DESC:STABLE AND BIOAVAILABLE PHARMACEUTICAL FORMULATIONS OF SEMAGLUTIDE
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FIELD OF THE INVENTION
The present invention relates to stable pharmaceutical formulations useful for the oral administration comprising Semaglutide and one or more permeation enhancers, along with pharmaceutically acceptable excipients and process for the preparation thereof. The oral administration of the formulations of the present invention can be used for the treatment of type 2 diabetes or obesity as well as a variety of other conditions.

BACKGROUND OF THE INVENTION
Oral administration of proteins and peptides is extremely difficult due to the nature of the digestive system, which is designed to break down polypeptides into amino acids before absorption. The low bioavailability of drugs is still an active area of research, and researchers have investigated several places in the gastrointestinal tract, but an important breakthrough that would be widely applicable to various proteins and peptides has not been achieved.

Semaglutide is a recombinant long acting GLP-1 receptor agonist. The theoretical relative monoisotopic molecular mass of Semaglutide is 4111.115 and the theoretical average molecular weight is 4113.58 g/mol. Semaglutide is structurally represented as:

Semaglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Currently, Semaglutide (3 mg, 7 mg, and 14 mg) is marketed under the brand name “RYBELSUS” in the United States by Novo Nordisk Inc. and is supplied as tablets for oral administration.

U.S. Patent No. 8,129,343 of discloses Semaglutide specifically and their formulation and/or method of use.

U.S. Patent No. 10,933,120 discloses formulation comprising first type of granules comprising sodium N-(8-(2-hydroxybenzoyl) amino) caprylic acid (SNAC) at least 75% (w/w) and no GLP-1 peptide and second type of granules comprising GLP-1 peptide, i.e., Semaglutide and no SNAC.
PCT Publication No. 2010/020978 discloses an oral pharmaceutical formulation comprising a protein, a protease inhibitor, and an absorption enhancer such as N-(8-[2-hydroxybenzoyl) amino) caprylate.

U.S. Patent No. 11,389,474 discloses formulation of at least one peptide; and a pharmaceutically acceptable amount of a combination of: (a) at least one metal in form of any or a combination of a salt thereof and a complex thereof; (b) at least one reducing agent; and c) an absorption enhancer.

U.S. Patent Application Publication No. 2023/0053812 discloses stable pharmaceutical formulation comprising peptide or protein drug and permeation enhancers other than sodium N-(8-(2-hydroxybenzoyl) amino) caprylate (SNAC).

Several attempts have been made in the prior art to provide optimal, stable, and bioavailable oral dosage form of Semaglutide. The aforementioned references disclose formulations of Semaglutide using high amounts of Salcaprozate, i.e., N-(8-(2-hydroxybenzoyl) amino) caprylate (NAC) and their sodium salt (SNAC) to enhance the oral bioavailability of semaglutide. However, Salcaprozate and its sodium salt is hygroscopic and has tendency of increasing water content of the final formulation during the storage which may lead to reduced shelf life. Further, manufacturing of Salcaprozate and its sodium salt is a very complex process and the use of high amounts of Salcaprozate and its sodium salt adds to the cost of final drug product. Hence, there still exists a need for developing more stable oral formulations of Semaglutide that are commercially viable and easy to manufacture. The inventors of the present invention after extensive experimentation have developed stable and bioavailable formulations of Semaglutide that is useful for oral administration using lesser amount or no Salcaprozate and its sodium salt. Further, the inventors of the present invention have also found that the excipients and the process of preparation used in the present invention stabilizes the formulation, provide rapid drug release, bioavailability, and alleviates the limitations in the art by providing commercially viable Semaglutide oral formulations with less degradation.

OBJECTIVE OF THE INVENTION
The Principal objective of the present invention is to provide a stable pharmaceutical formulation for oral administration having semaglutide and one or more permeation enhancers.

Another objective of the present invention is to provide a stable pharmaceutical formulation for oral administration having semaglutide and sodium caprylate as a permeation enhancer along with pharmaceutically acceptable excipients.
Another objective of the present invention is to provide an oral composition of semaglutide, one or more permeation enhancer and one or more pharmaceutically acceptable excipients; wherein the composition is used in the treatment of diabetes and obesity.

Another objective of the present invention is to provide a process for the preparation of the stable and bioavailable pharmaceutical formulation.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a stable pharmaceutical formulation for oral administration comprising Semaglutide and one or more permeation enhancers.

In one aspect, the present invention provides a stable and bioavailable pharmaceutical formulation for oral administration comprising semaglutide, one or more permeation enhancers, and one or more pharmaceutically acceptable excipients.

In another aspect, the present invention provides a stable pharmaceutical formulation for oral administration comprising semaglutide, one or more permeation enhancers selected from the group consisting of sodium caprate, sodium caprylate, carbomer, labrasol, fatty acids or their salts or their derivatives, monoglycerides, diglycerides, or triglycerides, amino acids, or a combination thereof, and one or more pharmaceutically acceptable excipients selected from the group consisting of diluent(s), disintegrant(s), binder(s), lubricant(s), glidant(s), pH modifier(s), surfactant(s), and anti-oxidant(s), or a combination thereof.

In another aspect, the present invention provides a stable pharmaceutical formulation comprising Semaglutide, salt of N-(8-(2-hydroxybenzoyl) amino) caprylate (NAC), and one or more other permeation enhancers.

In another aspect, the present invention provides a stable pharmaceutical formulation for oral administration comprising semaglutide, sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC) in an amount of 0.1 % w/w to 40% w/w based on the weight of pharmaceutical formulation; one or more permeation enhancers selected from the group consisting of sodium caprate, sodium caprylate, carbomer, labrasol, fatty acids, surfactants or their salts or their derivatives, monoglycerides, diglycerides, or triglycerides, amino acids, or a combination thereof, and one or more pharmaceutically acceptable excipients selected from the group consisting of diluent(s), disintegrant(s), binder(s), lubricant(s), pH modifier(s), and anti-oxidant(s), or a combination thereof.
The present invention further relates to a process for preparation of a stable pharmaceutical formulation of Semaglutide for oral administration, wherein the process comprises wet granulation (including reverse wet granulation), direct compression, dry granulation (roller compaction or slugging), or melt granulation.

The present invention further relates to a process for preparation of a stable pharmaceutical formulation of Semaglutide for oral administration, wherein the process comprises: (a) preparing blend or granules of Semaglutide, one or more permeation enhancers, and optionally one or more pharmaceutically acceptable excipients; (b) compressing the blend or granules to form tablets or filling the granules in capsules.

The present invention further relates to a process for preparation of a stable pharmaceutical formulation of Semaglutide for oral administration, wherein the process comprises: (a) preparing blend or granules of Semaglutide, and one or more pharmaceutically acceptable excipients; (b) adding one or more permeation enhancers to the blend or granules to obtain a final blend; c) compressing the final blend to form tablets or filling the granules in capsules.

In another aspect, the present invention provides a method for the treatment of NASH, NAFLD, diabetes or obesity comprising administering the formulations as defined herein to a patient in need thereof, wherein said formulation is administered orally.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a stable pharmaceutical formulation for oral administration comprising Semaglutide and one or more permeation enhancers.

As used in this specification, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to “a method” or “a process” includes one or more methods, one or more processes and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

The term “Semaglutide” or “Active Ingredient” herein refers to a pharmaceutically active molecule as well as its pharmaceutically acceptable and therapeutically active salts, esters, amides, prodrugs, metabolites, enantiomers, polymorphs, analogues, etc. that induce a desired pharmacological or physiological effect. Terms like “active”, “active agent”, and “active substance” may be used synonymously for “active ingredient” and/or “Semaglutide”.

As used herein the term “about” in reference to a numerical value means that variations of 10% above or below the numerical value are within the range as described to the specified value.

The term “salt” is used interchangeably in the context of the present invention. “salts” as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt, carbonate salts; organic acids such as succinic acid, formic acids, acetic acid, diphenyl acetic acid, palmoic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid and the like. The inorganic salts may further includes alkali metal and alkaline earth metal salts such as sodium, potassium, barium, lithium, calcium, magnesium, rhodium, zinc, cesium, selenium, and the like.

The term “formulation” or “solid oral formulation” or “dosage form” or “pharmaceutical formulation” or “formulation” as used herein synonymously include tablets such mono-layered tablets, bi-layered tablets, trilayered tablets, multilayer tablets, caplets, minitablets, capsules, tablet in tablet, tablets in a capsule, granules in a capsule, pellets, pellets in a capsule, powder, granules, suspension or any other suitable dosage form meant for oral administration. The pharmaceutical formulation includes immediate release, fast release, orally disintegrating, extended release, modified release, delayed release, pulsed release formulations and the like. The formulation may further be compounded in a drug carrier or drug delivery system, e.g. in order to improve stability and/or solubility or further improve bioavailability. The formulation may be a freeze-dried or spray-dried formulation.

The term “stable” according to present invention refers to a pharmaceutical formulation comprising Semaglutide in which the amount of impurity(ies) remains below FDA/ICH acceptable intake limit after exposure of the pharmaceutical formulation to 40 °C ± 5 °C /75% ± 5% RH for a period of six months or 25 °C ± 5 °C /60% ± 5% RH for a period of at least 12 months.
The term “comprising” means that the various components ingredients, or steps, conjointly employed in practicing the present invention. Accordingly, the term “comprising” encompasses the more restrictive terms “consisting essentially of” and “consisting of”.

The terms “FDA acceptable intake limit” of impurity(ies) as used in the present invention is the upper limit set by FDA for daily intake of impurity(ies) below which there is no harmful side-effect likely to occur on long term treatment with the therapeutically active agent.

The term “bioavailability” as used herein refers to the fraction of an administered dose of an active pharmaceutical ingredient (API) and/or active moieties, such as a semaglutide as defined herein, which reaches the systemic circulation unchanged or in another active form. By definition, when an API and/or active moieties are administered intravenously, their bioavailability is 100%. However, when it is administered via other routes (such as orally), their bioavailability decreases (due to incomplete absorption and/or first-pass metabolism). Absolute oral bioavailability is calculated as the relative exposure of the API and/or active moieties in systemic circulation following oral administration (estimated as the area under the plasma concentration versus time curve) compared to the exposure of the API following intravenous administration.

The term “permeation enhancer” refers to an agent whose function is to increase absorption by enhancing membrane permeation. The administration of an absorption enhancer improves or facilitates the mucosal absorption of the Semaglutide in the gastrointestinal tract and is advantageous particularly if the drug is a large molecule, e.g., a peptide drug having a molecular weight of about 1 kDa or more. The absorption enhancer may be, e.g., a zwitter-ionic absorption enhancer, a cationic absorption enhancer, an anionic absorption enhancer (e.g., an anionic absorption enhancer comprising one or more sulfonic acid groups (-S03H)), or a non-ionic absorption enhancer, particularly a zwitter-ionic absorption enhancer or a non-ionic absorption enhancer. It is preferred that the absorption enhancer is selected from C8-20 alkanoyl carnitine (preferably lauroyl carnitine, myristoyl carnitine or palmitoyl carnitine; e.g., lauroyl carnitine chloride, myristoyl carnitine chloride or palmitoyl carnitine chloride), salicylic acid (preferably a salicylate, e.g., sodium salicylate), a salicylic acid derivative (such as, e.g., 3-methoxysalicylic acid, 5-methoxysalicylic acid, or homovanillic acid, a C8-20 alkanoic acid (preferably a C8.20 alkanoate, more preferably a caprate, a caprylate, a myristate, a palmitate, or a stearate, such as, e.g., sodium caprate, sodium caprylate, sodium myristate, sodium palmitate, or sodium stearate), citric acid (preferably a citrate, e.g., sodium citrate), tartaric acid (preferably a tartrate), a fatty acid acylated amino acid (e.g., any of the fatty acid acylated amino acids described in US 2014/0056953 A1 which is incorporated herein by reference, including, without being limited thereto, sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartic acid, N-dodecanoyl-L- aspartic acid, sodium lauroyl cysteinate, N-dodecanoyl-L-cysteine, sodium lauroyl glutamic acid, N-dodecanoyl-L-glutamic acid, sodium lauroyl glutaminate, N-dodecanoyl-L-glutamine, sodium lauroyl glycinate, N-dodecanoyl-L-glycine, sodium lauroyl histidinate, N-dodecanoyl-L- histidine, sodium lauroyl isoleucinate, N-dodecanoyl-L-isoleucine, sodium lauroyl leucinate, N-dodecanoyl-L-leucine, sodium lauroyl methioninate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyl prolinate, N-dodecanoyl-L-proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, sodium lauroyl threoninate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L- tryptophane, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, sodium lauroyl sarcosinate, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-alanine, sodium capric asparaginate, N-decanoyl-L-asparagine, sodium capric aspartic acid, N-decanoyl-L-aspartic acid, sodium capric cysteinate, N-decanoyl- L-cysteine, sodium capric glutamic acid, N-decanoyl-L-glutamic acid, sodium capric glutaminate, N-decanoyl-L-glutamine, sodium capric glycinate, N-decanoyl-L-glycine, sodium caphc histidinate, N-decanoyl-L-histidine, sodium capric isoleucinate, N-decanoyl-L-isoleucine, sodium capric leucinate, N-decanoyl-L-leucine, sodium capric methioninate, N-decanoyl-L- methionine, sodium capric phenylalaninate, N-decanoyl-L-phenylalanine, sodium capric prolinate, N-decanoyl-L-proline, sodium capric serinate, N-decanoyl-L-serine, sodium capric threoninate, N-decanoyl-L-threonine, sodium capric tryptophanate, N-decanoyl-L-tryptophane, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, N-decanoyl-L-sarcosine, sodium oleoyl sarcosinate, sodium N-decylleucine, sodium stearoyl glutamate (e.g., Amisoft HS-11 P), sodium myristoyl glutamate (e.g., Amisoft MS-11), sodium lauroyl glutamate (e.g., Amisoft LS-11), sodium cocoyi glutamate (e.g., Amisoft CS-11), sodium cocoyi glycinate (e.g., Amilite GCS-11), sodium N-decyl leucine, sodium glycine, sodium glutamate, sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteinate, N-dodecanoyl-L-cysteine, sodium lauroyl glutamic acid, N-dodecanoyl-L-glutamic acid, sodium lauroyl glutaminate, N-dodecanoyl-L-glutamine, sodium lauroyl glycinate, N-dodecanoyl-L- glycine, sodium lauroyl histidinate, N-dodecanoyl-L-histidine, sodium lauroyl isoleucinate, N-dodecanoyl-L-isoleucine, sodium lauroyl leucinate, N-dodecanoyl-L-leucine, sodium lauroyl methinoninate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L- phenylalanine, sodium lauroyl prolinate, N-dodecanoyl-L-proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, sodium lauroyl threoninate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophane, sodium lauroyl tyrosinate, N-dodecanoyl-L- tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-alanine, sodium capric asparaginate, N-decanoyl-L-asparagine, sodium capric aspartic acid, N-decanoyl-L-aspartic acid, Sodium capric cysteinate, N-decanoyl-L-cysteine, sodium capric glutamic acid, N-decanoyl-L-glutamic acid, sodium capric glutaminate, N-decanoyl-L-glutamine, sodium capric glycinate, N-decanoyl-L-glycine, sodium capric histidinate, N-decanoyl-L-histidine, sodium capric isoleucinate, N-decanoyl-L- isoleucine, sodium capric leucinate, N-decanoyl-L-leucine, sodium capric methioninate, N-decanoyl-L-methionine, sodium capric phenylalaninate, N-decanoyl-L-phenylalanine, sodium capric prolinate, N-decanoyl-L-proline, sodium capric serinate, N-decanoyl-L-serine, sodium capric threoninate, N-decanoyl-L-threonine, sodium capric tryptophanate, N-decanoyl-L- tryptophane, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, sodium oleoyl sarcosinate, and pharmaceutically acceptable salts of any of the aforementioned compounds; or, e.g., C8-20 alkanoyl sarcosinate (e.g., a lauroyl sarcosinate, such as sodium lauroyl sarcosinate) or one of the standard proteinogenic amino acids that is acylated with a C8-20 alkanoic acid), an alkylsaccharide (e.g., alkylpolysaccharide like Multitrope™ 1620-LQ-(MV); or, e.g., n-octyl-beta-D-glucopyranoside, n-dodecyl-beta-D- maltoside, n-tetradecyl-beta-D-maltoside, tridecyl-beta-D-maltoside, sucrose laurate, sucrose myristate, sucrose palmitate, sucrose cocoate, sucrose mono-dodecanoate, sucrose mono- tridecanoate, sucrose mono-tetradecanoate, a coco-glucoside, or any of the alkylsaccharides described in US 5,661,130 or in WO 2012/112319 which are herein incorporated by reference), a cyclodextrine (e.g., a-cyclodextrin, ß-cyclodextrin, ?-cyclodextrin, methyl-ß- cyclodextrin, hydroxypropyl ß-cyclodextrin, or sulfobutylether ß-cyclodextrin), N-[8-(2- hydroxybenzoyl)amino]caprylic acid (preferably a N-[8-(2-hydroxybenzoyl)amino]caprylate, more preferably sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, also referred to as “SNAC”), a N-[8-(2-hydroxybenzoyl)amino]caprylate derivative (preferably a sodium N-[8-(2- hydroxybenzoyl)amino]caprylate derivative), a thiomer (also referred to as a thiolated polymer; may be synthesized, e.g., by immobilization of sulfhydryl bearing ligands on a polymeric backbone of well-established polymers such as, e.g., polyacrylic acid, carboxymethylcellulose or chitosan; exemplary thiomers include the thiomers that are described in Laffleur F et al., Future Med Chem. 2012, 4(17):2205-16 (which is incorporated herein by reference), a mucoadhesive polymer having a vitamin B partial structure (e.g., any of the mucoadhesive polymers described in US 8,980,238 B2 which is incorporated herein by reference; including, in particular, any of the polymeric compounds as defined in any one of claims 1 to 3 of US 8,980,238 B2), a calcium chelating compound (e.g., ethylenediaminetetraacetic acid (EDTA), ethylene glycol tetraacetic acid (EGTA), sodium citrate, or polyacrylic acid), cremophor EL (also referred to as “Kolliphor EL”), chitosan, ?, ?, ?-trimethyl chitosan, benzalkonium chloride, bestatin, cetylpyridinium chloride, cetyltrimethylammonium bromide, a C2.20 alkanol (e.g., ethanol, decanol, lauryl alcohol, myristyl alcohol, or palmityl alcohol), a C8-20 alkenol (e.g., oleyl alcohol), a C8.20 alkenoic acid (e.g., oleic acid), dextran sulfate, diethyleneglycol monoethyl ether (transcutol), 1-dodecylazacyclo-heptan-2-one (Azone®), caprylocaproyl polyoxylglycerides (such as, e.g., caprylocaproyl polyoxyglycerides; available, e.g., as Labrasol® or ACCONON® MC8-2, Kolliphor P188), ethyl caprylate, glyceryl monolaurate, lysophosphatidylchoiine, menthol, a C8.20 alkylamine, a C8-20 alkenylamine (e.g., oleylamine), phosphatidylcholine, a poloxamer, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, a polysorbate (e.g., polysorbate 20 or polysorbate 80), cholic acid (preferably a cholate, e.g., sodium chlolate), a deoxycholate (e.g., sodium deoxycholate), sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate (SDS), sodium decyl sulfate, sodium octyl sulfate, sodium laureth sulfate, N-lauryl sarcosinate, decyltrimethyl ammonium bromide, benzyldimethyl dodecyl ammonium chloride, myristyltrimethyl ammonium chloride, dodecyl pyridinium chloride, decyldimethyl ammonio propane sulfonate, myristyldimethyl ammonio propane sulfonate, palmityldimethyl ammonio propane sulfonate, ChemBetaine CAS, ChemBetaine Oleyl, Nonylphenoxypolyoxyethylene, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, sorbitan monooleate, Triton X-100, hexanoic acid, heptanoic acid, methyl laurate, isopropyl myristate, isopropyl palmitate, methyl palmitate, diethyl sebaccate, sodium oleate, urea, lauryl amine, caprolactam, methyl pyrrolidone, octyl pyrrolidone, methyl piperazine, phenyl piperazine, Carbopol 934P, glyccyrhetinic acid, bromelain, pinene oxide, limonene, cineole, octyl dodecanol, fenchone, menthone, trimethoxy propylene methyl benzene, a cell-penetrating peptide (e.g., klaklak, polyarginine (particularly octa-arginine), penetratin (particularly L-penetratin), a penetratin analog (particularly PenetraMax; see, e.g., El-Sayed Khafagy et a!., Eur J Pharm Biopharm. 2013; 85(3 Pt A):736-43), HIV-1 Tat, transportan, or any of the cell-penetrating peptides referred to in US 2012/0065124), macrogol- 15-hydroxystearate (e.g., Solutol HS 15), CriticalSorb (see., e.g., Ilium L et al. J Control Release. 2012; 162(1): 194-200), a taurocholate (e.g., sodium taurocholate), a taurodeoxycholate (e.g., sodium taurodeoxycholate), a sulfoxide (e.g., a (C1-20 alkyl)-(C1-20 alkyl)-sulfoxide, such as, e.g., decyl methyl sulfoxide, or dimethyl sulfoxide), cyclopentadecalactone, 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid (also referred to as “5-CNAC”), N-(10-[2-hydroxybenzoyl]amino)decanoic acid (also referred to as “SNAD”), dodecyl-2-N,N-dimethylamino propionate (also referred to as “DDAIP”), D-a-tocopheryl polyethylene glycol-1000 succinate (also referred to as “TPGS”), and pharmaceutically acceptable salts of the aforementioned compounds. Mixtures of two or more absorption enhancers, including any of the above-described absorption enhancers, can also be used.

The term “excipient” or “pharmaceutically acceptable excipients” means a pharmacologically inactive component such as a diluent/filler, binder, disintegrant, glidant, surfactant, pH modifier, anti-oxidant, preservative, lubricant, flavoring agent, plasticizer, colorant, opacifier, carrier, release modifying polymers and like, of a pharmaceutical product. The excipients may also include excipients for providing fast release, immediate release, extended release, delayed release, pulsed release, orally disintegration and the like. The excipients that are useful in preparing a dosage form are generally safe, non-toxic, and acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one excipient and more than one excipient.

Suitable diluents/fillers include, without limitation, microcrystalline cellulose, silicified microcrystalline cellulose, sugar alcohol selected from but not limited to alditols, polyols, mannitol, meglumine, xylitol, isomalt, sorbitol, lactitol, pentitol, arabitol, ribitol, galactitol, erythritol, glycerol, and the like, Carbohydrate selected from but not limited to monosaccharides, oligosaccharides, polysaccharides, dextrins, maltodextrin, pullulan, arabinose, dextrose, dextrates, lactose, lactose monohydrate, sucrose, sucralose, saccharin, fructose, maltose, trehalose, psicose, tagatose, sorbose, cellulose derivatives, cellobiose, starches, modified starches, sucrose fatty acid esters, and the like, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, kaolin, calcium sulfate, Crospovidone XL, and combinations thereof. When present, a filler may be employed in an amount ranging from about 1% to about 80% by weight of the pharmaceutical formulation. Preferably, a filler may be employed in an amount of ranging from about 10% to 70% by weight of the pharmaceutical formulation. More preferably, a filler may be employed in an amount of ranging from about 20% to 60% by weight of the pharmaceutical formulation.

Suitable binders include, without limitation, isopropyl alcohol, polyvinylpyrrolidone (PVP), e.g., PVP K 30 or PVP K90, polyethylene glycols (PEG), e.g., PEG 4000, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, both preferably of medium to high viscosity, e.g. viscosity grades 3 or 6 cps, copovidone, maltodextrins, pregelatinized starch, cellulose and their derivatives including microcrystalline cellulose, acacia, alginic acid, tragacanth, gelatin, liquid glucose; starch and their derivatives including corn starch; hydrocolloids; sugars; ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, and hydroxyethyl cellulose, carboxymethyl cellulose, sodium alginate, used either alone or combinations. When present, a binder may be employed in an amount ranging from about 0.1% to about 20%, by weight of the pharmaceutical formulation. More preferably, a binder may be employed in an amount ranging from about 1% to 10%, by weight of the pharmaceutical formulation.

Suitable disintegrants include, without limitation, cellulose and their derivatives including low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone, starch and modified starches such as corn starch, cross-linked sodium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium starch glycolate, crosslinked CMC (Ac-Di-Sol), Sodium carboxymethyl starch ion-exchange resins, formalin-casein, used either alone or combinations thereof. When present, a disintegrant may be employed in an amount ranging from about 0.1% to about 20%, by weight of the pharmaceutical formulation. More preferably, a disintegrant may be employed in an amount ranging from about 1% to 10%, by weight of the pharmaceutical formulation.

Suitable lubricants include, without limitation, zinc stearate, magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, colloidal silica, sodium lauryl sulfate, aluminum or calcium silicate, stearic acid, cutina, PEG 4000-8000, talc and combinations thereof. When present, a lubricant may be employed in an amount ranging from about 0.01% to about 10%, preferably from about 0.1% to about 5%, by weight of the pharmaceutical formulation,

Suitable glidants include, without limitation, colloidal silicon dioxide (e.g., Aerosil 200), magnesium trisilicate, powdered cellulose, starch, talc and combinations thereof. When present, a glidant may be employed in an amount ranging from about 0.01% to about 10%, preferably from about 0.1% to about 5%, by weight of the pharmaceutical formulation.

Suitable pH modifiers/ regulator include, without limitation, an acid selected from an organic or inorganic acid such as ascorbic acid, fumaric acid, citric acid, malic acid, succinic acid, adipic acid, maleic acid, lactic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, and the like or a base selected from organic bases such as pyridine, alkanamines, such as methylamine, diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, pyridine, imidazole, histidine, guanidine, poly ethyleneimine, poly(vinylpyridine), diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane (Tris), sodium glycine, imidazole, 1-methylimidazole, 2-methylimidazole, and 4(5)-methylimidazole, and 1,2-diaminoethane, 2-(bis(2-hydroxyethyl)amino)-2-(hydroxymethyl)propane-1,3-diol, sodium lysine, sodium histidine, and sodium arginine, polyvinyl imidazole, and copolymers thereof (e.g., a copolymer of poly ethyleneimine and one or more of poly(vinylpyridine) and polyvinylimidazole, or a copolymer of poly(vinylpyridine) with polyvinyl imidazole) or inorganic bases such as sodium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, magnesium oxide, sodium citrate, sodium hydroxide, potassium hydroxide, ammonium salts, salcaprazoic acid , and the like. When present, a pH modifier may be employed in an amount ranging from about 10% to about 50%, preferably from about 20% to about 40%, by weight of the pharmaceutical formulation.

Suitable antioxidants include, without limitation, ascorbic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, citric acid, malic acid, lactic acid, benzenesulfonic acid, oxalic acid, triphenylacetic acid, 1-hydroxy-2-naphthoic acid, 3-hydroxy-2-naphthoic acid, sodium ascorbate, alpha-tocopherol, butylated hydroxytoluene, butylated hydroxyanisole, gentisic acid (2,5-dihydroxy benzoic acid), acetyl cysteine, ascorbyl palmitate, cysteine, dithiothreitol, thioglycerol, thiourea, caffeic acid, propyl gallate, ferulic acid, sodium pyrosulfite, edetic acid, edetate salts, 2, 6-di-tert-butyl p-cresol, gallic acid and esters thereof, nordihydroguaiaretic acid, guaiacol ester, tea polyphenol, curcumin, chlorogenic acid, methionine, proline, biflavonoids, superoxide dismutase, silymarin, grape skin/seed extract, melanin, rosemary extract, sodium sulfite, sodium thiosulfate, sodium bisulfite, sodium metabisulfite, tert-butylhydroquinone, thiourea, methionine, sodium citrate, magnesium ascorbyl phosphate, sodium ascorbyl phosphate, 3,4-dihydroxybenzoic acid, butylated hydroxybenzoic acid and salts thereof, erythorbic acid and sodium salts thereof, sorbic acid and salts thereof, sodium formaldehyde sulfoxylate, glutathione, lipoic acid, dihydroxy fumaric acid, and the like.

The surfactants include, without limitation, anionic, cationic, non-ionic or amphoteric surfactants or those known to the person skilled in the art. Suitable surface active include, without limitation, sodium docusate, sodium lauryl sulfate, sodium stearyl fumarate, Tweens® and Spans (PEO modified sorbitan monoesters and fatty acid sorbitan esters), polyoxyethylene polypropyleneglycol, such as poloxamer® 124, poloxamer® 188, poloxamer® 237, poloxamer® 388, poloxamer® 407, polyoxyethylene castor oil derivatives, polyoxyethylene alkyl ethers, polyoxyethylene alkylaryl ethers, polyethylene glycol fatty acid esters poly(ethylene oxide)-polypropylene oxide-poly(ethylene oxide) block copolymers (Pluronics); complexing agents such as low molecular weight polyvinyl pyrrolidone and low molecular weight hydroxypropyl methylcellulose; molecules that aid solubility by molecular entrapment such as cyclodextrins. When present, a surfactant may be employed in an amount ranging from about 1% to about 20%, preferably from about 5% to about 15%, by weight of the pharmaceutical formulation.

Suitable preservatives include, without limitation, benzyl alcohol, parabens (methyl, propyl, butyl), benzalkonium chloride, chlorobutanol, and thiomersal.

Suitable extended release or delayed release excipients include, without limitation, hydrophilic or hydrophobic agents comprise one or more of polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, a fatty acid, a fatty acid ester, an alkyl alcohol, a wax, xanthan gum, gellan gum, shellac, rosin, zein (prolamine from corn), povidone, kollidon SR (polyvinyl acetate and povidone), a poly(meth)acrylate, poly(ethylene oxide), polyuronic acid salts, cellulose ethers, xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan gum locust bean gum, alkali metal salts of alginic acid or pectic acid, sodium alginate, potassium alginate, ammonium alginate, polyethylene oxide, carbomer homopolymer, hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxypropyl methyl cellulose, carboxyvinyl polymers, polymerized gelatin, shellac, methacrylic acid copolymer type C NF, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate, hydrogenated castor oil, stearic acid, hydrogenated vegetable oil, glyceryl behenate, glyceryl monostearate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and acrylic acid polymers and copolymers like methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate with copolymers of acrylic and methacrylic acid esters (Eudragit NE, Eudragit RL, Eudragit RS) and the like. Polymer may be used from 0.1- 50% by weight of the formulation, preferably 10-50% by weight of the formulation.

Suitable coating agents according to present invention may be selected from immediate release, extended release, or delayed release coatings but not limited to, Shellac, cellulose acetate phthalate (CAP), polyvinylacetate phthalate (PVAP), hyroxylpropyl cellulose, hyroxypropyl methylcellulose (HPMC), acrylates, phthalates, and Zein (a corn protein derivative), Hydroxyproply methyl cellulose, Methyl hydroxyethyl cellulose, Ethylcellulose, Povidone, Opadry, and the like. When present, a coating agent or immediate release, extended release or delayed release may be employed in an amount ranging from about 1% to about 20%, preferably from about 5% to about 15%, by weight of the pharmaceutical formulation.

In an embodiments, the invention relates to a formulations comprising a Semaglutide, sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC), and other one or more permeation enhancers comprising, soybean lecithin, arginine, (8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylate), (N-(4-chlorosalicyloyl)-4-aminobutyrate), lysine, phenyl alanine, tryptophan, sodium caprylate, sodium caprate, capsaicin analog, i.e., 10-Hydroxy-N-[(4-hydroxy-3-methoxyphenyl)methyl]decanamide, carbomer, sodium laurate, sodium chenodeoxycholate, propyl gallate, dodecyl maltoside, tridecyl maltoside, tetradecyl maltoside, sucrose mono-dodecanoate, sucrose mono-tridecanoate, sucrose mono-tetradecanoate, sodium dodecyl sulfate, sodium hexanoate, sodium heptanoate, sodium octanoate, sodium nonanoate, sodium decanoate, sodium undecanoate, sodium dodecanoate, sodium tridecanoate, sodium tetradecanoate and combinations thereof.

In another embodiment, the present invention provides a stable pharmaceutical formulation for oral administration comprising semaglutide, one or more permeation enhancers, and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides an oral composition of semaglutide, wherein the particle size of semaglutide D90 is in the range of 1µm to 40 µm, preferably in the range of 2µm to 20 µm, more preferably in the range of 3µm to 10 µm.

In another embodiment, the present invention provides a stable pharmaceutical formulation for oral administration comprising Semaglutide and no Sodium N-(8-(2-hydroxybenzoyl) amino) caprylate or less than 40% w/w SNAC, based on the weight of the pharmaceutical formulation.

In another embodiment of the present invention it provides a pharmaceutical formulation comprising semaglutide, sodium N-(8-(2-hydroxybenzoyl) amino) caprylate (SNAC), one or more permeation enhancers, and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a stable pharmaceutical formulation for oral administration comprising Semaglutide and Sodium N-(8-(2-hydroxybenzoyl) amino) caprylate (SNAC) in an amount of less than 0.8 mmol, preferably less than 0.6 mmol.

In another embodiment, the present invention provides a stable pharmaceutical formulation for oral administration, wherein the amount of SNAC is up to 0.5mmol. More preferably the amount of SNAC is 0.01mmol to 0.5mmol.

In another aspect, the present invention provides a pharmaceutical formulation comprising Semaglutide, salt of N-(8-(2-hydroxybenzoyl) amino) caprylate (NAC), and one or more other permeation enhancers, wherein salt of NAC is present in an amount of 0.1 % w/w to 40% w/w based on the weight of pharmaceutical formulation.

In another aspect, the present invention provides a pharmaceutical formulation comprising Semaglutide, salt of N-(8-(2-hydroxybenzoyl) amino) caprylate (NAC), and one or more other permeation enhancers, wherein the salt of NAC is present in the range of 0.01mmol- 0.5mmol.

In another aspect, the present invention provides a pharmaceutical formulation comprising Semaglutide, salt of N-(8-(2-hydroxybenzoyl) amino) caprylate (NAC), and one or more other permeation enhancers, wherein the salt of N-(8-(2-hydroxybenzoyl) amino) caprylate (NAC) is present in an amount of less than 45% by weight of the pharmaceutical formulation.

In another embodiment, the present invention provides a stable pharmaceutical formulation for oral administration comprising semaglutide, one or more permeation enhancers selected from the group consisting of sodium caprate, sodium caprylate, carbomer, labrasol, fatty acids or their salts or derivatives, monoglycerides, diglycerides, or triglycerides, amino acids, or a combination thereof, and one or more pharmaceutically acceptable excipients selected from the group consisting of diluent(s), disintegrant(s), binder(s), lubricant(s), pH modifier(s), surfactant(s), and anti-oxidant(s), or a combination thereof.

In another embodiment, the one or more permeation enhancers are present in an amount of less than 45% by weight of the pharmaceutical formulation.

In another embodiment, the present invention provides a stable pharmaceutical formulation, wherein the one or more permeation enhancer is present in an amount of less than 70% by weight of the pharmaceutical formulation.

In another embodiment, the present invention provides a stable pharmaceutical formulation for oral administration comprising semaglutide, sodium N-(8-(2-hydroxybenzoyl) amino) caprylate (SNAC) in an amount of 0.1 % to 40% by weight of the pharmaceutical formulation; one or more permeation enhancers selected from the group consisting of sodium caprate, sodium caprylate, carbomer, labrasol, fatty acids or their salts or derivatives, monoglycerides, diglycerides, or triglycerides, amino acids, or a combination thereof, and one or more pharmaceutically acceptable excipients selected from the group consisting of solvent, diluent(s), disintegrant(s), binder(s), lubricant(s), pH modifier(s), surfactant and anti-oxidant(s), or a combination thereof.

In another embodiment, the present invention provides a stable pharmaceutical formulation for oral administration comprising semaglutide in an amount of 0.1% to 30% by weight of the pharmaceutical formulation, sodium N-(8-(2-hydroxybenzoyl) amino) caprylate (SNAC) in an amount of 0% to 40% by weight of the pharmaceutical formulation; one or more permeation enhancers other than SNAC in an amount of 10% to 95% by weight of the pharmaceutical formulation, and one or more pharmaceutically acceptable excipients in an amount of 1% to 80% by weight of the pharmaceutical formulation.

In another embodiment, the pharmaceutical formulation according to the invention is an oral formulation in the form of a tablet or a capsule. In one embodiment, the tablet according to the invention is an immediate-release tablet. The pharmaceutical formulation of present invention can be formulated by any suitable granulation methods known in the art such as reverse wet granulation, direct compression, dry granulation, or melt granulation.

The present invention further relates to a process for preparation of a pharmaceutical formulation comprising Semaglutide, wherein the process comprises inert gas purging to reduce the oxygen concentration or substitution with oxygen-free gas or bubbling with oxygen-free gas.

The present invention further relates to a package or storage container for packaging or storing the pharmaceutical formulation, wherein the package or container is made up of material that blocks oxygen or is impervious to oxygen or comprises an oxygen scavenger.

In another embodiment, the amount of one or more permeation enhancers in the formulation is at least 20 mg, such as at least 25 mg, such as at least 50 mg, such as at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg and at least 380 mg per dose unit.

In another embodiment, a dose unit of the pharmaceutical formulation of the invention comprises 0.1-100 mg or 0.2 to 100 mg of Semaglutide. In embodiments, a dose unit of the formulation comprises an amount of Semaglutide in the range of 0.2 to 50 mg or 1 to 40 mg.

In another embodiment, the weight of the unit dose is in the range of 50 mg to 1000 mg, in the range of 50-750 mg, or in the range of 100-500 mg.

In another embodiment, the present invention provides a pharmaceutical formulation, wherein the pharmaceutical formulation is an enteric coated composition.

In another embodiment, the present invention provides a stable pharmaceutical formulation of Semaglutide and a process for preparing the same by using dry granulation, wet granulation, direct compression, melt granulation, reverse granulation or solid dispersion process.

In another embodiment, the present invention provides a stable pharmaceutical formulation for oral administration comprising semaglutide in an amount of 0.1% to 30% by weight of the pharmaceutical formulation, SNAC in an amount of 0% to 40% by weight of the pharmaceutical formulation; one or more permeation enhancers other than SNAC in an amount of 10% to 95% by weight of the pharmaceutical formulation, and one or more pharmaceutically acceptable excipients in an amount of 1% to 80% by weight of the pharmaceutical formulation, wherein the particle size of semaglutide D90 is in the range of 3µm to 10 µm.

In another embodiment, the formulations may be granulated prior to being compacted. The formulations may comprise an intragranular part and an extra granular part, wherein the intragranular part has been granulated and the extra granular part has been added after granulation. In some embodiments, the intragranular part may comprise the Semaglutide, and/or the permeation enhancer. In some embodiments, the extra granular part may comprise the Semaglutide, and/or the permeation enhancer. The extra granular part may comprise filler, binder, disintegrant, lubricant and/or a glidant.

In another embodiment, an immediate release dosage form as disclosed herein releases more than about 75% of the drug contained therein within a period of time selected from less than one hour, less than 45 minutes, less than 30 minutes, less than 15 minutes, and less than 10 minutes after administration.

In another embodiment of the present invention, there is provided a stable pharmaceutical formulation of Semaglutide, wherein said formulation is stable at 40 °C ± 5 °C and 75% ± 5% Relative Humidity (RH) for at least one month, at least three months, at least six months.

In another embodiment of the present invention, there is provided a stable pharmaceutical formulation of Semaglutide, wherein the formulation is having impurities below FDA acceptable daily intake limit. The total impurity(ies) of about 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less at 40 °C ± 5 °C and 75% ± 5% RH for a period of at least six months.

In another embodiment of the present invention, there is provided a stable pharmaceutical formulation of Semaglutide, wherein the pharmaceutical formulation having less than 10% moisture content (measured after 1-month storage), more preferably less than 6% moisture content, more preferably about 4% to 5% moisture content, when measured by Karl Fisher titration or loss on drying method.

In another embodiment of the present invention, the invention relates to a formulation or a granule as defined herein for use in medicine, such as for the treatment of diabetes, obesity, Nonalcoholic fatty liver disease (NAFLD) or Nonalcoholic steatohepatitis (NASH), wherein said formulation is administered orally.

In another embodiment, the present invention provides a process for the preparation of stable pharmaceutical formulation of semaglutide and one or more permeation enhancers along with one or more excipients comprising the steps of co-sifting and mixing semaglutide, permeation enhancers and other excipients; preparing granules using granulation methods; and adding other excipients and compressing into tablet.

In another embodiment, the present invention provides a process for the preparation of stable pharmaceutical formulation of semaglutide comprising (a) co-sifting and mixing semaglutide, permeation enhancers and other excipients; (b) preparing binder solution by dissolving binder in the water; (c) granulating the mixture of step (a) with binder solution of step (b); (d) drying the granules of step (c); (e) adding the diluent and lubricant to blend of step (d) and compressing into tablet.

In another embodiment, the present invention provides a process for the preparation of the stable pharmaceutical formulation of Semaglutide comprising the steps of (i) Sifting all the ingredients through appropriate sieves followed by dry mixing the pre-sifted ingredients of dry mix stage in a suitable blender; (ii) adding semaglutide and povidone into water then add isopropyl alcohol to form drug binder dispersion along with adding drug dispersion into dry mix ingredients and granulate; (iii) drying the granules as obtained in step (ii) in a dryer (fluidized bed dryer/tray dryer), size the dry granules through appropriate sieves (100% should pass through sieve), (iv) pre-lubricating the blend as obtained in step (iii) with pre-sifted colloidal silicon dioxide and citric acid in a blender, further lubricating the blend as obtained with pre-sifted magnesium stearate in a blender; (v) compressing the lubricated blend as obtained in step (iv) into tablets followed by packing the tablets in suitable packs as per the requirement.

In another embodiment, the present invention provides a process for the preparation of the stable pharmaceutical formulation of semaglutide comprising the steps of (i) Sifting all the ingredients through appropriate sieves, followed by dry mixing the pre-sifted ingredients of dry mix stage in a suitable blender; (ii) adding povidone into isopropyl alcohol to form binder dispersion, further adding binder dispersion into dry mix ingredients as obtained above and granulate; (iii) drying the granules as obtain in the step (ii) in a dryer size the dry granules through appropriate sieves followed by pre-lubricating the blend as obtained above with pre-sifted crospovidone XL in a blender, (iv) lubricating the blend as obtain in step (iii) with pre-sifted magnesium stearate in a blender followed by compressing the lubricated blend as obtain above into tablets and further packing the tablets in suitable packs as per the requirement.

In another embodiment, the present invention provides a process for the preparation of the stable pharmaceutical formulation of semaglutide comprising the steps of (i) sifting all the ingredients through appropriate sieves and dry mixing the pre-sifted ingredients in a suitable blender, followed by lubricating the dry mixed ingredients with pre-sifted magnesium stearate in a blender; (ii) passing the blend as obtained in step (i) through roller compactor to obtain dry granules and further milling and sifting the dry granules through appropriate sieves followed by blending the granules in a suitable blender; (iii) lubricating the blend as obtain in step (ii) with pre-sifted magnesium stearate in a blender, followed by compressing the lubricated blend into tablets and further packing the tablets in suitable packs as per the requirement.

In another embodiment, the present invention provides a process for the preparation of the stable pharmaceutical formulation of semaglutide comprising the steps of (i) sifting all the ingredients through appropriate sieves followed by dry mixing the pre-sifted ingredients of dry mix stage in a suitable blender and further adding semaglutide and povidone into water then add isopropyl alcohol to form drug binder dispersion; (ii) adding drug dispersion as obtained in step (i) into dry mix ingredients as obtain above and granulate, followed by drying the granules in a dryer, size the dry granules through appropriate sieves; (iii) pre-lubricating the blend as obtained in step (ii) with pre-sifted colloidal silicon dioxide and citric acid in a blender, followed by lubricating the blend with pre-sifted magnesium stearate in a blender and further compressing the lubricated blend into tablets; (iv) coating the compressed tablets with seal coating dispersion in a suitable coating machine, followed by coating the seal coated tablets with enteric coating dispersion in a suitable coating machine and further packing the tablets in suitable packs as per the requirement.

In another embodiment, the present invention provides a process for the preparation of the stable pharmaceutical formulation of semaglutide comprising the steps of (i) Sifting all the ingredients through appropriate sieves and dry mixing the pre-sifted ingredients of dry mix part in a suitable blender, followed by lubricating the dry mixed ingredients with pre-sifted calcium stearate in a blender; (ii) passing the blend through roller compactor to obtain dry granules and further sifting the dry granules through appropriate sieves (100% should pass through sieve), (iii) Granulation - adding Magnesium Aluminometasilicate and Polyvinyl alcohol into PEG-8 caprylic/Capric glyceride and let it soak for appropriate time followed by drying the granules in a dryer and size the dry granules through appropriate sieve; (iv) mixing both blends obtained in step ii and step (iii) in a suitable blender and further lubricating the blend with pre-sifted calcium stearate in a blender, followed by compressing the lubricated blend into tablets and then packing the tablets in suitable packs as per the requirement.

According to another embodiment, the present invention relates to a stable pharmaceutical formulation comprising semaglutide, one or more permeation enhancers, and one or more pharmaceutically acceptable excipients, wherein the formulation optionally further comprises one or more additional therapeutic agents. Alternatively, a compound of this invention may be administered to a patient in need thereof in combination with the administration of one or more other therapeutic agents.

While selected embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

EXAMPLES
The invention now will be described in particularity with the following illustrative examples; however, the scope of the present invention is not intended to be, and shall not be, limited to the exemplified embodiments below:

Example 1: Oral Pharmaceutical formulation of Semaglutide
Ingredient %w/w
Semaglutide 0.1-20
SNAC 0-40
Other permeation enhancer 10-95
Diluent/Filler 1-75
Binder 0-20
Disintegrant 0-20
Lubricant or Glidant 0-10
The composition is prepared by Dry granulation (roller compaction) or wet granulation process.

Example 2: Oral Composition of Semaglutide
Ingredient Qty./Tablet (mg) Qty./Tablet (mg) Qty./Tablet (mg)
Semaglutide 3 7 14
SNAC 150 150 150
Sodium caprate/caprylate 180 180 180
Tryptophan 30 30 30
Povidone 4 4 4
Microcrystalline Cellulose 41 37 30
Mag. Stearate 2 2 2
The composition is prepared by Wet granulation or roller compaction process.

Example 3: Pharmaceutical formulation of Semaglutide
Ingredient Qty./Tablet (mg)
Semaglutide 14
Carbomer 125
Sodium caprate 170
Arginine 50
Microcrystalline Cellulose 35
Mag. Stearate 2
The composition is prepared by roller compaction or slugging process.

Example 4: Pharmaceutical formulation of Semaglutide
Ingredient Qty./Tablet (mg)
Semaglutide 14
SNAC 120
Carbomer 200
Povidone 4
Microcrystalline Cellulose 60
Mag. Stearate 2
The composition is prepared by dry granulation (compaction) process.

Example 5: Pharmaceutical formulation of Semaglutide
Ingredient Qty./Tablet (mg)
Semaglutide 14
Sodium caprate/caprylate 292
Povidone 28
Crospovidone 12
Microcrystalline Cellulose 52
Mag. Stearate 2
The composition is prepared by roller compaction process.

Example 6: Pharmaceutical formulation of Semaglutide
Ingredient Qty./Tablet (mg)
Semaglutide 3.000 7.000 14.000
Salcaprazoate sodium 158.000 158.000 158.000
Salcaprazoic acid 142.000 142.000 142.000
Poloxamer P188 30.000 30.000 30.000
Sodium bicarbonate 30.000 30.000 30.000
Microcrystalline cellulose (Avicel PH 112) 29.900 25.900 18.900
Povidone (PVP K90) 10.000 10.000 10.000
Isopropyl alcohol q.s. q.s. q.s.
Crospovidone XL 20.000 20.000 20.000
Magnesium stearate 5.100 5.100 5.100
Tablet weight 428.000 428.000 428.000

Process
sifting all the ingredients through appropriate sieves;
dry mixing the pre-sifted ingredients of dry mix stage in a suitable blender;
adding semaglutide, povidone into water & add isopropyl alcohol to form drug binder dispersion;
adding drug dispersion into dry mix ingredients as obtained in step 2 and granulate;
drying the granules as obtained in step (iv) in a dryer, size the dry granules through sieves;
pre-lubricating the blend as obtained in step (v) with pre-sifted colloidal silicon dioxide and sodium bicarbonate in a blender;
lubricating the blend as obtained in step (vi) with pre-sifted magnesium stearate in a blender;
compressing the lubricated blend as obtained in step (vii) into tablets using suitable tooling.
packing the tablets in suitable packs as per the requirement.

Example 7: Pharmaceutical formulation of Semaglutide
Ingredient Qty./Tablet (mg)
Semaglutide 3.000 7.000 14.000
Salcaprazoate sodium 158.000 158.000 158.000
Poloxamer P188 35.000 35.000 35.000
Microcrystalline cellulose 188.9 184.9 177.9
Povidone (PVP K90) 10.000 10.000 10.000
Isopropyl alcohol q.s. q.s. q.s.
Crospovidone XL 20.000 20.000 20.000
Magnesium stearate 5.100 5.100 5.100
Tablet weight 420.000 420.000 420.000

Process -
sifting all the ingredients through appropriate sieves;
dry mixing the pre-sifted ingredients of dry mix stage in a suitable blender;
adding povidone into isopropyl alcohol to form binder dispersion;
adding binder dispersion into dry mix ingredients as obtained in step (ii) and granulate;
drying the granules as obtain in the step (iv) in a dryer (fluidized bed dryer/tray dryer), size the dry granules through appropriate sieves (100% should pass through sieve);
pre-lubricating the blend as obtained in step (v) with crospovidone XL in a blender;
lubricating the blend as obtain in step (vi) with pre-sifted magnesium stearate in a blender;
compressing the lubricated blend as obtain in step (vii) into tablets using suitable tooling;
packing the tablets in suitable packs as per the requirement.

Example 8: Pharmaceutical formulation of Semaglutide
Ingredient Qty./Tablet (mg)
Semaglutide 3.000 7.000 14.000
Salcaprozate sodium 150.000 150.000 150.000
Sodium Caprate 50.000 50.000 50.000
Microcrystalline cellulose 182.000 178.000 171.000
Povidone K90 10.000 10.000 10.000
Magnesium stearate 3.000 3.000 3.000
Magnesium stearate 2.000 2.000 2.000
Tablet weight 400.00 400.00 400.00

Process-
sifting all the ingredients through appropriate sieves;
dry mixing the pre-sifted ingredients in a suitable blender;
lubricating the dry mixed ingredients as obtained in step (ii) with pre-sifted magnesium stearate in a blender;
passing the blend as obtained in step (iii) through roller compactor to obtain dry granules;
milling and sifting the dry granules as obtained in step (iv) through appropriate sieves (100% should pass through sieve);
blending the granules obtained from step (v) in a suitable blender;
lubricating the blend as obtain in step (vi) with pre-sifted magnesium stearate in a blender;
compressing the lubricated blend as obtained in step (vii) into tablets using suitable tooling;
packing the tablets in suitable packs as per the requirement.

Example 9: Pharmaceutical formulation of Semaglutide
Ingredient Qty./Tablet (mg)
Sodium caprate 100.000 100.000 100.000
Microcrystalline cellulose 160.000 156.000 149.000
Lactose monohydrate 100.000 100.000 100.000
Semaglutide 3.000 7.000 14.000
Povidone K90 10.000 10.000 10.000
Isopropyl alcohol q.s. q.s. q.s.
Purified water q.s. q.s. q.s.
Colloidal silicon dioxide 4.000 4.000 4.000
Citric acid anhydrous 150.000 150.000 150.000
Magnesium stearate 3.000 3.000 3.000
Hypromellose 2910 17.520 17.520 17.520
Macrogol (polyethylene glycol) 5.010 5.010 5.010
Titanium dioxide 3.465 3.465 3.465
Talc 0.505 0.505 0.505
Isopropyl alcohol q.s. q.s. q.s.
Purified Water q.s. q.s. q.s.
Methacrylic Acid-Methyl Methacrylate Copolymer (1:2) 47.303 47.303 47.303
Triethyl citrate (Citrofol A1) 8.348 8.348 8.348
Purified Water q.s. q.s. q.s.
Coated tablet weight 612.150 612.150 612.150

Process
Sifting all the ingredients through appropriate sieves;
dry mixing the pre-sifted ingredients of dry mix stage in a suitable blender;
adding semaglutide and povidone into water then add isopropyl alcohol to form drug binder dispersion;
adding drug dispersion as obtained in step (iii) into dry mix ingredients as obtained in step (ii) and granulate;
drying the granules as obtained in step (iv) in a dryer (fluidized bed dryer/tray dryer), size the dry granules through appropriate sieves (100% should pass through sieve);
pre-lubricating the blend as obtained in step (v) with pre-sifted colloidal silicon dioxide and citric acid in a blender;
lubricating the blend as obtain in step (vi) with pre-sifted magnesium stearate in a blender;
compressing the lubricated blend as obtain in step (vii) into tablets using suitable tooling;
sealing coat, the compressed tablets with seal coating dispersion in a suitable coating machine;
coating the seal coated tablets with enteric coating dispersion in a suitable coating machine;
packing the tablets in suitable packs as per the requirement.

Example 10: Pharmaceutical formulation of Semaglutide
Ingredient Qty./Tablet (mg)
Semaglutide 3.000 7.000 14.000
Microcrystalline Cellulose 76.200 72.200 65.200
Calcium stearate 0.800 0.800 0.800
Magnesium Aluminometasilicate 100.000 100.000 100.000
PEG-8 caprylic/Capric glyceride 300.000 300.000 300.000
Polyvinyl alcohol 50.000 50.000 50.000
Calcium stearate 4.000 4.000 4.000
Tablet weight 534.000 534.000 534.000

Process
Sifting all the ingredients through appropriate sieves;
dry mixing the pre-sifted ingredients of dry mix part in a suitable blender;
lubricating the dry mixed ingredients as obtained in step 2 with pre-sifted calcium stearate in a blender;
passing the blend through roller compactor to obtain dry granules;
sifting the dry granules through appropriate sieves (100% should pass through sieve);
adding Magnesium Aluminometasilicate and Polyvinyl alcohol into PEG-8 caprylic/Capric glyceride in a different apparatus and let it soak for appropriate time;
drying the granules as obtain in step (vi) in a dryer (fluidized bed dryer/tray dryer) and size the dry granules through appropriate sieve (100% should pass through sieve);
mixing the blends obtained in step v and step vii in a suitable blender;
lubricating the blend as obtain in step (viii) with pre-sifted calcium stearate in a blender;
compressing the lubricated blend as obtained in step (ix) into tablets using suitable tooling;
packing the tablets in suitable packs as per the requirement.

It was known in the art that the SNAC has hygroscopic property and composition containing more than 50% w/w (by total weight of composition) of SNAC absorb moisture very rapidly (when left in open) and destabilize the composition. Inventors has tried various excipients and combination of excipients to develop the composition of Semaglutide, which is stable while storage as well as bio-available. While working on the present invention, Inventors has surprisingly found that when less than 50% w/w of SNAC is used along with other excipients, is absorb very less amount of moisture and stabilize the composition and shows bioavailability also. Inventors has formulated two composition comprising SNAC and semaglutide along with other excipients. First composition comprising more than 50% w/w of SNAC and second composition comprising less than 50% w/w of SNAC. Both the composition was packed in the bottle without any desiccant/ moisture absorbent. Moisture content is determined initial level and after 1 month by Karl Fisher titration or loss on drying method. The results are as follows:
Moisture content (Initial) Moisture content (After 1.5 month)
Composition with <50% w/w of SNAC 4.02% 4.15%
Composition with > 50% w/w of SNAC 4.32% More than 10%

From the table, it is evident that the composition comprising more than 50% w/w of SNAC absorb moisture and destabilize the composition. Whereas the pharmaceutical formulation of present invention comprising less than 50% w/w of SNAC is absorbing very less amount of moisture while storage and is stable for a long period of time.

Further, the pharmaceutical composition of present invention is subjected to stability study in accelerated conditions (40°C±5°C /74% ±10%RH). The result is as follows:
Tests Initial 1.5 Months
Description White, oval, biconvex, uncoated tablets White, oval, biconvex, uncoated tablets
Assay (%) 96.8% 95.4%

Dissolution Study: Pharmaceutical formulation of present invention is subjected to dissolution test to determine the release profile of composition. The dissolution test is carried out in 500 ml of Phosphate buffer pH 6.8 with 0.05% polyoxyethylene lauryl ether at 37 °C using USP apparatus II with paddle speed at 100 rpm. The release profile is as follows:

Time Points [Min] % drug release
10 68
15 85
20 97
30 99
45 102

While working on the present invention, Inventors has found that the release of drug from the pharmaceutical formulation is dependent on the particle size of semaglutide. To determine the effect of particle size on the release profile, inventors has prepared two compositions of semaglutide. First composition was prepared with less than 10µm particle size of semaglutide and second composition was prepared with more than 20µm (which says more than 10 µm) particle size of semaglutide. Both compositions were subjected to dissolution test. The dissolution test is carried out in 500 ml of Phosphate buffer pH 6.8 with 0.05% polyoxyethylene lauryl ether at 37 °C using USP apparatus II with paddle speed at 100 rpm. The release profile of the both compositions were compared with the marketed formulation of Semaglutide Tablet Rybelsus®. The results are as follows:

Time Points [Min] Semaglutide (Particle size less than 10µm) Semaglutide (Particle size more than 10µm) Rybelsus® (Semaglutide)
10 68 27 66
15 85 45 86
20 97 62 99
30 99 75 103
45 102 83 103
60 102 89 104
75 102 95 104

From the above table, it is evident that the composition having less than 10 µm particle size shows identical release profile when compared with the marketed formulation of Semaglutide Rybelsus®, whereas the composition having particle size more than 10µm shows slow release when compared with marketed composition
,CLAIMS:We Claim:

1. A pharmaceutical formulation comprising semaglutide, salt of N-(8-(2-hydroxybenzoyl) amino) caprylate (NAC), one or more permeation enhancers, and one or more pharmaceutically acceptable excipients.

2. The pharmaceutical formulation as claimed in claim 1, wherein salt of NAC is present in an amount of 0.1 % w/w to 40% w/w based on the weight of pharmaceutical formulation.

3. The pharmaceutical formulation as claimed in claim 1, wherein the salt of NAC is present in the range of 0.01mmol- 0.5mmol.

4. The pharmaceutical formulation as claimed in claim 1, wherein the salt of N-(8-(2-hydroxybenzoyl) amino) caprylate (NAC) is present in an amount of less than 45% by weight of the pharmaceutical formulation.

5. The pharmaceutical formulation as claimed in claim 1, wherein the one or more permeation enhancer is present in an amount of less than 70% by weight of the pharmaceutical formulation.

6. The pharmaceutical formulation as claimed in claim 1, wherein the particle size of semaglutide D90 is in the range of 3µm to 10 µm.

7. The pharmaceutical formulation as claimed in claim 1, wherein the composition is in the form of tablet, capsule, capsule, granule, tablet in tablet, granules in a capsule, pellets, pellets in a capsule or powder dosages form.

8. The pharmaceutical formulation as claimed in claim 1, wherein the pharmaceutical formulation is an enteric coated composition.

9. A stable pharmaceutical formulation for oral administration comprising semaglutide in an amount of 0.1% to 30% by weight of the pharmaceutical formulation, sodium N-(8-(2-hydroxybenzoyl) amino) caprylate (SNAC) in an amount of 0% to 40% by weight of the pharmaceutical formulation; one or more permeation enhancers other than SNAC in an amount of 10% to 95% by weight of the pharmaceutical formulation, and one or more pharmaceutically acceptable excipients in an amount of 1% to 80% by weight of the pharmaceutical formulation, wherein the particle size of semaglutide D90 is in the range of 3µm to 10 µm.

10. A process for the preparation of a stable pharmaceutical formulation as claimed in claim 1, comprises the steps of:
(i) sifting all the ingredients through appropriate sieves followed by dry mixing the pre-sifted ingredients of dry mix stage in a blender and further adding semaglutide and povidone into water then add isopropyl alcohol to form drug binder dispersion;
(ii) adding drug dispersion as obtained in step (i) into dry mix ingredients as obtain in step (i) and granulate, followed by drying the granules in a dryer, and size the dry granules through appropriate sieves;
(iii) pre-lubricating the blend as obtained in step (ii) with pre-sifted colloidal silicon dioxide and citric acid in a blender, followed by lubricating the blend with pre-sifted magnesium stearate in a blender and further compressing the lubricated blend into tablets;
(iv) coating the compressed tablets with seal coating dispersion, followed by enteric coating dispersion and packing.

Dated 10th Day of May, 2024
For Mankind Pharma Ltd.

Dr. Anil Kumar

Chief Scientific Officer