g., insulin, Semaglutide, becomes more amorphous than crystalline or becomes completely amorphous or yield an amorphous form in the microcapsules or microspheres.

BRIEF DESCRIPTION OF THE DRAWINGS

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.

Figure 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.

EMBODIMENTS OF THE INVENTION

Definitions

Pharmaceutical dosage forms or dosage forms

The term “Pharmaceutical dosage forms or dosage forms” ; depending on the method/route of administration, pharmaceutical 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 modifier

The terms 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. The term "pH regulator" , “pH modifier” 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.

Examples of 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. 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 (NaHCO₃) , barium chloride dehydrate (BaCl₂) , sodium sulfite (Na₂SO₃) , sodium sulfate (Na₂SO₄) , barium sulfate (BaSO₄) , barium sulfite (BaSO₃) , barium carbonate (BaCO₃) , choline, choline hydroxide, choline chloride, choline bicarbonate, geranic acid, choline geranate, stearic acid, , propionic acid, linoleic acid, oleic acid, choline oleate, choline propionate, choline stearate, choline linoleate, choline fatty acids, choline amino acids, ionic liquids, Deep Eutectic Solvents, choline based ionic liquids.

Penetration enhancer

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.

Poorly permeable active pharmaceutical ingredients

Generally, 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) .

Auxiliary excipients

Generally, the term "auxiliary excipients" as used herein 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.

Formulation and composition

The terms “formulation” and “composition” may be used interchangeably.

Pharmaceutical active ingredient

The term “pharmaceutical active ingredient, ” “active agent, ” or “active substance” 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.

The way of making and the exact dose and frequency of administration of 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.

EXAMPLES

The following examples are illustrative only, and not limiting of the remainder of the disclosure in any way whatsoever.

Example 1. Insulin Tablets or Capsules Type 1

Step 1. Preparation of Insulin-Complex particles

Step 1.1 Preparation of BaCl₂ solution

Method:

Add BaCl₂ to water while stirring until dissolved, according to each composition.

Step 1.2 Preparation of Na₂SO₄ solution

Method:

Add Na2SO4 to water while stirring until dissolved, according to each composition.

Step 1.3 Preparation of Insulin solution

Method:

(a) Add Tween 80, polyethylene glycol, aprotinin and or sodium glycocholate, and dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane and lysine (where applicable) to water while stirring.

(b) Gradually add Insulin and adjust the solution to acid pH using HCI until the powder is fully dissolved.

Step 1.4 Preparation of 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)

Method:

(a) Gradually add Insulin solution to a vortex of sodium sulphate solution while stirring.

(b) Gradually add solution from step 1.4a to the vortex of barium chloride solution while stirring vigorously until addition is complete

(c) Continue stirring for 30 minutes

(d) Wash the particles with sufficient water to solubilize the sodium chloride. The solution and sodium chloride can be separated by a filtration process leaving the undissolved particles behind. This process may be repeated as necessary to remove all the sodium chloride

(e) Dry or heat the particles at temperature below 61 Degrees centigrade

Step 2. Preparation of Insulin Tablets or Capsules Type 1

Carry out the following to obtain the different types of Insulin tablets/Capsules (composition 1, 2, 3 and 4)

Method 1:

(a) Granulate the materials for each type using a dry granulation (at temperatures equal to or less than 61 degrees centigrade) or wet granulation technique.

(b) If wet granulation (the granulating liquid is 5-15%PVP alcoholic solution or alcohol and or water without PVP) , dry the wet granules at temperatures at equal to or less than 61 degrees centigrade to a loss on drying value of less than 10%and ethanol less than 20000 PPM. Pass the dry granules through a mill.

(c) Blend and lubricate the milled granules.

(d) Compress blend into tablets or fill into capsules based on the potency of the blend and the dosage strength required.

Method 2:

(a) In an alternative method the Insulin-Complex particles and or the Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.

Example 2. Insulin Tablets/Capsules Type 2

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.

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.

Example 3. Semaglutide Tablets/Capsules Type 1

Step 1. Preparation of Semaglutide-Complex particles Type 1

Step 1.1 Preparation of BaCl₂ solution

Method:

Step 1.2 Preparation of Na₂SO₄ solution

Method:

Add Na₂SO₄ to water while stirring until dissolved, according to each composition.

Step 1.3 Preparation of Semaglutide solution

Method:

(a) Add Tween 80, polyethylene glycol, and dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane and lysine (where applicable) to water while stirring.

(b) Gradually add Semaglutide to the solution while stirring. Mix for 30 minutes.

Step 1.4 Preparation of Semaglutide-Complex particles Composition 1, 2, 3 and 4

Carry out the following to obtain the different types of Semglutide-Complex particles (1, 2, 3 and 4)

Method:

(a) Gradually add Semaglutide solution to a vortex of sodium sulphate solution while stirring.

(b) Gradually add solution from step 1.4a to the vortex of barium chloride solution while stirring vigorously until addition is complete.

(c) Continue stirring for 30 minutes.

(d) Wash the particles with sufficient water to solubilize the sodium chloride. The solution and sodium chloride can be separated by a filtration process leaving the undissolved particles behind. This process may be repeated as necessary to remove all the sodium chloride.

(e) Dry or heat the particles at temperature above the glass transition temperature of polyethylene glycol.

Step 2. Preparation of Semaglutide Tablets Type 1

Carry out the following to obtain the different types of Semaglutide tablets (composition 1, 2, 3 and 4)

Method 1:

(a) Granulate the materials for each type using a dry granulation (at temperatures equal to or below 61 degrees centigrade) or wet granulation technique.

(b) If wet granulation, dry the wet granules at temperatures equal to or below 61 degrees centigrade to a loss on drying value of less than 10%and ethanol less than 20000 PPM.

(c) Pass the dry granules through a mill.

(d) Blend and lubricate the milled granules.

(e) Compress into tablets or fill into capsules based on the potency of the blend and the dosage strength required.

Method 2:

In an alternative method the Semaglutide-Complex particles and or the

Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.

Example 4. Semaglutide Tablets/Capsules Type 2

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.

Example 5 Semaglutide-Insulin Combo Tablets or Capsules Type 1

Step 1. Preparation of Semaglutide-Insulin-Complex particles

Step 1.1 Preparation of BaCl₂ solution

Method:

Add BaCl2 to water while stirring until dissolved, according to each composition.

Step 1.2 Preparation of Na₂SO₄ solution

Method:

Step 1.3 Preparation of Semaglutide-Insulin solution

Method:

Add Tween 80, polyethylene glycol, and dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane and lysine (where applicable) to water while stirring at temperatures below 61 degrees centigrade.

Gradually add Insulin to water and adjust the solution to acid pH using HCI until the powder is fully dissolved at temperatures below 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)

Method:

(a) Gradually add Insulin solution to a vortex of sodium sulphate solution while stirring at temperatures below 61 degrees centigrade.

(b) Gradually add Semaglutide to the Insulin-sodium sulphate solution while stirring at temperatures below 61degrees centigrade.

(c) Gradually add solution from step 1.4b to the vortex of barium chloride solution while stirring vigorously until addition is complete.

(d) Continue stirring for 30 minutes.

(e) Wash the particles with sufficient water to solubilize the sodium chloride. The solution and sodium chloride can be separated by a filtration process leaving the undissolved particles behind. This process may be repeated as necessary to remove all the sodium chloride.

(f) Dry or heat the particles at temperature below 61 Degrees centigrade.

Step 2. Preparation of Semaglutide-Insulin Tablets or Capsules Type 1

Method 1:

(a) Granulate the materials for each composition using a dry granulation (at temperatures equal to or lower than 61 degrees centigrade) or wet granulation technique.

(b) If wet granulation, dry the wet granules at temperatures equal to or lower than 61 degrees centigrade to a loss on drying value of less than 10%and ethanol less than 20000 PPM. Pass the dry granules through a mill.

(c) Blend and lubricate the milled granules.

(d) Compress into tablets or fill granules into capsules based on the potency of the blend and the dosage strength required.

Method 2:

(a) In an alternative method the Semaglutide-Insulin-Complex particles and or the Crospovidone and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.

Example 6. Semaglutide- Insulin Tablets/Capsules Type 2

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.

Example 7. Insulin Tablets/Capsules Type 3

Composition and preparation steps:

Step 1: Preparation of Insulin Loaded Granulation liquid

Method:

(a) Add geranic acid to Ammonium bicarbonate while stirring followed by insulin

(b) Add Tween and or polyethylene glycol followed by dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane to water and or ethanol while stirring

(c) Add the mixture from Step (b) to that from Step (a) while stirring vigorously. Continue stirring for 30 minutes.

(d) Note: Insulin may be added at Step (b) or Step (c) .

Step 2: Preparation of Insulin Granules and Tablets/Capsules Type 3

Carry out the following to obtain the different types of Insulin tablets/Capsules Type 3 (composition 1, 2, 3 and 4)

Method 1:

(a) Granulate the materials for each composition type using the corresponding Insulin Loaded Granulation liquid by wet granulation technique.

(b) Dry the wet granules at temperatures equal to or lower than 61 degrees centigrade to a loss on drying value of less than 10%and ethanol less than 20000 PPM. Pass the dry granules through a mill.

(c) Blend and lubricate the milled granules.

(d) Compress the blended granules into tablets or fill granules into capsules based on the potency of the blend and the dosage strength required.

Method 2:

In an alternative method the Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.

Example 8. Insulin Tablets/Capsules Type 4

Method:

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.

Example 9. Insulin Tablets/Capsules Type 5

Method:

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.

Different concentrations of coating solution of Methacrylic acid –methyl methacrylate copolymer (1: 1) Type A aqueous suspension was prepared according to the compositions 1, 2, 3, and 4 above.

Example 10. Somatropin HGH Tablets/Capsules Type 1

Composition and preparation steps:

Step 1: Preparation of Somatropin Loaded Granulation liquid

Method:

(a) Add geranic acid to Ammonium bicarbonate while stirring followed by somatropin

Note: Somatropin may be added at Step (b) or Step (c) .

Step 2: Preparation of Somatropin Granules and Tablets/Capsules Type 1

Carry out the following to obtain the different types of somatropin tablets/Capsules Type 1 (composition 1, 2, 3 and 4)

Method 1:

(a) Granulate the materials for each composition type using the corresponding somatropin Loaded Granulation liquid by wet granulation technique.

(c) Blend and lubricate the milled granules.

Method 2:

Example 11. Somatropin Tablets/Capsules Type 2

Method:

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.

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.

Example 12. Semaglutide-Insulin Tablets/Capsules Type 4

Composition and preparation steps:

Step1: Preparation of Semaglutide-Insulin Loaded Granulation liquid

Method:

(a) Add geranic acid to Ammonium bicarbonate while stirring followed by Semaglutide and insulin.

(b) Add Tween and or polyethylene glycol followed by dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane to water and or ethanol while stirring.

Note: 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

Carry out the following to obtain the different types of Semaglutide-Insulin tablets/Capsules Type 1 (composition 1, 2, 3 and 4)

Method 1:

(a) Granulate the materials for each composition type using the corresponding Semaglutide-Insulin Loaded Granulation liquid by wet granulation technique.

(c) Blend and lubricate the milled granules.

Method 2:

Example 13. Semaglutide-Insulin Tablets/Capsules Type 5

Method:

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.

Example 14. Semaglutide-Insulin Tablets/Capsules Type 6

Method:

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. Different concentrations of coating solution of 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.

Example 15. Semaglutide-Insulin Tablets/Capsules Type 7

Composition and preparation steps:

Step 1. Preparation of Granulation liquid

Step 1.1 Preparation of Choline bicarbonate Granulation liquid

Method:

Add water to Ammonium bicarbonate while stirring to obtain 20-80%solution.

Step 1.2 Preparation of Semaglutide-Insulin Granulation liquid

Method:

Add Semaglutide and insulin to geranic acid while stirring.

Step 1.3 Preparation of dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane solution

Method:

Add Tween and or polyethylene glycol followed by dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane to water and or ethanol while stirring.

Step 1.4. Preparation of Semaglutide-Insulin Loaded Geranic Acid Granulation liquid

Method:

Add the mixture from Step 1.3 to that from Step 1.2 while stirring vigorously. Continue stirring for 30 minutes.

Note: Semaglutide and or Insulin may be added at Step 1.1 or Step 1.2.

Step 2. Preparation of Semaglutide-Insulin Granules and Tablets/Capsules Type 7

Carry out the following to obtain the different types of Semaglutide-Insulin tablets/Capsules Type 7 (composition 1, 2, 3 and 4)

Method 1:

(a) Granulate a portion of the excipients for each composition type using the corresponding Semaglutide-Insulin Loaded Geranic Acid Granulation liquid from Step 1d.

(b) Granulate the remaining portion of the excipients for each composition type using the corresponding choline bicarbonate granulating solution from Step 1b.

(c) Dry the two wet granulates together or separately in a fluid bed or oven at temperatures equal to or lower than 61 degrees centigrade to a loss on drying value of less than 10%and ethanol less than 20000 PPM.

(d) Pass the dry granules through a co-mill.

(e) Blend and lubricate the dry granules.

(f) Compress the blended granules into tablets or fill granules into capsules based on the potency of the blend and the dosage strength required.

Method 2:

Example 16. Semaglutide-Insulin Tablets/Capsules Type 8

Method:

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.

Example 17. Semaglutide-Insulin Tablets/Capsules Type 9

Method:

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.

Example 18. Semaglutide and or Insulin Tablets/Capsules Type 9

Compositions of Examples 7 to 17 in which geranic acid is replaced with succinic, glutaric or adipic acid.

Example 19. Semaglutide and or Insulin Tablets/Capsules Type 10

Compositions of Examples 18 in which urea is used in conjunction or combination with choline bicarbonate, geranic acid, succinic, glutaric or adipic acid or their bi-products (choline dicarboxylates)

Example 20. Insulin Tablets/Capsules Type 6

Composition and preparation steps:

Step 1. Preparation of Insulin Loaded Spray Drying Feed Liquid

Method:

(a) Add geranic acid to Ammonium bicarbonate while stirring followed by insulin.

(b) Add Tween and or polyethylene glycol and lysine followed by dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane to water and or ethanol while stirring.

Note: Insulin may be added at Step (b) or Step (c) .

Step 2: Preparation of Insulin Granules

Insulin granules/microcapsules/nanocapsules are prepared by spray drying the insulin loaded spray drying feed liquid in a spray dryer.

Step 3: Preparation of Insulin Tablets/Capsules Type 6

Method 1:

(a) Mix the excipients (with exception of Sodium Stearyl Fumarate) and the insulin spray dried granules and pass the mixture through a co-mill.

(b) Blend the milled granules.

(c) Lubricate the milled granules with Sodium Stearyl Fumarate.

(d) Compress the lubricated granules into tablets or fill granules into capsules based on the potency of the blend and the dosage strength required.

Method 2:

In an alternative method:

(a) Mix and granulate the excipients (with exception of Sodium Stearyl Fumarate and the insulin spray dried granules) with polyvinyl pyrrolidone granulating liquid.

(b) Dry the wet granules in a fluid bed or oven and pass the dried granules through a co-mill.

(c) Blend the milled granules with the insulin spray dried granules.

(d) Lubricate the blended granules with Sodium Stearyl Fumarate.

(e) Compress the lubricated granules into tablets or fill granules into capsules based on the potency of the blend and the dosage strength required.

Method 3:

In an alternative method the insulin spray dried granules, Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending and lubrication step.

Example 21. Insulin Tablets/Capsules Type 7

Method:

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.

Example 22. Insulin Tablets/Capsules Type 8

Method:

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. Different concentrations of coating solution of 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.

Example 23. Semaglutide-Insulin Tablets/Capsules Type 11

Composition and preparation steps:

Step 1: Preparation of Insulin Loaded Spray Drying Feed Liquid

Method:

Note: Insulin may be added at Step (b) or Step (c) .

Step 2: Preparation of Insulin Granules

Step 3: Preparation of Semaglutide-Insulin Tablets/Capsules Type 11

Carry out the following to obtain the different types of Semaglutide-Insulin tablets/Capsules Type 11 (composition 1, 2, 3 and 4)

Method 1:

(a) Mix the excipients (with exception of Sodium Stearyl Fumarate) , semaglutide and the insulin spray dried granules and pass the mixture through a co-mill.

(b) Blend the milled granules.

(c) Lubricate the milled granules with Sodium Stearyl Fumarate.

Method 2:

In an alternative method:

(a) Mix and granulate the excipients (with exception of Sodium Stearyl Fumarate, semaglutide and the insulin spray dried granules) with polyvinyl pyrrolidone granulating liquid.

(c) Blend the milled granules with the semaglutide and insulin spray dried granules.

(d) Lubricate the blended granules with Sodium Stearyl Fumarate.

Method 3:

In an alternative method the Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending and lubrication step.

Example 24. Semaglutide-Insulin Tablets/Capsules Type 12

Method:

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.

Example 25. Semaglutide- Insulin Tablets/Capsules Type 13

Method:

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. Different concentrations of coating solution of 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.

Example 26. Semaglutide-Insulin Tablets/Capsules Type 14

Composition and preparation steps:

Step 1: Preparation of Semaglutide-Insulin Loaded Spray Drying Feed Liquid

Method:

(b) Add Tween80 and or polyethylene glycol and lysine followed by dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane to water and or ethanol while stirring.

Note: Semaglutide and or Insulin may be added at Step (b) or Step (c) .

Step 2: Preparation of Semaglutide-Insulin Granules

Semaglutide-Insulin granules/microcapsules/nanocapsules are prepared by spray drying the semaglutide-insulin loaded spray drying feed liquid in a spray dryer.

Step 3: Preparation of Semaglutide-Insulin Tablets/Capsules Type 14

Carry out the following to obtain the different types of Semaglutide-Insulin tablets/Capsules Type 3 (composition 1, 2, 3 and 4)

Method 1:

(a) Mix the excipients (with exception of Sodium Stearyl Fumarate) and the Semaglutide-Insulin spray dried granules and pass the mixture through a co-mill.

(b) Blend the milled granules.

(c) Lubricate the milled granules with Sodium Stearyl Fumarate.

Method 2:

In an alternative method:

(a) Mix and granulate the excipients (with exception of Sodium Stearyl Fumarate and the Semaglutide-Insulin spray dried granules) with polyvinyl pyrrolidone granulating liquid.

(c) Blend the milled granules with the insulin spray dried granules.

(d) Lubricate the blended granules with Sodium Stearyl Fumarate.

Method 3:

Example 27. Semaglutide-Insulin Tablets/Capsules Type 15

Method:

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.

Example 28. Semaglutide-Insulin Tablets/Capsules Type 16

Method:

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. Different concentrations of coating solution of 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.

Example 29 Semaglutide Tablets/Capsules Type 3

Composition and preparation steps:

Step 1: Preparation of Semaglutide Loaded Spray Drying Feed Liquid

Method:

(a) Add geranic acid to Ammonium bicarbonate while stirring followed by Semaglutide.

Note: Semaglutide may be added at Step (b) or Step (c) .

Step 2: Preparation of Insulin Granules

Semaglutide granules/microcapsules/nanocapsules are prepared by spray drying the Semaglutide loaded spray drying feed liquid in a spray dryer.

Step 3: Preparation of Semaglutide Tablets/Capsules Type 3

Carry out the following to obtain the different types of Semaglutide tablets/Capsules Type 3 (composition 1, 2, 3 and 4)

Method 1:

(a) Mix the excipients (with exception of Sodium Stearyl Fumarate) and the Semaglutide spray dried granules and pass the mixture through a co-mill.

(b) Blend the milled granules.

(c) Lubricate the milled granules with Sodium Stearyl Fumarate.

Method 2:

In an alternative method:

(a) Mix and granulate the excipients (with exception of Sodium Stearyl Fumarate and the Semaglutide spray dried granules) with polyvinyl pyrrolidone granulating liquid.

(c) Blend the milled granules with the Semaglutide spray dried granules.

(d) Lubricate the blended granules with Sodium Stearyl Fumarate.

Method 3:

Example 30. Semaglutide Tablets/Capsules Type 4

Method:

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.

Example 31. Semaglutide Tablets/Capsules Type 5

Method:

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. Different concentrations of coating solution of 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.

Example 32. Semaglutide Tablets/Capsules Type 6

Composition and preparation steps:

Step 1. Preparation of Granulation liquid

Step 1.1 Preparation of Choline bicarbonate Granulation liquid

Method:

Add water to Ammonium bicarbonate while stirring to obtain 20-80%solution.

Step 1.2 Preparation of Semaglutide Granulation liquid

Method:

Add Semaglutide to geranic acid while stirring.

Method:

Add Tween80 and or polyethylene glycol followed by dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane to water and or ethanol while stirring.

Step 1.4. Preparation of Semaglutide Loaded Geranic Acid Granulation liquid

Method:

Note: Semaglutide may be added at Step 1.1 or Step 1.3.

Step 2. Preparation of Semaglutide Granules and Tablets/Capsules Type 6

Carry out the following to obtain the different types of Semaglutide tablets/Capsules Type 6 (composition 1, 2, 3 and 4)

Method 1:

(a) granulate a portion of the excipients for each composition type using the corresponding Semaglutide Loaded Geranic Acid Granulation liquid from Step 1d.

(d) pass the dry granules through a co-mill.

(e) blend and lubricate the dry granules.

Method 2:

Example 33. Semaglutide Tablets/Capsules Type 7

Method:

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.

Example 34. Semaglutide Tablets/Capsules Type 9

Method:

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. Different concentrations of coating solution of 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.

Example 35. Semaglutide Tablets/Capsules Type 9

Composition and preparation steps:

Step 1. Preparation of Semaglutide Loaded Granulation liquid

Method:

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.

Note: Semaglutide may be added at Step 1b or Step 1c.

Step 2. Preparation of Semaglutide Granules and Tablets/Capsules Type 9

Carry out the following to obtain the different types of Semaglutide tablets/Capsules Type 9 (composition 1, 2, 3 and 4)

Method 1:

(c) Blend and lubricate the milled granules.

Method 2:

Example 36. Semaglutide Tablets/Capsules Type 10

Method:

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.

Example 37. Semaglutide Tablets/Capsules Type 11

Method:

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. Different concentrations of coating solution of 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.

Example 38. Insulin Tablets/Capsules Type 9

Composition and preparation steps:

Step 1. Preparation of Insulin Granulation Suspension

Method:

Step 1a. Preparation of Talc Suspension

Add Talc and triethyl citrate, Polysorbate 80 followed by dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane to water and homogenise.

Step 1b. Preparation of Insulin Granulation suspension

(i) Gradually add the Talc suspension into the Ammonio methacrylate copolymer type A and or Ammonio methacrylate copolymer type B while stirring

(ii) Add Insulin while stirring and mix.

Note: Insulin may be added at Step 1a.

Step 2. Preparation of Insulin Granules and Tablets/Capsules Type 9

Carry out the following to obtain the different types of Insulin tablets/Capsules Type 9 (composition 1, 2, 3 and 4)

Method 1:

(i) -granulate the excipients (with exception of Sodium Stearyl Fumarate) for each composition type using the corresponding Insulin granulation suspension from Step 1b.

(ii) -dry the wet granulates in a fluid bed or oven at temperatures equal to or lower than 61 degrees centigrade to a loss on drying value of less than 10%.

(iv) -Pass the dry granules through a co-mill.

5-blend and then lubricate the dry granules with Sodium Stearyl Fumarate

6-Compress the blended granules into tablets or fill granules into capsules based on the potency of the blend and the dosage strength required

Method 2:

Example 39. Insulin Tablets/Capsules Type 10

Method:

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.

Example 40. Insulin Tablets/Capsules Type 11

Method:

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. Different concentrations of coating solution of 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.

Example 41. Semaglutide Tablets/Capsules Type 12

Composition and preparation steps:

Step 1. Preparation of Semaglutide Granulation Suspension

Method:

Step 1a. Preparation of Talc Suspension

Step 1b. Preparation of Semaglutide Granulation suspension

(ii) Add Semaglutide while stirring and mix.

Note: Insulin may be added at Step 1a.

Step 2. Preparation of Semaglutide Granules and Tablets/Capsules Type 12

Method 1:

(ii) -dry the wet granulates in a fluid bed or oven at temperatures equal to or lower than 61 degrees centigrade to a loss on drying value of less than 10%

(iv) -Pass the dry granules through a co-mill.

5-blend and then lubricate the dry granules with Sodium Stearyl Fumarate

Method 2:

Example 42. Semaglutide Tablets/Capsules Type 13

Method:

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.

Example 43. Semaglutide Tablets/Capsules Type 14

Method:

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. Different concentrations of coating solution of 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.

Example 44. Semaglutide Tablets/Capsules Type 15

Composition and preparation steps:

Step 1. Semaglutide Loaded Spray Dried particles

Method:

Step 1a. Preparation of Talc Suspension

Step 1b. Preparation of Semaglutide Loaded Spray Drying Feed Suspension

(ii) Add Semaglutide while stirring and mix.

Note: Semaglutide may be added at Step 1a.

Step 1c. Preparation of Semaglutide Loaded Spray Dried Particles

Semaglutide particles/microcapsules/nanocapsules are prepared by spray drying the semaglutide loaded spray drying feed liquid in a spray dryer.

Step 2. Preparation of Semaglutide Granules and Tablets/Capsules Type 15

Carry out the following to obtain the different types of Semaglutide tablets/Capsules Type 15 (composition 1, 2, 3 and 4)

Method 1:

(i) -granulate the semaglutide loaded spray dried particles and excipients (with exception of Sodium Stearyl Fumarate) for each composition type using Polyvinylpyrrolidone granulation solution (5-15%wt/wt) .

(iv) -Pass the dry granules through a co-mill.

5-blend and then lubricate the dry granules with Sodium Stearyl Fumarate

Method 2:

In an alternative method the semaglutide loaded spray dried particles, Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.

Example 45. Semaglutide Tablets/Capsules Type 16

Method:

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.

Example 46. Semaglutide Tablets/Capsules Type 17

Method:

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. Different concentrations of coating solution of 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.

Example 47. Insulin Tablets/Capsules Type 12

Composition and preparation steps:

Step 1. Insulin Loaded Spray Dried particles

Method:

Step 1a. Preparation of Talc Suspension

Step 1b. Preparation of Insulin Loaded Spray Drying Feed Suspension

(ii) Add Insulin while stirring and mix.

Note: Insulin may be added at Step 1a.

Step 1c. Preparation of Insulin Loaded Spray Dried Particles

Insulin particles/microcapsules/nanocapsules are prepared by spray drying the insulin loaded spray drying feed suspension in a spray dryer.

Step 2. Preparation of Insulin Granules and Tablets/Capsules Type 12

Carry out the following to obtain the different types of Insulin tablets/Capsules Type 12 (composition 1, 2, 3 and 4)

Method 1:

(i) -granulate the Insulin spray dried particles and excipients (with exception of Sodium Stearyl Fumarate) for each composition type using Polyvinylpyrrolidone granulation solution (5-15%wt/wt) .

(iv) -Pass the dry granules through a co-mill.

5-blend and then lubricate the dry granules with Sodium Stearyl Fumarate

Method 2:

In an alternative method the Insulin spray dried particles, Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.

Example 48. Insulin Tablets/Capsules Type 13

Method:

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.

Example 49. Insulin Tablets/Capsules Type 14

Method:

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. Different concentrations of coating solution of 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.

Example 50. Insulin Tablets/Capsules Type 15

Composition and preparation steps:

Step 1. Insulin Loaded Spray Dried particles

Method:

Step 1a. Preparation of Diluent Suspension

Add talc or magenesium stearate and triethyl citrate, polysorbate 80 followed by dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane to 50%of the Ethanol/water solution and homogenise.

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 Loaded Spray Drying Feed Suspension

(i) Gradually add the diluent suspension from step 1a into the Methacrylic acid –methyl methacrylate copolymer Solution while stirring

(ii) Add Insulin while stirring and mix.

Note: Insulin may be added at Step 1a or step 1b

Step 1d. Preparation of Insulin Loaded Spray Dried Particles

Step 2. Preparation of Insulin Granules and Tablets/Capsules Type 15

Carry out the following to obtain the different types of Insulin tablets/Capsules Type 15 (composition 1, 2, 3 and 4)

Method 1:

(i) granulate the Insulin loaded spray dried particles and excipients (with exception of Sodium Stearyl Fumarate) for each composition type using Polyvinylpyrrolidone granulation solution (5-15%wt/wt) .

(ii) dry the wet granulates in a fluid bed or oven at temperatures equal to or lower than 61 degrees centigrade to a loss on drying value of less than 10%

(iii) pass the dry granules through a co-mill.

(iv) blend and then lubricate the dry granules with Sodium Stearyl Fumarate

(v) compress the blended granules into tablets or fill granules into capsules based on the potency of the blend and the dosage strength required.

Method 2:

In an alternative method the Insulin loaded spray dried particles, Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.

Example 51. Insulin Tablets/Capsules Type 16

Method:

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.

Example 52. Insulin Tablets/Capsules Type 17

Method:

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. Different concentrations of coating solution of 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.

Example 53. Insulin Tablets/Capsules Type 18

The 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

Composition and preparation steps:

Step 1. Insulin-Transferrin Loaded Spray Dried particles

Method:

Step 1a. Preparation of Talc Suspension

Step 1b. Preparation of Insulin Loaded Spray Drying Feed Suspension

(a) Gradually add the Talc suspension into the Ammonio methacrylate copolymer type A and or Ammonio methacrylate copolymer type B while stirring

(ii) . Add Insulin while stirring and mix.

Note: Insulin may be added at Step 1a.

Step 1c. Preparation of Insulin-Transferrin Spray Drying Feed Suspension

(i) . Gradually add the transferrin to the insulin loaded suspension while stirring.

(ii) . Continue mixing to incorporate the transferrin.

Step 1d. Preparation of Insulin-Transferrin Loaded Spray Dried Particles

Insulin-Transferrin particles/microcapsules/nanocapsules are prepared by spray drying the insulin-Transferrin loaded spray drying feed suspension in a spray dryer.

Step 2. Preparation of Insulin-Transferrin Granules and Tablets/Capsules Type 1

Carry out the following to obtain the different types of Insulin-Transferin tablets/Capsules Type 1 (composition 1, 2, 3 and 4)

Method 1:

(i) -granulate the Insulin-Transferrin spray dried particles and excipients (with exception of Sodium Stearyl Fumarate) for each composition type using Polyvinylpyrrolidone granulation solution (5-15%wt/wt) .

(iv) -Pass the dry granules through a co-mill.

5-blend and then lubricate the dry granules with Sodium Stearyl Fumarate

Method 2:

In an alternative method the Insulin spray-Transferrin dried particles, Crospovidone/Croscarmellose sodium and or microcrystalline and or Sodium Stearyl Fumarate is incorporated during the blending step.

Example 55. Insulin-Transferrin Tablets/Capsules Type 2

Method:

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.

Example 56. Insulin-Transferrin Tablets/Capsules Type 3

Method:

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. Different concentrations of coating solution of 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.

Example 57. Insulin-Transferrin Tablets/Capsules Type 4

Composition and preparation steps:

Step 1. Insulin-Transferrin Loaded Spray Dried particles

Method:

Step 1a. Preparation of Diluent Suspension

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

(ii) Add Insulin while stirring and mix.

(iii) Gradually add Transferin.

(iv) Continue mixing until both are incorporated.

Note: Insulin and or Transferrin may be added at Step 1a or step 1b

Step 1c. Preparation of Insulin-Transferrin Loaded Spray Dried Particles

Step 2. Preparation of Insulin-Transferrin Granules and Tablets/Capsules Type 4

Carry out the following to obtain the different types of Insulin-Transferrin tablets/Capsules Type 4 (composition 1, 2, 3 and 4)

Method 1:

(v) granulate the Insulin-Transferrin loaded spray dried particles and excipients (with exception of Sodium Stearyl Fumarate) for each composition type using Polyvinylpyrrolidone granulation solution (5-15%wt/wt) .

(vi) dry the wet granulates in a fluid bed or oven at temperatures equal to or lower than 61 degrees centigrade to a loss on drying value of less than 10%

(vii) pass the dry granules through a co-mill.

(viii) blend and then lubricate the dry granules with Sodium Stearyl Fumarate

(ix) compress the blended granules into tablets or fill granules into capsules based on the potency of the blend and the dosage strength required.

Method 2:

In an alternative method the 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

Method:

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.

Example 59. Insulin Tablets/Capsules Type 6

Method:

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. Different concentrations of coating solution of 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.

Example 60. Insulin-Transferrin Tablets/Capsules Type 7

Composition and preparation steps:

i) Preparation of Insulin-Transferrin Loaded Spray Drying Feed Liquid

Method:

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

Note: Insulin and or Transferrin may be added at Step 1b or Step 1c.

ii) Preparation of Insulin-Transferrin Particles

Insulin-Transferrin granules/microcapsules/nanocapsules are prepared by spray drying the insulin-Transferrin loaded spray drying feed liquid in a spray dryer.

iii) Preparation of Insulin-Transferrin Tablets/Capsules Type 7

Carry out the following to obtain the different types of Insulin-Transferrin tablets/Capsules Type 7 (composition 1, 2, 3 and 4)

Method 1:

(a) Mix the excipients (with exception of Sodium Stearyl Fumarate) and the insulin-Transferrin spray dried granules and pass the mixture through a co-mill.

(b) Blend the milled granules.

(c) Lubricate the milled granules with Sodium Stearyl Fumarate.

Method 2:

In an alternative method:

(a) Mix and granulate the excipients (with exception of Sodium Stearyl Fumarate and the insulin-Transferrin spray dried granules) with polyvinyl pyrrolidone granulating liquid.

(c) Blend the milled granules with the insulin-Transferrin spray dried granules.

(d) Lubricate the blended granules with Sodium Stearyl Fumarate.

Method 3:

In an alternative method 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 61. Insulin-Transferrin Tablets/Capsules Type 8

Method:

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.

Example 62. Insulin Tablets/Capsules Type 9

Method:

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 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.

Example 63. Semaglutide-Insulin-Transferrin Tablets/Capsules Type 1

Composition and preparation steps:

Step 1. Insulin-Transferrin Loaded Spray Dried particles

Method:

Step 1a. Preparation of Talc Suspension

Step 1b. Preparation of Insulin Loaded Spray Drying Feed Suspension

(ii) Add Insulin while stirring and mix.

Note: Insulin may be added at Step (a)

Step 1c. Preparation of Insulin-Transferrin Spray Drying Feed Suspension

(i) Gradually add the transferrin to the insulin loaded suspension while stirring

(ii) Continue mixing to incorporate the transferrin

Step 1d. Preparation of Insulin-Transferrin Loaded Spray Dried Particles

Step 2. Preparation of Semaglutide-Insulin-Transferrin Granules and Tablets/Capsules Type 1

Carry out the following to obtain the different types of Semaglutide-Insulin-Transferrin tablets/Capsules Type 1 (composition 1, 2, 3 and 4)

Method 1:

(i) granulate the Semaglutide, Insulin-Transferrin spray dried particles and excipients (with exception of Sodium Stearyl Fumarate) for each composition type using Polyvinylpyrrolidone granulation solution (5-15%wt/wt) .

(ii) dry the wet granulates in a fluid bed or oven at temperatures equal to or lower than 61 degrees centigrade to a loss on drying value of less than 10%.

(iii) pass the dry granules through a co-mill.

(iv) blend and then lubricate the dry granules with Sodium Stearyl Fumarate.

Method 2:

In an alternative method the 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.

Example 64. Semaglutide-Insulin-Transferrin Tablets/Capsules Type 2

Method:

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. 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.

Example 65. Semaglutide-Insulin-Transferrin Tablets/Capsules Type 3

Method:

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. Different concentrations of coating solution of 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.

Example 66. Semaglutide-Insulin-Transferrin Tablets/Capsules Type 4

Composition and preparation steps:

Step 1. Semaglutide-Insulin-Transferrin Loaded Spray Dried particles

Method:

Step 1a. Preparation of Diluent Suspension

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

(i) Gradually add the diluent suspension from step 1a into the Methacrylic acid –methyl methacrylate copolymer Solution while stirring.

(ii) Add Insulin while stirring and mix.

(iii) Gradually add Transferin.

(iv) Continue mixing until both are incorporated.

Note: Insulin and or Transferrin may be added at Step 1a or step 1b.

Step 1d. Preparation of Insulin-Transferrin Loaded Spray Dried Particles

Step 2. Preparation of Semaglutide-Insulin-Transferrin Granules and Tablets/Capsules Type 4

Carry out the following to obtain the different types of Semaglutide-Insulin-Transferrin tablets/Capsules Type 4 (composition 1, 2, 3 and 4)

Method 1:

(i) granulate the Semaglutide, Insulin-Transferrin loaded spray dried particles and excipients (with exception of Sodium Stearyl Fumarate) for each composition type using Polyvinylpyrrolidone granulation solution (5-15%wt/wt) .

(iii) pass the dry granules through a co-mill.

(iv) blend and then lubricate the dry granules with Sodium Stearyl Fumarate

Method 2:

In an alternative method the 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.

Example 67. Semaglutide-Insulin-Transferrin Tablets/Capsules Type 5

Method:

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.

Example 68. Semaglutide-Insulin Tablets/Capsules Type 6

Method:

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. Different concentrations of coating solution of 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.

Example 69. Semaglutide-Insulin-Transferrin Tablets/Capsules Type 7

Composition and preparation steps:

Step 1. Preparation of Insulin-Transferrin Loaded Spray Drying Feed Liquid

Method:

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.

Note: Insulin and or Transferrin may be added at Step 1b or Step 1c.

Step 2. Preparation of Insulin-Transferrin Particles

Step 3. Preparation of Semaglutide-Insulin-Transferrin Tablets/Capsules Type 7

Carry out the following to obtain the different types of Semaglutide-Insulin-Transferrin tablets/Capsules Type 7 (composition 1, 2, 3 and 4)

Method 1:

(i) Mix the excipients (with exception of Sodium Stearyl Fumarate) and the insulin-Transferrin spray dried granules and pass the mixture through a co-mill.

(ii) Blend the milled granules.

(iii) Lubricate the milled granules with Sodium Stearyl Fumarate.

(iv) Compress the lubricated granules into tablets or fill granules into capsules based on the potency of the blend and the dosage strength required.

Method 2:

In an alternative method:

(i) Mix and granulate the excipients (with exception of Sodium Stearyl Fumarate and the insulin-Transferrin spray dried granules) with polyvinyl pyrrolidone granulating liquid.

(ii) Dry the wet granules in a fluid bed or oven and pass the dried granules through a co-mill.

(iii) Blend the milled granules with the insulin-Transferrin spray dried granules.

(iv) Lubricate the blended granules with Sodium Stearyl Fumarate.

(v) Compress the lubricated granules into tablets or fill granules into capsules based on the potency of the blend and the dosage strength required.

Method 3:

Example 70. Semaglutide-Insulin-Transferrin Tablets/Capsules Type 8

Method:

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.

Example 71. Semaglutide-Insulin Tablets/Capsules Type 9

Method:

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 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.

Example 72. Insulin Tablets/Capsules Type 19

Composition and preparation steps:

Step 1. Preparation of Insulin Loaded Spray Drying Feed Liquid

Method:

(a) Add geranic acid to Ammonium bicarbonate while stirring followed by insulin and water and/or alcohol. Continue mixing.

(b) To water and or alcohol, add polyvinyl alcohol, Tween and/or polyethylene glycol, talc, followed by sodium citrate. Add Sodium 8- [ (2-hydroxybenzoyl) amino] octanoate and/or Sodium N- [10- (2-hydroxybenzoyl) amino] decanoate, silicone dioxide and dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane while stirring until no lumps is seen.

(c) Add the mixture from Step (a) to that from Step (b) while stirring vigorously. Continue stirring for greater than 10 minutes.

In the method, insulin also could be added at Step (b) or Step (c) .

Step 2: Preparation of Insulin Granules/Microspheres/Nanospheres

Step 3: Preparation of Insulin Tablets/Capsules Type 19

Carry out the following to obtain the different types of Insulin tablets/Capsules Type 19 (composition 1, 2, 3 and 4)

Method 1:

(a) Mix the excipients (with exception of Magnesium stearate) and the insulin spray dried granules and pass the mixture through a co-mill.

(b) Blend the milled granules.

(c) Lubricate the milled granules with Magnesium stearate,

Method 2:

In an alternative method:

(a) Mix and granulate the excipients (with exception Magnesium stearate and the insulin spray dried granules) with polyvinyl pyrrolidone granulating liquid.

(c) Blend the milled granules with the insulin spray dried granules.

(d) Lubricate the blended granules with Magnesium stearate.

Method 3:

In an alternative method the insulin spray dried granules, Crospovidone and or microcrystalline and or Magnesium stearate is incorporated during the blending and lubrication step.

Example 73. Insulin Tablets/Capsules Type 20

Method:

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.

Example 74. Insulin Tablets/Capsules Type 21

Method:

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 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.

Example 75. Semaglutide Tablets/Capsules

This was prepared as in example 72 except that Insulin is replaced with Semaglutide.

Example 76. Semaglutide Tablets/Capsules Type 19

This was prepared as in example 73 except that Insulin is replaced with Semaglutide.

Example 77. Semaglutide Tablets/Capsules Type 19

This was prepared as in example 74 except that Insulin is replaced with Semaglutide.

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.

Unlike compositions and processes known in the prior art, 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. The Figures support that the novel composition and process of the invention results in successful microencapsulation of API, and with no other peak or new peak observed in the microencapsulated sample, which confirms that the novel composition and process does not result in chemical interaction, but rather physical encapsulation/adsorption of the API. Furthermore, that microencapsulation of the API does not result in the occurrence of any new structure.

The onGPS platform (Placebo) and Insulin remain intact without any chemical reaction. The complete disappearance of the Insulin XRD peaks present at 2θ = 3.14° (2724) , 4.56° (2323) , 5.68° (2303) , 6.50° (2044) , 7.46° (3235) , 7.72° (2561) , 9.42° (3229) and 9.42° (3229) indicate that the composition and process result in the decrease in crystallinity and increase in amorphousity. So also, is the disappearance of the Insulin “hump” between 2θ = 19.0° and 2θ = 23.0 and the increase in diffraction peaks intensity of the microencapsulated Insulin.

No obvious characteristic peaks were observed in the XRPD spectra, indicating that Insulin was in an amorphous form in the microcapsules.

Figure 8, Figure 9A (from Example 72) , and Figure 9B (from Example 73) 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:

The theoretical expected potency was 8.06%and actual potency results are (average of 8.3%) shown in the following table. A loading efficiency of greater 100%and low %RSD was observed thereby supporting that the composition and process of the invention is capable of yielding very high drug loading with high consistency unlike what has been reported in the prior art. The results also confirm that the composition and process of the invention did not result in significant destruction or degradation of the Insulin API unlike other reported prior art composition and process.

Claims

A pharmaceutical composition comprising:

i) at least one poorly stable, poorly soluble, poorly permeable and or poorly bioavailable active pharmaceutical ingredient,

ii) at least one pH regulator,

iii) at least one penetration enhancer and or glycoprotein,

iv) dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane or related compounds,

v) optionally one or more enzyme inhibitor,

vi) at least one pharmaceutical excipient,

wherein when the composition or pharmaceutical product from the composition is exposed or dissolved or mixed with 1mL or more of acidic environment (pH 1-2) it alters the pH of the environment to greater than pH 2.
A pharmaceutical composition comprising:

i) at least one poorly stable, poorly soluble, poorly permeable and or poorly bioavailable active pharmaceutical ingredient,

ii) at least one pH regulator,

iii) at least one penetration enhancer and or glycoprotein,

iv) dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane or related compounds,

v) at least one pharmaceutical excipient,

wherein when the composition or pharmaceutical product from the composition is exposed or dissolved or mixed with 1mL or more of acidic environment (pH 1-2) it alters the pH of the environment to greater than pH 2.
A pharmaceutical composition comprising:

i) at least one poorly stable, poorly soluble, poorly permeable and or poorly bioavailable active pharmaceutical ingredient,

ii) at least one penetration and or absorption enhancer and or glycoprotein,

iii) dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane or related compounds,

iv) polyethylene glycol,

v) at least one pharmaceutical excipient.
The composition of claims 1, 2 and 3 wherein when the composition or pharmaceutical product from the composition is exposed or dissolved in water or gastric fluid medium, the contact angle and or surface tension is reduced.
The composition of claims 1, 2 and 3 wherein the pharmaceutical composition is a solid, semisolid, or liquid form.
The composition of claims 1, 2 and 3 wherein the poorly stable, poorly soluble, poorly permeable and or poorly bioavailable active pharmaceutical ingredient is a macromolecule and with or without a glycoprotein.
The composition of claims 1, 2 and 3 wherein the poorly stable, poorly soluble, poorly permeable and or poorly bioavailable active pharmaceutical ingredient is a small molecule and with or without a glycoprotein.
The composition of claims 1, 2 and 3 wherein the poorly stable, poorly soluble, poorly permeable and or poorly bioavailable active pharmaceutical ingredient is a peptide or hormone and with or without a glycoprotein.
The composition of claims 1, 2 and 3 wherein the poorly stable, poorly soluble, poorly permeable and or poorly bioavailable active pharmaceutical ingredient is a protein and with or without a glycoprotein.
The composition of claims 7, 8 and 9 wherein the small molecule, peptide, hormone or protein is one or more of biopharmaceutical classification system class III molecules or class IV, ipamorelin, hexarelin, examorelin, pralmorelin, sermorelin, acyline , somatostatin, encephalin, incretin mimetics, cyclosporine, insulin, glucagon-like-peptide 1 analogues, salmon calcitonin, octreotide, parathyroid hormone, LHRH analogues such as leuprolide, teragastrin, thyrotropin releasing hormone, phenyl alanine, glycine, teriparatide, human growth hormone, 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, buserelin, unfractionated heparin, low-molecular weight heparins, antisense oligonucleotides and vancomycin, bisphosphonates, acyline, amphotericin, camptothecin and gentamycin.
The composition of claims 1, 2 and 3 wherein said penetration enhancer is one or more of sorbitan esters, ethoxylated sorbitan esters, sodium dodecyl sulphate, sodium glycocholate, simethicone, dimethicone, silica, poly (dimethylsiloxane) , sodium caprate, sodium caprylate, salcaprozate sodium, chitosans, lectins, zonula occludens toxin, cell-penetrating peptides, bile salts, Na2EDTA, citric acid (sodium citrate) , lysine, histidine, glutamic acid, aspartic acid, salicylates, glycoprotein, transferrin, polyacrylates and n-lauryl-beta-D-maltopyranoside, copolymer of methyl acrylate with different acidic or alkaline end groups; copolymers of methyl acrylate; ethacrylic acid and methyl methacrylate; methyl methacrylate and methacrylic acid; methacrylic acid and ethyl acrylate copolymer; ethyacrylate methyl methacrylate; cationic copolymer based on dimethylaminoethyl methacrylate; butyl methacrylate, 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, sodium hydrogen carbonate (NaHCO₃) , barium chloride dehydrate (BaCl₂) , sodium sulfite (Na₂SO₃) , sodium sulfate (Na₂SO₄) , barium sulfate (BaSO₄) , barium sulfite (BaSO₃) , and barium carbonate (BaCO₃) , urea, choline, choline hydroxide, choline chloride, choline bicarbonate, geranic acid, choline geranate, stearic acid, propionic acid, linoleic acid, oleic acid, adipic acid, succinic acid, glutaric acid, 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 or their combinations.
The composition of claims 1, 2 and 3 wherein the active pharmaceutical ingredient (s) is selected from 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 or their combinations.
The composition of claim 12 wherein 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.
The composition of claims 1, 2 and 3 wherein the active pharmaceutical ingredient is derived from plant, animal, microorganisms or synthetic origin.
The composition of claims 1, 2 and 3 wherein when the composition is exposed to or dissolved or mixed with 1mL-5mL or more of acidic environment (pH 1-2) , it alters the pH of the environment to between pH 3 and pH 11.
The composition of claims 1, 2 and 3 wherein when the composition is exposed to or dissolved or mixed with 1mL-5mL or more of acidic environment (pH 1-2) , it alters the pH of the environment to greater than pH 6.8.
The composition of claims 1, 2 and 3 wherein when the enzyme inhibitor (s) is pepstatin, sodium glycocholate, soybean trypsin inhibitor, aprotinin, puromycin, N-acetylcysteine, sodium glycocholate, sodium tauroglycocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, sodium glycodihydrofusidate, camostat mesylate, bacitracin or combinations thereof.
The composition of claims 1 and 2 wherein the pH regulator is from the group consisting of sodium hydroxide, sodium silicate, magnesium hydroxide, magnesium trisilicate, aluminium hydroxide, magnesium oxide, calcium carbonate, sodium bicarbonate, sodium citrate, sodium carbonate, sodium acetate, magnesium carbonate, L-arginine, meglumine, N- (5-chlorosalicyloyl) -8-aminocaprylic acid (5-CNAC) , 4- ( [4-chloro-2-hydroxybenzoyl] -amino) butanoic acid (4-CNAB) , N- (8- [2-hydroxybenzoyl] -amino) caprylic acid, also known as salcaprozate sodium (SNAC) and or related compounds or combinations thereof.
The composition of claims 1 and 2 wherein the pH regulator is capable of modifying, controlling and/or adjusting the pH of the surrounding, external or interior environment of the gastrointestinal tract and or a dosage form typically by making the environment have or maintain a basic pH or increase the pH.
The composition of claims 1, 2 and 3 wherein said composition is in the form of powder, crystals, nanocapsules, nanoparticles, microcapsules, granules, tablets, beads, spheres, pellets, capsule, sachet, liquid, aerosol, gel or combinations thereof.
The composition of claim 1 wherein said composition contains at least one pharmaceutical excipients.
The composition of claim 21 wherein 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, glycoprotein, humectant, surface active agent, solubuliser, antioxidant, sweetening agent, flavouring agent, non-polar solvents, buffering agents, mucoadhesive agents, super disintegrant.
The composition of claim 20 wherein the dosage form is manufactured by a dry granulation or wet granulation of a homogeneous blend of the active pharmaceutical ingredient (s) and its carrier and pharmaceutical excipients.
The composition of claim 23 wherein the homogeneous blend is made in a process involving i) Preparing active pharmaceutical ingredient and its carrier by spray drying process (ii) dry granulating or wet granulating/drying of one or more excipients/penetration enhancers/enzyme inhibitors/pH regulators to yield homogenous granules with or without active pharmaceutical ingredient or its carrier and iii) blending the dry granulated granules with a lubricant magnesium stearate, stearic acid, and sodium stearyl fumarate or mixture thereof.
The composition of claim 23 wherein the homogeneous blend is made in a three-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 ii) passing the granules through a mill and iii) blending the dry granulated milled granules with a lubricant such as magnesium stearate, stearic acid, and sodium stearyl fumarate or mixture thereof.
The composition of claim 20 wherein the tablet is a multilayer tablet.
The composition of claim 26 wherein at least one layer contains the pH regulator or modifier.
The composition of claim 19 in which 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.
A tablet, bead, sphere, granule or capsule according to claims 1 and 2 wherein the pH regulator or modifier is coated onto it.
The composition of claims 1 and 2 wherein the pH regulator or modifier is less than 500 mg.
The composition of claims 1 and 2 wherein the pH regulator or modifier is less than 2000 mg.
The composition of claims 1 and 2 wherein the penetration enhancer or enzyme inhibitor is less than 750 mg.
The composition of claims 1 and 2 wherein the penetration enhancer or enzyme inhibitor is less than 1500 mg.
The composition of claims 1 and 2 wherein the glycoprotein is less than 1500 mg.
The composition of claims 1, 2 and 3 wherein the active pharmaceutical ingredient is less than 2000 mg.
The composition of claims 1, 2 and 3 in which silicone dioxide (silica) is present.
The composition of claims 1, 2 and 3 in which simethicone and or polydimethylsiloxane is present.
The composition of claims 1, 2 and 3 in which the active ingredient is an herbal medicine, Chinese herbal medicine, or Ayurvedic medicine.
The composition of claims 1, 2 and 3 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 β-cell proliferation.
The composition of claims 1, 2 and 3 used for cardio-and neuroprotective effects, decreasing inflammation and apoptosis, for treating depression, improving learning and memory.
The composition of claims 1, 2 and 3 used for improving transdermal or transmucosal permeability of active pharmaceutical ingredients via oral, nasal, buccal, ocular and pulmonary routes.
The composition of claims 1, 2 and 3 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.
The composition of claims 1, 2 and 3 containing protein stabilizers, anti-protein aggregation agents, glycoprotein, surfactants, chelating agents, Ethylenediamine Tetraacetate sodium (EDTA) , bile salts, polyvinyl alcohol, polyvinyl acetate, non-ionic, cationic and anionic polymers, cellulose esters, cellulose ethers, polyethylene glycols, thiomers, acylcarnitines, fatty acids and their derivatives.
The composition of claim 20 wherein said composition is in the form of powder, crystals, granules, beads, spheres, pellets, liquid or combinations thereof dispersed or embedded in a patch or tablet.
The composition of claim 44 wherein said composition the penetration enhancer is not located in the beads, spheres, or pellets, but dispersed in the tablet.
The composition of claims 1, 2 and 3 wherein when the composition or pharmaceutical product from the composition is 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.
The composition of claims 1, 2 and 3 wherein, the composition or pharmaceutical product imparts hydrophobicity to the surroundings, external or interior environment of the gastrointestinal tract and or dosage form and its constituents.
The composition of claims 1, 2 and 3 wherein, drug release targets the stomach.
The composition of claims 1, 2 and 3 wherein, drug release targets the duodenum.
The composition of claims 1, 2 and 3 wherein, drug release targets the mid-jejunum or jejunum.
The composition of claims 1, 2 and 3 wherein, drug release targets the small intestine or ileum.
The composition of claims 1, 2 and 3 wherein, drug release targets the large intestine.
The composition of claims 1, 2 and 3 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 of claims 1, 2 and 3 wherein, present is one or more of the following, glycoprotein, transferrin, 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 of claims 1, 2 and 3 wherein, present is one or more of the following: glycoprotein, transferrin, 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) , and barium carbonate (BaCO₃) or a combination or their derivatives.
The composition of claims 1, 2 and 3 wherein, present is one or more of the following, glycoprotein, transferrin, 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 methyl methacrylate; cationic copolymer based on dimethylaminoethyl methacrylate; Butyl methacrylate, 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 of claims 1, 2 and 3 wherein, sodium hydrogen carbonate (NaHCO3) , barium chloride dehydrate (BaCl2) , sodium sulfite (Na2SO3) , sodium sulfate (Na2SO4) , barium sulfate (BaSO4) , barium sulfite (BaSO3) , and barium carbonate (BaCO3) , 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 when present are less than 97%weight by weight.
The composition of claims 54, 55 and 56 wherein the manufacturing process include at least one of the following steps: emulsification, wet granulation, extrusion spheronization, encapsulation, tableting, hot melt extrusion, coating, drying, spray drying, freeze drying, 3-D printing and curing step.
The composition of claims 54, 55 and 56 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 β-cell proliferation.
A pharmaceutical composition according to claims 1, 2 and 3 wherein, present is one or more of the following, lysine, histidine, glutamic acid, aspartic acid, glycoprotein, transferrin, 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 methyl methacrylate; cationic copolymer based on dimethylaminoethyl methacrylate; butyl methacrylate, 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; 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, ethylacrylate methyl methacrylate, 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.
A pharmaceutical composition comprising:

i) at least one poorly stable, poorly soluble, poorly permeable and or poorly bioavailable active pharmaceutical ingredient,

ii) at least one penetration and or absorption enhancer and or glycoprotein and or pH modifier/stabilizer,

iii) at least dioxosilane; methoxy-dimethyl-trimethylsilyloxysilane and or polyethylene glycol or related compounds,

iv) at least one surface tension and or contact angle reducing agent.
A pharmaceutical composition according to claim 61 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-trimethylammonioethyl methacrylate chloride) ; cellulose esters; 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, ethylacrylate 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 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.
A pharmaceutical composition according to claims 61 wherein, present is one or more of the following, lysine, histidine, glutamic acid, aspartic acid, pepstatin, aprotinin, sodium glycocholate, soybean trypsin inhibitor, aprotinin, puromycin, N-acetylcysteine, sodium glycocholate, sodium tauroglycocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, sodium glycodihydrofusidate, camostat mesylate, bacitracin, 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- trimethylammonioethyl methacrylate chloride) ; copolymer of methyl acrylate with different acidic or alkaline end groups, cellulose esters; and or more of the following sodium hydrogen carbonate (NaHCO₃) , barium chloride dehydrate (BaCl₂) , sodium sulfite (Na₂SO₃) , sodium sulfate (Na₂SO₄) , barium sulfate (BaSO₄) , barium sulfite (BaSO₃) , barium carbonate (BaCO₃) , and 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, combinations or complexes with active pharmaceutical ingredients or excipients.
A pharmaceutical composition according to claim 62 wherein, present is one or more of the following, molecules that fall into the biopharmaceutical classification system describing class III molecules; peptides such as: insulin, glucagon-like-peptide 1 analogues, salmon calcitonin, octreotide, parathyroid hormone and LHRH analogues such as leuprolide; nonpeptide macromolecules with permeability issues such as unfractionated heparin, low-molecular weight heparins, antisense oligonucleotides and vancomycin; small molecules such as bisphosphonates, acyline, amphotericin, camptothecin and gentamycin.
A pharmaceutical composition according to claims 63 wherein, present is one or more of the following, molecules that fall into the biopharmaceutical classification system describing class III and IV molecules; peptides such as: insulin, glucagon-like-peptide 1 analogues, salmon calcitonin, octreotide, parathyroid hormone and LHRH analogues such as leuprolide; nonpeptide macromolecules with permeability issues such as unfractionated heparin, low-molecular weight heparins, antisense oligonucleotides and vancomycin; small molecules such as bisphosphonates, acyline, amphotericin, camptothecin and gentamycin.
A composition and method according to claims 1, 2 and 3 which involves drying, curing or heating steps/process at temperature below 61 Degrees centigrade.
A composition and method according to claims 62 and 63 which involves spray drying, drying, curing or heating steps/process at temperatures below 500 Degrees centigrade.
A composition and method according to claims 11, 58 and 63 wherein some or all of the penetration/solubility enhancer (s) or pH modifying agent (s) with or without active pharmaceutical ingredient (s) incorporated is used as a coating or granulating liquid or aid.
A composition and method which involves the following manufacturing steps, preparing an ionic liquid or deep eutectic solvent, incorporating an active pharmaceutical ingredient and optionally auxiliary excipients into the ionic liquid, using the ionic liquid or mixture containing active pharmaceutical ingredient as a granulation liquid to granulate penetration enhancers and or other pharmaceutical excipients, drying the wet granules between 20 and 80 degrees centigrade, optionally milling the granules, optionally blending and lubricating the granules, compressing the granules into tablets or encapsulating the granules into either hard gelatin capsules, soft gelatin capsules, HPMC capsules, pullulan capsules or other delivery device and optionally coating the tablets or capsules with pH sensitive coat or non pH sensitive coat or combination.
A composition and method which involves (a) incorporating a solution of the active pharmaceutical ingredient and optionally auxiliary excipients into sodium sulphate solution (b) adding this solution to barium chloride solution, (c) removing the sodium chloride formed in solution to a level less than 20% (d) Drying the Barium sulphate-active pharmaceutical ingredient complex particles formed at temperatures less than 61 degrees centigrade (e) optionally milling the Barium sulphate-active pharmaceutical ingredient complex particles (f) blending the milled granules with penetration enhancer (s) and or excipients and (g) optionally wet granulating and drying the blend at 20-61 degrees centigrade (h) optionally milling the granules (i) optionally blending and lubricating the granules (j) compressing the granules into tablets or encapsulating the granules into either hard gelatin capsules, soft gelatin capsules, HPMC capsules, pullulan capsules or other delivery device and (k) optionally coating the tablets or capsules with pH sensitive coat or non pH sensitive coat or combination.
A composition and method according to claims 60 and 70 in which the molar concentration of barium chloride dehydrate (BaCl₂) used is lower than that of Sodium Sulphate (Na₂SO₄) .
A composition and method which involves the following manufacturing steps, preparing an ionic liquid or deep eutectic solvent, incorporating an active pharmaceutical ingredient and optionally auxiliary excipients during the preparation or after the preparation of the ionic liquid, spray drying the ionic liquid or mixture containing active pharmaceutical ingredient (s) , incorporating the spray dried granules by a dry granulation or wet granulation process with penetration enhancers and or enzyme inhibitors and or other pharmaceutical excipients, drying the wet granules at less than 80 degrees centigrade, optionally milling the granules, optionally blending and lubricating the granules, compressing the granules into tablets or encapsulating the granules into either hard gelatin capsules, soft gelatin capsules, HPMC capsules, pullulan capsules or other delivery device and optionally coating the tablets or capsules with pH sensitive coat or non pH sensitive coat or a combination.
A composition and method which involves the following manufacturing steps, preparing an ionic liquid or deep eutectic solvent, incorporating an active pharmaceutical ingredient and optionally auxiliary excipients during the preparation or after the preparation of the ionic liquid, spray drying the ionic liquid or mixture containing the active pharmaceutical ingredient (s) , incorporating the spray dried granules with or without pharmaceutical excipients, into tablets or encapsulating the spray dried granules into either hard gelatin capsules, soft gelatin capsules, HPMC capsules, pullulan capsules or other delivery device and optionally coating the tablets or capsules with pH sensitive coat or non pH sensitive coat or a combination.
A composition and method which involves the following manufacturing steps, incorporating an active pharmaceutical ingredient and optionally auxiliary excipients during the preparation or after the preparation of Methacrylic acid -methyl methacrylate copolymer (s) and or Ammonio methacrylate copolymer (s) emulsion, suspension or dispersion, spray drying the emulsion, suspension or dispersion containing the active pharmaceutical ingredient (s) , incorporating the spray dried granules by a dry granulation or wet granulation process with penetration enhancers and or enzyme inhibitors and or other pharmaceutical excipients, drying the wet granules at less than 80 degrees centigrade, optionally milling the granules, optionally blending and lubricating the granules, compressing the granules into tablets or encapsulating the granules into either hard gelatin capsules, soft gelatin capsules, HPMC capsules, pullulan capsules or other delivery device and optionally coating the tablets or capsules with pH sensitive coat or non pH sensitive coat or a combination.
A composition and method which involves the following manufacturing steps, incorporating an active pharmaceutical ingredient and optionally auxiliary excipients during the preparation or after the preparation of Methacrylic acid -methyl methacrylate copolymer (s) and or Ammonio methacrylate copolymer (s) emulsion, suspension or dispersion, spray drying the emulsion, suspension or dispersion containing the active pharmaceutical ingredient (s) , incorporating the spray dried granules with or without pharmaceutical excipients, into tablets or encapsulating the spray dried granules into either hard gelatin capsules, soft gelatin capsules, HPMC capsules, pullulan capsules or other delivery device and optionally coating the tablets or capsules with pH sensitive coat or non pH sensitive coat or a combination.
A composition and method which involves the following manufacturing steps, incorporating an active pharmaceutical ingredient and optionally auxiliary excipients during the preparation or after the preparation of anionic copolymer (s) and or cationic copolymer (s) emulsion, suspension or dispersion, spray drying the emulsion, suspension or dispersion containing the active pharmaceutical ingredient (s) , incorporating the spray dried granules with or without pharmaceutical excipients, into tablets or encapsulating the spray dried granules into either hard gelatin capsules, soft gelatin capsules, HPMC capsules, pullulan capsules or other delivery device and optionally coating the tablets or capsules with pH sensitive coat or non pH sensitive coat or a combination.
A composition and method wherein active pharmaceutical ingredients loaded particles are made by spray drying process using ionic liquids as a spray drying feed medium.
A 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.
A 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.
A composition and method according to claims 77, 78 and 79 wherein active the pharmaceutical ingredients are macromolecules such as proteins, peptides, hormones, their derivatives or combinations.
A composition and method according to claim 80 which contains 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.
A composition and method according to claim 42 wherein the API becomes more amorphous than crystalline or becomes completely amorphous or yield an amorphous form in the microcapsules or microspheres.