DESC:
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to and the benefit of Indian Patent Application No. 202321076643 filed on November 09, 2023.

FIELD OF THE INVENTION:
The present invention relates to pharmaceutical compositions comprising glucagon-like peptide-1 (GLP-1) receptor agonist and a permeation enhancer. In particular, the present invention provides stabilized pharmaceutical compositions comprising semaglutide and permeation enhancer and its process of preparation. The invention also relates to the use of said stable composition for the treatment of type 2 diabetes as well as a variety of other conditions.
BACKGROUND OF THE INVENTION:
The GLP-1 receptor has a wide tissue distribution being present virtually in organ system (pancreas, lung, heart, vascular smooth muscle cells, endothelial cells, macrophages and monocytes, kidney, gastrointestinal tract [stomach and intestine], central nervous system [brain], and peripheral nervous system). GLP-1 analogues have shown that they are useful not only in patients with T2DM but also in patients with T1DM. They have shown to significantly reduce fasting and post-prandial blood glucose, HbA1c, weight, and daily insulin requirements.
A large body of preclinical and clinical research data suggests that GLP-1 compounds show great promise as a treatment for type 2 diabetes and other conditions. GLP-1 induces numerous biological effects such as stimulating insulin secretion, inhibiting glucagon secretion, inhibiting gastric emptying, enhancing glucose utilization, and inducing weight loss. Further, pre-clinical studies suggest that GLP-1 may also act to prevent the ßcell deterioration that occurs as the disease
progresses. Perhaps the most salient characteristic of GLP-1 is its ability to stimulate insulin secretion without the associated risk of hypoglycemia that is seen when using insulin therapy or some types of oral therapies that act by increasing insulin expression.
Semaglutide is a GLP-1 receptor agonist. The peptide backbone is produced by yeast fermentation. The main protraction mechanism of semaglutide is albumin binding, facilitated by modification of position 26 lysine with a hydrophilic spacer and a C18 fatty di-acid. Furthermore, semaglutide is modified in position 8 to provide stabilization against degradation by the enzyme dipeptidyl-peptidase 4 (DPP-4). A minor modification was made in position 34 to ensure the attachment of only one fatty di-acid. The molecular formula is C187H291N45O59 and the molecular weight is 4113.58 g/mol. Structural formula of semaglutide as:

Currently, semaglutide oral tablets available in 3mg, 7mg, and 14mg Strengths and is marketed under the brand name RYBELSUS® in the United States by Novo Nordisk Inc.
Several prior attempts have been made to provide stable solid dosage form comprising GLP-1 compound. Human GLP-1 and analogues thereof have a low oral bioavailability. Exposure and bioavailability of human GLP-1 and analogues thereof is very low following oral administration. Human GLP-1 and analogues thereof can only be detected in plasma after oral administration if formulated with certain absorption enhancers in a specific amount. Steinert et al. (Am J Clin Nutr, October 2010; 92: 810-817) discloses oral administration of a tablet comprising GLP-1(7-36) amide and 150 mg sodium N-(8-(2-hydroxybenzoyl) amino) caprylate (SNAC).
U.S. Patent No. 8,129,343 discloses semaglutide specifically and its composition and/or method of use. U.S. Patent No. 9,278,123 discloses a solid composition comprising GLP-1 agonist semaglutide and sodium N-(8-(2-hydroxybenzoyl) amino) caprylic acid is in the range of 0.8-1.3 mmol which is also known as SNAC i.e. salcaprozate sodium, has been added to the formulation to enhance the bioavailability of semaglutide.
U.S. Patent No. 10,933,120 discloses pharmaceutical compositions comprising a first type of granules and a second type of granules of , wherein said first type of granules comprises a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and no GLP-1 peptide, and wherein said second type of granules comprises a GLP-1 peptide and no salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, as well as the intermediate granules, processes for the preparation of the granules and compositions, and use thereof in medicine.
However, SNAC has the tendency of increasing water content during the storage which is evident from its stability studies, further manufacturing of Salcaprozate sodium is a very complex process. Therefore, there is still a need for a stable pharmaceutical composition of a GLP-1 agonist and permeation enhancer other than SNAC or arginine or combination thereof.
In addition to stable pharmaceutical composition of a GLP-1 agonist and SNAC, several other permeation enhancers were tried e. g. sodium caprylate, sodium caprate and sodium laurate; but no commercially viable formulation was produced.
U.S. Patent No. 8,828,431 discloses use of absorption enhancer such as sodium salt of a medium chain fatty acid, sodium caprylate, sodium caprate and sodium laurate for delivery of peptide or protein.
U.S. Patent application No. 20230053812 discloses stable pharmaceutical formulation useful for the oral administration comprising a peptide or protein drug and a permeation enhancer. In particular, the invention relates to stabilized pharmaceutical formulations comprising GLP-1 receptor agonist such as semaglutide and a permeation enhancer and its process for preparation.
Additionally, N-nitrosamine impurities are possible in the synthesis of Semaglutide or derivative thereof. The N-nitrosamine impurities may originate from any or all of the active pharmaceutical ingredient, excipients, pharmaceutical packaging materials, and/or manufacturing process and equipment. Examples of N-nitrosamine impurities include, but are not limited to N-Nitrosodimethyl amine (“NDMA”), N-Nitrosodiethyl amine (“NDEA”), N-Nitrosodiisopropylamine (“NDIPA”), N-Nitrosoethylisopropylamine (“NIPEA”), N-nitroso-N-methyl-4-aminobutyric acid (“NMBA”), N-Nitrosodibutylamine (“NDBA”), and N-Methyl-N-phenylnitrosamine (“NMPA”). N-nitrosamines are generally formed when a secondary or tertiary amine reacts with a nitrosating agent. While the amounts of the N-nitrosamine impurities in drugs is generally low, some levels have been above the US Food and Drug Administration’s acceptable daily limit, potentially exposing many people to a slightly increased risk of cancer. Because of the aforementioned health-related effects, stringent limitations have been placed upon the permissible amounts of N-nitrosamine impurities in drug products. Because of the exceptionally low allowable limits for N-nitrosamine impurities in these products it becomes important to control the nitrosamine impurities during synthesis of active pharmaceutical ingredient or drug formulation.
Surprisingly, inventors of the present invention developed stable oral composition of semaglutide made by using permeation enhancers other than sodium N-(8-(2-hydroxybenzoyl) amino) caprylate (SNAC) or arginine or combination thereof, which exhibits improved or acceptable bioavailability, rapid release, and less degradation of semaglutide.

OBJECT OF THE INVENTION:
It is an object of the present invention to overcome the drawbacks of the prior art.
It is also an object of the present invention to provide a stable pharmaceutical composition comprising GLP-1 receptor agonist such as semaglutide.
It is another object of the present invention to provide a pharmaceutical composition comprising semaglutide and a permeation enhancer other than sodium N-(8-(2-hydroxybenzoyl) amino) caprylate (SNAC) or arginine or combination thereof.
It is yet another object of the present invention to provide a pharmaceutical composition comprising semaglutide and a permeation enhancer, sodium caprylate.
It is yet another object of the present invention to provide a pharmaceutical composition comprising semaglutide, sodium caprylate, disodium hydrogen phosphate and disintegrant selected from the group consisting of crospovidone, sodium starch glycolate and combination thereof.
It is a further object of the present invention to provide a method of preparing a pharmaceutical composition comprising semaglutide and a permeation enhancer, sodium caprylate.

SUMMARY OF THE INVENTION:
In an aspect of the present invention, there is provided a pharmaceutical composition comprising semaglutide and one or more permeation enhancers selected from soyabean lecithin, lysine, phenyl alanine, tryptophan, sodium caprylate, sodium caprate, capsaicin analogue, sodium laurate, sodium chenodeoxycholate, propyl gallate, sodium octanoate, sodium nonanoate, sodium decanoate, sodium undecanoate, sodium dodecanoate, sodium tridecanoate, dodecyl maltoside, tridecyl maltoside, tetradecyl maltoside, sucrose mono-dodecanoate, sucrose mono-tridecanoate, sucrose mono-tetradecanoate, sodium dodecyl sulfate, sodium hexanoate, sodium heptanoate, sodium tetradecanoate, and combinations thereof.
In another aspect of the present invention, there is provided a pharmaceutical composition comprising a) semaglutide from about 0.1 to about 10 % w/w; b) a permeation enhancer, sodium caprylate from about 40 % w/w to about 80 % w/w; c) a pH adjusting agent, disodium hydrogen phosphate from about 0.05% w/w to about 0.20% w/w d) disintegrant, crospovidone and/or sodium starch glycolate from about 1%w/w to about 10% w/w and e) optionally, other pharmaceutically acceptable excipients selected from the group consisting of binders, solubilizer, diluents, disintegrants, lubricants, glidants, antioxidants, flavouring agent, colorants, sweetening agent, and combinations thereof.
In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a) about 0.1 to about 10 % w/w of semaglutide, b) about 40 % w/w to about 80 % w/w of permeation enhancer, c) about 1 % w/w to about 20 % w/w of binders, d) about 0.05 % w/w to about 2 % w/w of solubilzer, e) about 5 % w/w to about 30 % w/w of diluents, f) about 2 % w/w to about 20 % w/w of disintegrant, g) about 0.2 % w/w to about 5 % w/w of lubricants, h) about 0.2 % w/w to about 5 % w/w of glidants, i) about 0.05% w/w to about 0.20% w/w of pH adjusting agents, j) optionally about 0.02 % w/w to about 0.5 % w/w of colorants, and optionally other pharmaceutically acceptable excipients, wherein the composition contains total impurity less than 8% w/w.
In yet another aspect of the present invention, there is provided a process for preparing the pharmaceutical composition as described herein, the process comprising the steps of: a) sifting the permeation enhancer through a sieve; b)preparing a binder component; c) adding the binder component of step (b) to the permeation enhancer of step (a) to obtain a granule; d)adding semaglutide and diluent, disintegrant, glidant, binder, colorant to the granule of step (c); e) adding lubricant to the mixture of step (d) to obtain the pharmaceutical composition.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides a pharmaceutical composition comprising GLP-1 agonist.
The present invention can be more readily understood by reading the following description of the invention and study of the included examples.
The use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and/or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one."
The term "about" as used herein means a deviation within 10%, more preferably within 5%, and even more preferably, within 2% of the numbers reported.
The term ‘‘stable’’ refers to formulations that substantially retain the labelled amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.
The term “impurity” refers to undesired contents present or produced in a pharmaceutical composition.
The term “therapeutically effective amount” is defined to mean the amount or quantity of the active drug is sufficient to elicit an appreciable pharmacological response, when administered to the patient.
As used herein, the term "bioavailability" denotes the degree to which a drug or other substance becomes available to the target tissue after administration.
“Pharmaceutically acceptable excipient(s)” are components that are added to the pharmaceutical composition other than the active ingredient. Pharmaceutically acceptable excipient(s) includes, but not limited to, diluent, binder, disintegrant, lubricant/glidants, antioxidant, plasticizer, surfactants, solvent/vehicle, flavors or colorants, coating materials and any other excipient known to the art for making solid oral pharmaceutical composition.
The term “core” as used herein, refers to an interior compartment of a unit dosage form.
The term ‘‘w/w’’ refers to total weight of substance/excipients with respect to total composition weight or the proportion of a particular substance within a mixture, as measured by weight or mass.
The term “excipient” means a pharmacologically inactive component such as a binder, solvent, diluent, disintegrant, carrier, lubricant, or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, inert, non-toxic and are acceptable for human use.
By the term “pharmaceutical composition” or “solid oral pharmaceutical composition" or "composition" or "formulation" as used herein refers to a solid dosage form comprising semaglutide suitable for administration such as a tablet, caplet, hard or soft gelatin capsule, mini-tablets, pellets, granules, pills, suspension and the like. The pharmaceutical dosage form can be prepared by methods known in the art, such as dry granulation or wet granulation or direct compression. The compression of the blend to tablet cores can be carried out using a conventional tabletting machine or a rotary compression machine. The tablet cores may vary in shape and can be, for example, round, oval, oblong, cylindrical or any other suitable shape. The cores may also vary in size depending on the concentration of the therapeutic agent. The material obtained by suitable methods known in the art can be filled into capsules or made into tablets.
The term “active ingredient” or “active agent” or “drug” used interchangeably, is defined to mean active drug i.e. semaglutide and its salt, solvate, esters, isomers, polymorphs that induce a desired pharmacological or physiological effect.
The term “semaglutide” includes all pharmaceutically acceptable salts, esters, isomers, stereo isomers, crystalline and amorphous forms.
In one embodiment of the invention, an oral stable pharmaceutical capsule composition comprising about 0.1 about 10 % w/w of semaglutide and one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention relates to a pharmaceutical composition comprising about 1 to about 50 mg, preferably about 2 to about 20mg, more preferably about 3 mg, 7 mg or 14 mg of semaglutide.
In embodiments, as used herein, the term “permeation enhancer” refers to an agent whose function is to increase absorption by enhancing membrane permeation, rather than increasing solubility.
The present invention provides a pharmaceutical composition comprising GLP-1 agonist and one or more permeation enhancers.
The present invention provides a pharmaceutical formulation comprises GLP-1 receptor agonist is selected from semaglutide, liraglutide, exenatide, exendin-4, lixisenatide, taspoglutide, albiglutide, dulaglutide, langlenatide, beinaglutide, efpeglenatide, coumaglutide and pharmaceutically acceptable salts thereof.
The present invention provides a pharmaceutical composition comprising semaglutide and one or more permeation enhancers.
The present invention provides a pharmaceutical composition comprising semaglutide and one or more permeation enhancers other than SNAC or arginine or combination thereof.
Another embodiment of the invention, the pharmaceutical composition comprises semaglutide and pharmaceutically acceptable excipients selected from the group consisting of permeation enhancer, binders, solubilzer, diluents, disintegrants, lubricants, glidants, antioxidants, pH adjusting agents, flavouring agent, colorants and sweetening agent.
In embodiments, the pharmaceutical formulation provided herein comprises permeation enhancers, which are included in formulations to improve the absorption of a pharmacologically active drug. Permeation enhancers according to the present invention are selected from, but not limited to soyabean lecithin, lysine, phenyl alanine, tryptophan, sodium caprylate, sodium caprate, capsaicin analogue, 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 the like used either alone or in combinations thereof and the most preferably used permeation enhancer is sodium caprylate. Permeation enhancers may be present in an amount of about 40 % w/w to about 80 % w/w, preferably about 50 % w/w to about 70% w/w, more preferably about 60 % w/w of the composition.
The present invention provides a pharmaceutical composition comprising semaglutide and one or more permeation enhancers selected from soyabean lecithin, lysine, phenyl alanine, tryptophan, sodium caprylate, sodium caprate, capsaicin analogue, sodium laurate, sodium chenodeoxycholate, propyl gallate, sodium octanoate, sodium nonanoate, sodium decanoate, sodium undecanoate, sodium dodecanoate, sodium tridecanoate, dodecyl maltoside, tridecyl maltoside, tetradecyl maltoside, sucrose mono-dodecanoate, sucrose mono-tridecanoate, sucrose mono-tetradecanoate, sodium dodecyl sulfate, sodium hexanoate, sodium heptanoate, sodium tetradecanoate, and combinations thereof.
Preferably, the permeation enhancer is sodium caprylate.
The pharmaceutical composition comprises about 0.1 to about 10 % w/w of semaglutide and about 40 % w/w to about 80 % w/w of permeation enhancer.
The pharmaceutical composition further comprises pharmaceutically acceptable excipients selected from the group consisting of binders, solubilzer, diluents, disintegrants, lubricants, glidants, antioxidants, pH adjusting agents, flavouring agent, colorants, sweetening agent, and combinations thereof.
Binders according to the present invention are selected from, but not limited to, , cellulose and its derivatives including, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and hydroxyethyl cellulose, carboxymethyl cellulose; gelatin, liquid glucose; starch and its derivatives; hydrocolloids; sugars; polyvinyl pyrrolidone (PVP; K-15, K-30, K-60, K-90), sodium alginate, acacia, alginic acid, tragacanth, used either alone or in combinations thereof and most preferably used binder is polyvinyl pyrrolidone. Binder may be present in an amount of about 1 % w/w to about 20 % w/w, preferably about 2 % w/w to about 15 % w/w, more preferably about 4 % w/w or about 6 % w/w or about 8 % w/w of the composition.
“Solubilizer” refers to any substance which enhances the solubility of a drug. Solubilzer according to the present invention are selected from, but not limited to, glycerol monostearate, sorbitan monolaurate, tween 60, tween 80 (polysorbate 80) used either alone or in combinations thereof and most preferably used solubilizer is polysorbate 80. Solubilizer may be present in an amount of about 0.05 % w/w to about 2 % w/w, preferably about 0.05 % w/w to about 0.2 % w/w, more preferably about 0.08 % w/w to about 0.15 % w/w of the composition.
Diluents according to the present invention are selected from, but not limited to, silicon dioxide, titanium dioxide, talc, powdered cellulose, microcrystalline cellulose (Avicel-PH-101; Avicel-PH-102), dicalcium phosphate, mannitol, sorbitol or other sugar alcohols, isomalt, sucrose, lactose, and the like used either alone or in combinations thereof and the most preferably used diluent is microcrystalline cellulose. Diluent may be present in an amount of about 5 % w/w to about 30 % w/w, preferably about 10 % w/w to about 25% w/w, more preferably about 15 % w/w to about 20 % w/w of the composition.
Disintegrants according to the present invention are selected from, but not limited to, croscarmellose sodium, crospovidone (Kollidon CL), carmellose calcium, sodium starch glycolate, polacrilin potassium, starches, substituted hydroxypropyl cellulose, powdered agar and like used either alone or in combinations thereof and the most preferably used disintegrant is crospovidone or sodium starch glycolate or mixture of crospovidone or sodium starch glycolate. The disintegration test basically consists of placing a dosage form in an immersion medium under defined experimental conditions and measuring the time taken for the dosage form to disintegrate. The time in which the tablet or capsule should disintegrate is defined in the applicable monograph. Disintegrant may be present in an amount of about 2 % w/w to about 20 % w/w, preferably about 2 % w/w to about 10 % w/w, more preferably about 3 % w/w to about 6 % w/w, more specifically about 4 % w/w of the composition.
Lubricants according to the present invention are selected from, but not limited to, sodium stearyl fumarate, magnesium stearate, calcium stearate, aluminium stearate, sucrose stearate, sucrose fatty acid ester, stearic acid, fumaric acid, palmitic acid, polyethylene glycol, talc, and the like used either alone or in combinations thereof and the most preferably used lubricant is magnesium stearate. Lubricant may be present in an amount of about 0.2 % w/w to about 5 % w/w, preferably about 0.4 % w/w to about 3 % w/w, more preferably about 0.75 % w/w to about 2 % w/w of the composition.
Glidants according to the present invention are selected from, but not limited to, calcium silicate, magnesium silicate, silicon hydrogel, colloidal silicon dioxide, cornstarch, talc, and the like used either alone or in combinations thereof and the most preferably used glidant is colloidal silicon dioxide or talc or mixture of colloidal silicon dioxide and talc. Glidants may be present in an amount of about 0.2 % w/w to about 5 % w/w, preferably about 0.5 % w/w to about 4 % w/w, more preferably about 1 % w/w or about 1.5 % w/w of the composition.
Antioxidants are used to prevent oxidation, thereby preventing the deterioration of the preparation. Suitable antioxidants for use in the present invention include but not limited to propyl gallate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and combinations thereof.
pH adjusting agent according to the present invention are selected from, but not limited to, sodium hydroxide, potassium hydroxide, disodium hydrogen phosphate dihydrate, magnesium hydroxide, sodium carbonate, alone or in combination thereof. pH adjusting agent may be present in an amount of about 0.05 % w/w to about 2 % w/w, preferably about 0.05 % w/w to about 0.2 % w/w, more preferably about 0.08 % w/w to about 0.15 % w/w of the composition.
A ‘‘Solvent/vehicle’’ is a substance that dissolves a solute (a chemically distinct liquid, solid or gas), resulting in a solution. Examples include but not limited to purified water, alcoholic solvents methanol, ethanol; ketones such as acetone, propanone; esters such as ethyl acetate, n-propyl acetate, isopropylacetate and nbutyl acetate and the like; ethers such as dimethylether, diethylether, methyltertiarybutylether, ethylmethylether, diisopropylether, and dioxane.
‘‘Flavouring agent’’ refers to a substance that gives another substance flavor, altering the characteristics of the solute, causing it to become sweet, sour, etc. Pharmaceutically acceptable flavors include but not limited to cherry, orange, vanilla.
‘‘Colorants’’ is a substance that is preferably added to the coating agent for coating of the tablet. Pharmaceutically acceptable colorants include but not limited to red iron oxide, iron oxide black, Ferrosoferric oxide, tartrazine, erythrosine, amaranth lake, opadry systems, titanium dioxide, yellow iron oxide, or combinations thereof. Colorants may be included within the tablet or within the capsule shell or within the capsule fill, and also coloring agents added for the coating of the tablet.
Sweetening agents may be used to mask unpleasant taste or to achieve a desired taste. Examples of sweetening agents are glucose, sucrose, fructose, sorbitol, glycerol, cyclamate, aspartame, acesulfame potassium and neohesperidin dihydrochalcon.
The pharmaceutical composition is in the form of tablet, caplet, hard or soft gelatin capsule, mini-tablets, pellets, granules, pills, or suspension.
In one embodiment, there is provided a pharmaceutical composition comprising a) semaglutide from about 0.1 to about 10 % w/w; b) a permeation enhancer, sodium caprylate from about 40 % w/w to about 80 % w/w; and c) pharmaceutically acceptable excipients selected from the group consisting of binders, solubilizer, diluents, disintegrants, lubricants, glidants, antioxidants, flavouring agent, colorants, sweetening agent, and combinations thereof.
In another embodiment, there is provided a pharmaceutical composition comprising a) semaglutide from about 0.1 to about 10 % w/w; b) a permeation enhancer, sodium caprylate from about 40 % w/w to about 80 % w/w; c) a pH adjusting agent, disodium hydrogen phosphate from about 0.05% w/w to about 0.20% w/w; and d) optionally, other pharmaceutically acceptable excipients selected from the group consisting of binders, solubilizer, diluents, disintegrants, lubricants, glidants, antioxidants, flavouring agent, colorants, sweetening agent, and combinations thereof.
In a further embodiment, there is provided a pharmaceutical composition comprising a) semaglutide from about 0.1 to about 10 % w/w; b) a permeation enhancer, sodium caprylate from about 40 % w/w to about 80 % w/w; c) a pH adjusting agent, disodium hydrogen phosphate from about 0.05% w/w to about 0.20% w/w; d) disintegrant, crospovidone and/or sodium starch glycolate from about 1%w/w to about 10% w/w and e) optionally, other pharmaceutically acceptable excipients selected from the group consisting of binders, solubilizer, diluents, disintegrants, lubricants, glidants, antioxidants, flavouring agent, colorants, sweetening agent, and combinations thereof.
In one embodiment, there is provided a pharmaceutical composition comprising a) about 1 to about 20 mg of semaglutide, and b) about 200 to about 400mg of sodium caprylate.
In one embodiment, there is provided a pharmaceutical composition comprising: a) about 0.1 to about 10 % w/w of semaglutide; b) about 90 to about 99.5% w/w of pharmaceutically acceptable excipients; wherein, said pharmaceutical composition is in the form of tablet or capsule.
Another embodiment of the present invention provides pharmaceutical composition comprising a) about 0.1 to about 10 % w/w of semaglutide, b) about 40 % w/w to about 80 % w/w of permeation enhancer, c) about 1 % w/w to about 20 % w/w of binders, d) about 0.05 % w/w to about 2 % w/w of solubilzer, e) about 5 % w/w to about 30 % w/w of diluents, f) about 2 % w/w to about 20 % w/w of disintegrant, g) about 0.2 % w/w to about 5 % w/w of lubricants, h) about 0.2 % w/w to about 5 % w/w of glidants, i) optionally, about 0.05% w/w to about 0.20% w/w of pH adjusting agents, j) optionally about 0.02 % w/w to about 0.5 % w/w of colorants, and optionally other pharmaceutically acceptable excipients.
Another embodiment of the present invention provides pharmaceutical composition comprising a) about 0.1 to about 10 % w/w of semaglutide, b) about 40 % w/w to about 80 % w/w of permeation enhancer, c) about 1 % w/w to about 20 % w/w of binders, d) about 0.05 % w/w to about 2 % w/w of solubilzer, e) about 5 % w/w to about 30 % w/w of diluents, f) about 2 % w/w to about 20 % w/w of disintegrant, g) about 0.2 % w/w to about 5 % w/w of lubricants, h) about 0.2 % w/w to about 5 % w/w of glidants, i) optionally, about 0.05% w/w to about 0.20% w/w of pH adjusting agents, j) optionally about 0.02 % w/w to about 0.5 % w/w of colorants and optionally other pharmaceutically acceptable excipients; wherein the pharmaceutical composition is stable for at least 24 hours.
A preferred embodiment of the present invention provides pharmaceutical composition comprising a) about 0.1 to about 10 % w/w of semaglutide, b) about 40 % w/w to about 80 % w/w of permeation enhancer, c) about 1 % w/w to about 20 % w/w of binders, d) about 0.05 % w/w to about 2 % w/w of solubilizer, e) about 5 % w/w to about 30 % w/w of diluents, f) about 2 % w/w to about 20 % w/w of disintegrant, g) about 0.2 % w/w to about 5 % w/w of lubricants, h) about 0.2 % w/w to about 5 % w/w of glidants, i) optionally, about 0.05% w/w to about 0.20% w/w of pH adjusting agents, j) optionally about 0.02 % w/w to about 0.5 % w/w of colorants and optionally other pharmaceutically acceptable excipients; wherein the pharmaceutical composition is stable for at least 6 months.
Another embodiment of the present invention provides pharmaceutical composition comprising a) about 0.1 to about 10 % w/w of semaglutide, b) about 40 % w/w to about 80 % w/w of sodium caprylate, c) about 1 % w/w to about 20 % w/w of polyvinylpyrrolidone, d) about 0.05 % w/w to about 2 % w/w of polysorbate 80, e) about 5 % w/w to about 30 % w/w of microcrystalline cellulose, f) about 2 % w/w to about 20 % w/w of disintegrants selected from the group consisting of crospovidone, sodium starch glycolate, starches, substituted hydroxypropyl cellulose, powdered agar, and mixtures thereof, g) about 0.2 % w/w to about 5 % w/w of magnesium stearate, h) about 0.2 % w/w to about 5 % w/w of glidants selected from the group consisting of colloidal silicon dioxide, talc and mixtures thereof, and optionally other pharmaceutically acceptable excipients; wherein, said pharmaceutical composition is in the form of capsule or tablet.
In yet another embodiment of the present invention there is provided pharmaceutical composition of tablet comprising: a) about 0.6 % w/w of semaglutide, b) about 60 % w/w of sodium caprylate, c) about 9 % w/w of polyvinylpyrrolidone, d) about 0.1 % w/w of polysorbate 80, e) about 19 % w/w of microcrystalline cellulose, f) about 4 % w/w of crospovidone, g) about 4 % w/w of sodium starch glycolate, h) about 1 % w/w of magnesium stearate, i) about 1.5 % w/w of colloidal silicon dioxide, j) about 1 % w/w of talc, and k) optionally other pharmaceutically acceptable excipients.
In yet another embodiment of the present invention there is provided pharmaceutical composition of tablet comprising: a) about 1.4 % w/w of semaglutide, b) about 60 % w/w of sodium caprylate, c) about 9 % w/w of polyvinylpyrrolidone, d) about 0.1 % w/w of polysorbate 80, e) about 18 % w/w of microcrystalline cellulose, f) about 4 % w/w of crospovidone, g) about 4 % w/w of sodium starch glycolate, h) about 1 % w/w of magnesium stearate, i) about 1.5 % w/w of colloidal silicon dioxide, j) about 1 % w/w of talc, and k) optionally other pharmaceutically acceptable excipients.
In yet another embodiment of the present invention there is provided pharmaceutical composition of tablet comprising: a) about 2.8 % w/w of semaglutide, b) about 60 % w/w of sodium caprylate, c) about 9 % w/w of polyvinylpyrrolidone, d) about 0.1 % w/w of polysorbate 80, e) about 17 % w/w of microcrystalline cellulose, f) about 4 % w/w of crospovidone, g) about 4 % w/w of sodium starch glycolate, h) about 1 % w/w of magnesium stearate, i) about 1.5 % w/w of colloidal silicon dioxide, j) about 1 % w/w of talc, and k) optionally other pharmaceutically acceptable excipients.
In another embodiment of the present invention there is provided a pharmaceutical composition comprising a) about 0.1 to about 10 % w/w of semaglutide, b) about 40 % w/w to about 80 % w/w of permeation enhancer, c) about 1 % w/w to about 20 % w/w of binders, d) about 0.05 % w/w to about 2 % w/w of solubilizer, e) about 5 % w/w to about 30 % w/w of diluents, f) about 2 % w/w to about 20 % w/w of disintegrant, g) about 0.2 % w/w to about 5 % w/w of lubricants, h) about 0.2 % w/w to about 5 % w/w of glidants, i) about 0.05% w/w to about 0.20% w/w of pH adjusting agents, j) optionally about 0.02 % w/w to about 0.5 % w/w of colorants, and optionally other pharmaceutically acceptable excipients, wherein the composition contains total impurity less than 8% w/w.
Another embodiment of the present invention provides pharmaceutical composition comprising a) about 1 to about 20 mg of semaglutide, b) about 200 to about 400mg of sodium caprylate, c) about 30 to about 60 mg of polyvinylpyrrolidone, d) about 0.25 to about 1mg of polysorbate 80, e) about 50 to about 120 mg of microcrystalline cellulose, f) about 10 to about 75 mg of disintegrants selected from the group consisting of crospovidone, sodium starch glycolate, starches, substituted hydroxypropyl cellulose, powdered agar, and mixtures thereof, g) about 1 to about 10 mg of magnesium stearate, h) about 2 to about 20 mg of glidants selected from the group consisting of colloidal silicon dioxide, talc, and mixtures thereof and optionally other pharmaceutically acceptable excipients; wherein, said pharmaceutical composition is in the form of capsule or tablet.
Yet another embodiment of the present invention provides pharmaceutical composition of tablet comprising a) about 3 mg of semaglutide, b) about 300 mg of sodium caprylate, c) about 40 mg of polyvinylpyrrolidone, d) about 0.5 mg of polysorbate 80, e) about 94 mg of microcrystalline cellulose, f) about 20 mg of crospovidone, g) about 20 mg of sodium starch glycolate h) about 5 mg of magnesium stearate, i) about 7.5 mg of colloidal silicon dioxide, j) about 5 mg of talc, and optionally other pharmaceutically acceptable excipients.
Yet another embodiment of the present invention provides pharmaceutical composition of tablet comprising a) about 7 mg of semaglutide, b) about 300 mg of sodium caprylate, c) about 40 mg of polyvinylpyrrolidone, d) about 0.5 mg of polysorbate 80, e) about 90 mg of microcrystalline cellulose, f) about 20 mg of crospovidone, g) about 20 mg of sodium starch glycolate h) about 5 mg of magnesium stearate, i) about 7.5 mg of colloidal silicon dioxide, j) about 5 mg of talc, and optionally other pharmaceutically acceptable excipients.
In yet another embodiment of the present invention there is provided pharmaceutical composition of tablet comprising a) about 14 mg of semaglutide, b) about 300 mg of sodium caprylate, c) about 40 mg of polyvinylpyrrolidone, d) about 0.5 mg of polysorbate 80, e) about 83 mg of microcrystalline cellulose, f) about 20 mg of crospovidone, g) about 20 mg of sodium starch glycolate h) about 5 mg of magnesium stearate, i) about 7.5 mg of colloidal silicon dioxide, j) about 5 mg of talc, and optionally other pharmaceutically acceptable excipients.
In a preferred embodiment of the present invention there is provided pharmaceutical composition of tablet comprising a) about 14 mg of semaglutide, b) about 300 mg of sodium caprylate, c) about 40 mg of polyvinylpyrrolidone, d) about 0.5 mg of polysorbate 80, e) about 0.5 mg of disodium hydrogen phosphate dihydrate f) about 82.30 mg of microcrystalline cellulose, g) about 20 mg of crospovidone, h) about 20 mg of sodium starch glycolate i) about 5 mg of magnesium stearate, j) about 7.5 mg of colloidal silicon dioxide, k) about 5 mg of talc, and optionally other pharmaceutically acceptable excipients.
The present invention also provides a process for preparing the pharmaceutical composition as described herein above. The process comprises the steps of: a) sifting the permeation enhancer through a sieve; b) preparing a binder component; c) adding the binder component of step (b) to the permeation enhancer of step (a) to obtain a granule; d) adding semaglutide and diluent, disintegrant, glidant, binder, colorant to the granule of step (c); e) adding lubricant to the mixture of step (d) to obtain the pharmaceutical composition.
The binder component of step (b) is prepared by dissolving the binder and solubilizer in water. The permeation enhancer is loaded on to Fluidized Bed Processor in step (a) after sifting through a sieve and binder component is added to the permeation enhancer in the Fluidized Bed Processor in step (c) to obtain a granule. The granule is dried at 60-70°C. The active, semaglutide is mixed with diluent, disintegrant, glidant, remaining binder, and colorant before adding to the dried granule. The mixture is blended for 10 minutes. The lubricant is added to the mixture bend for 5 minutes to form the pharmaceutical composition. The pharmaceutical composition is compressed to form tablets.
In yet another embodiment of the present invention provides process for preparation of tablet composition, wherein process comprises steps of: 1) Sifting- Sifting permeation enhancer through 20# S.S. Sieve 2) Loading the step no. 1 material in Fluidized Bed Processor (FBP) 3) Binder Preparation- Dissolving first amount of binder and solubilizer in purified water under continuous stirring 4) Fluidization- Gradually adding the above binder of step no.3 to the dry mix of step no. 2 while operating the FBP to get a proper granule 5) Drying- Drying the wet granules at 60+ 10°C of step no 04 till loss on drying (LOD) achieved between 3% to 4% at 105°C 6) Dry Screening- Passing dried granules of step no. 5 through 24# SS Sieve 7) Pre-lubrication- Geometrically mixing semaglutide with diluent, disintegrant, glidant, and remaining amount of binder through 30 # screen. Further glidant and optionally color through 100# screen 8) Mixing- Blending sifted material of step no. 07 and step no. 06 for 10 minutes 9) Lubrication- Sifting lubricant through 60 # screen and mix with step no. 08 for 5 min 10) Compression- commencing compression operation on rotary tablet compression machine.
In yet another embodiment of the present invention provides process for preparation of tablet composition, wherein process comprises steps of: 1) Sifting- Sifting sodium caprylate through 20# S.S. Sieve 2) Loading the step no. 1 material in Fluidized Bed Processor (FBP) 3) Binder Preparation- Dissolving polyvinylpyrrolidone and polysorbate 80 in purified water under continuous stirring 4) Fluidization- Gradually adding the above binder of step no.3 to the dry mix of step no. 2 while operating the FBP to get a proper granule 5) Drying- Drying the wet granules at 60+ 10°C of step no 04 till loss on drying (LOD) achieved between 3% to 4% at 105°C 6) Dry Screening- Passing dried granules of step no. 5 through 24# SS Sieve 7) Pre-lubrication- Geometrically mixing semaglutide with microcrystalline cellulose, sodium starch glycolate, crospovidone, colloidal silicon dioxide, and remaining polyvinylpyrrolidone through 30 # screen. Further talc and optionally color through 100# screen 8) Mixing- Blending sifted material of step no. 07 and step no. 06 for 10 minutes 9) Lubrication- Sifting magnesium stearate through 60 # screen and mixing with step no. 08 for 5 min 10) Compression- Proceeding to commence compression operation on rotary tablet compression machine.
In yet another embodiment of the invention, semaglutide and optionally disodium hydrogen phosphate, can also be added during binder preparation stage for the preparation of tablet composition.
In yet another embodiment of the present invention provides process for preparation of tablet composition, wherein process comprises steps of: 1) Sifting- Sifting of sodium caprylate through 20# S.S. Sieve 2) Loading the step (1) material in fluidized bed processor (FBP) 3) Drug solution and binder preparation- Dissolving disodium hydrogen phosphate dihydrate in purified water. Then adding and dissolving semaglutide into it. Then adding and dissolving polyvinylpyrrolidone and polysorbate 80 in the solution under continuous stirring 4) Fluidization- Gradually adding the above binder of step no.3 to the dry mix of step no. 2 while operating the FBP to get proper granules 5) Drying- Drying the wet granules at 60+ 10°C of step no. 04 till loss on drying (LOD) achieved between 3% to 4% at 105°C 6) Dry Screening- Passing dried granules of step no. 5 through 24# SS Sieve 7) Pre-lubrication- Sifting microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, crospovidone and remaining polyvinylpyrrolidone through 30 # screen. Further talc and optionally colorants through 100# screen 8) Mixing- Blending sifted material of step no. 07 and step no. 06 for 10 minutes 9) Lubrication- Sifting magnesium stearate through 60 # screen and mix with step no 08 for 5 min 10) Compression- Proceeding to commence compression operation on rotary tablet compression machine.
In yet another embodiment, the semaglutide can be available in particulate form or in the solution form. Particularly semaglutide can be mixed with other excipients or can be dissolved with solvents to form solution.
In yet another embodiment, the semaglutide can be dissolved with solvents to form solution and spraying of the semaglutide solution onto the other excipients to form granules.
In another embodiment there is provided a pharmaceutical composition comprising semaglutide with low N-nitrosamine impurity in acceptable amounts. In a further embodiment there is provided a pharmaceutical composition comprising semaglutide with no N-nitrosamine impurity.
In yet another embodiment, the composition obtained in present invention are subjected for tests such as dissolution, assay, impurity profiling, related substances, content uniformity, blend uniformity, Hardness, thickness, Friability, Bulk density, tapped density, Hausner ratio (HR), Compressibility Index, Particle Size Distribution, Loss on drying (LOD), etc.
In yet another embodiment, the present invention relates to a pharmaceutical composition comprising semaglutide used for the treatment of treatment of type 2 diabetes as well as a variety of other conditions.
In yet another embodiment, the present invention relates to a method of treating type 2 diabetes as well as a variety of other conditions by a pharmaceutical composition comprising semaglutide.
In yet another embodiment, the present invention relates to a use of pharmaceutical composition comprising semaglutide for the treatment of type 2 diabetes as well as a variety of other conditions.
In a further embodiment, the invention relates to a method of treating diabetes or obesity comprising administering the formulation as defined herein to a patient in need thereof, wherein said formulation is a tablet and is administered orally.
The composition of the invention can be packed into suitable packaging system e. g. Blister packs, strip packs, alu-alu packs, bottles such as glass and plastic bottles, etc.

EXAMPLES
The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

Example - 1: Tablet composition 3 mg strength (Table 1)
Sr. No. Ingredients Ex. 1A Ex. 1B Ex. 1C
Qty. (mg)/ Tab
1 Sodium Caprylate 320 300 310
2 Polyvinylpyrrolidone (PVP) K-30 30 40 32
3 Polysorbate 80 (Tween 80) 0.5 0.5 0.5
4 Purified Water q.s. q.s. q.s.
5 Semaglutide 3 3 3
6 Crospovidone 20 20 16
7 Sodium Starch Glycolate 20 20 16
8 Colloidal Silicon Dioxide 7.5 7.5 7.5
9 Microcrystalline cellulose 84 94 100
10 Polyvinylpyrrolidone (PVP) K-30 5 5 5
11 Talc 5 5 5
12 Magnesium stearate 5 5 5
Tablet Weight (mg) 500 500 500

q.s.: Quantity sufficient.

Manufacturing process for example 1:
1) Sifting- Sift sodium caprylate through 20# S.S. Sieve
2) Load the step no. 1 material in Fluidized Bed Processor (FBP)
3) Binder Preparation- Dissolve polyvinylpyrrolidone and polysorbate 80 in purified water under continuous stirring.
4) Fluidization- Gradually add the above binder of step no.3 to the dry mix of step no. 2 while operating the FBP to get a proper granule.
5) Drying- Dry the wet granules at 60+ 10°C of step no 04 till loss on drying (LOD) achieved between 3% to 4% at 105°C
6) Dry Screening- Pass dried granules of step no. 5 through 24# SS Sieve.
7) Pre-lubrication- Geometrically mix semaglutide with microcrystalline cellulose, sodium starch glycolate, crospovidone, colloidal silicon dioxide, and polyvinylpyrrolidone through 30 # screen. Further talc and optionally color through 100# screen.
8) Mixing- Blend sifted material of step no. 07 and step no. 06 for 10 minutes
9) Lubrication- Sift magnesium stearate through 60 # screen and mix with step no. 08 for 5 min.
10) Compression- Proceed to commence compression operation on rotary tablet compression machine.
Example - 2: Tablet composition 7 mg strength (Table 2)
Sr. No. Ingredients Ex. 2A Ex. 2B Ex. 2C
Qty. (mg)/ Tab
1 Sodium caprylate 295 300 320
2 Polyvinylpyrrolidone (PVP) K-30 45 40 30
3 Polysorbate 80 (Tween 80) 0.5 0.5 0.5
4 Purified water q.s. q.s. q.s.
5 Semaglutide 7 7 7
6 Crospovidone 15 20 20
7 Sodium starch glycolate 20 20 15
8 Yellow iron oxide 0.2 0.2 0.2
9 Colloidal silicon dioxide 7.5 7.5 5
10 Microcrystalline cellulose 94.8 89.8 87.3
11 Polyvinylpyrrolidone (PVP) K-30 5 5 5
12 Talc 5 5 5
13 Magnesium stearate 5 5 5
Tablet Weight (mg) 500 500 500

Manufacturing process for example 2: As described above in example 1.

Example - 3: Tablet composition 14 mg strength (Table 3)
Sr. No.
Ingredients Ex. 3A Ex. 3B Ex. 3C
Qty. (mg)/ Tab
1 Sodium Caprylate 320 300 310
2 Polyvinylpyrrolidone (PVP) K-30 25 40 35
3 Polysorbate 80 (Tween 80) 0.5 0.5 0.5
4 Purified water q.s. q.s. q.s.
5 Semaglutide 14 14 14
6 Crospovidone 20 20 18
7 Sodium starch glycolate 20 20 18
8 Red iron oxide 0.2 0.2 0.2
9 Colloidal silicon dioxide 7.5 7.5 7.5
10 Microcrystalline cellulose 77.8 82.8 81.8
11 Polyvinylpyrrolidone (PVP) K-30 5 5 5
12 Talc 5.5 5 5.5
13 Magnesium stearate 4.5 5 4.5
Tablet Weight (mg) 500 500 500

Manufacturing process for example 3: As described above in example 1.

Example - 4: Semaglutide Tablet % w/w composition (Table 4)
Sr. No. Ingredients % w/w

1. Sodium caprylate 40-80
2. Polyvinylpyrrolidone (PVP) K-30 1-20
3. Polysorbate 80 (Tween 80) 0.05 - 2
4. Purified Water ---
5. Semaglutide 0.1-10
6. Crospovidone 1-10
7. Sodium starch glycolate 1-10
8. Yellow iron oxide 0.02-0.06
9. Red iron oxide 0.02-0.06
8. Colloidal silicon dioxide 0.2-5
9. Microcrystalline cellulose 5-30
11. Talc 0.2-5
12. Magnesium stearate 0.2-5

Manufacturing process for example 4: As described above in example 1.

Example - 5: Semaglutide Tablet % w/w composition (Table 5)
Sr. No. Ingredients % w/w

1. Sodium caprylate 40-80
2. Polyvinylpyrrolidone (PVP) K-30 1-20
3. Polysorbate 80 (Tween 80) 0.05 - 2
4. Disodium hydrogen Phosphate
dihydrate 0- 2
5. Purified Water ---
6. Semaglutide 0.1-10
7. Crospovidone 1-10
8. Sodium starch glycolate 1-10
9. Yellow iron oxide 0.02-0.06
10. Red iron oxide 0.02-0.06
11. Colloidal silicon dioxide 0.2-5
12. Microcrystalline cellulose 5-30
13. Talc 0.2-5
14. Magnesium stearate 0.2-5

Manufacturing process for example 5:
1) Sifting- Sifting of sodium caprylate through 20# S.S. Sieve
2) Load the step (1) material in fluidized bed processor (FBP)
3) Drug solution and binder preparation- Dissolve disodium hydrogen phosphate dihydrate in
purified water. Then add and dissolve semaglutide into it. Then add and dissolve polyvinylpyrrolidone and polysorbate 80 in the solution under continuous stirring.
4) Fluidization- Gradually add the above binder of step no.3 to the dry mix of step no. 2 while operating the FBP to get proper granules.
5) Drying- Dry the wet granules at 60+ 10°C of step no. 04 till loss on drying (LOD) achieved between 3% to 4% at 105°C
6) Dry screening- Pass dried granules of step no. 5 through 24# SS Sieve.
7) Pre-lubrication- Sift microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, crospovidone and remaining polyvinylpyrrolidone through 30 # screen. Further talc and optionally colorants through 100# screen.
8) Mixing- Blend sifted material of step no. 07 and step no. 06 for 10 minutes
9) Lubrication- Sift magnesium stearate through 60 # screen and mix with step no 08 for 5 min.
10) Compression- Proceed to commence compression operation on rotary tablet compression
machine.

Example 6- Semaglutide Tablets-14 mg tablets
Table 6
Sr. No.
Ingredients Ex. 6A Ex. 6B Ex. 6C
Qty. (mg)/ Tab
1 Sodium Caprylate 320 300 310
2 Polyvinylpyrrolidone (PVP) K-30 25 40 35
3 Polysorbate 80 (Tween 80) 0.5 0.5 0.5
4 Purified water q.s. q.s. q.s.
5 Semaglutide 14 14 14
6 Disodium hydrogen phosphate 0.5 0.5 0.5
7 Crospovidone 20 20 18
8 Sodium starch glycolate 20 20 18
9 Red iron oxide 0.2 0.2 0.2
10 Colloidal silicon dioxide 7.5 7.5 7.5
11 Microcrystalline cellulose 77.3 82.3 81.3
12 Polyvinylpyrrolidone (PVP) K-30 5 5 5
13 Talc 5.5 5 5.5
14 Magnesium stearate 4.5 5 4.5
Tablet Weight (mg) 500 500 500

Manufacturing Process-
1) Sifting-Sift Sodium Caprylate through 20# S.S. Sieve
2) Load the step (1) material in Fluidized Bed Processor
3) Drug Solution and Binder Preparation- Dissolve Disodium hydrogen phosphate dihydrate in purified water. Then add and dissolve drug Semaglutide into it. Then add and dissolve PVP K-30 and Polysorbate 80 in the solution under continuous stirring.
4) Fluidization (FBP) - Gradually add the above binder of step no.3 to the Dry Mix of step no. 2 while operating the FBP to get a proper granules.
5) Drying- Dry the wet granules at 60+ 10°C of step no 04 till LOD achieved between 3% to 4% at 105°C
6) Rasping / Dry Screening- Pass dried granules of step no 5 through 24# SS Sieve.
7) Pre lubrication- Sift MCC 102, Sodium Starch Glycolate, Aerosil 200, Crospovidone and PVP K-30 through 30 # screen. Talc and Colour through 100# screen.
8) Mixing- Blend sifted material of step no – 07 and step no – 06 for 10 minutes
9) Lubrication- Sift Magnesium stearate through 60 # screen and mix with step no 08 for 5 min.
10) Compression- Proceed to commence Compression operation on Rotary Tablet compression machine with 15 X 8 mm Capsule shaped, standard concave punch sets having plain on both sides at average weight of 500.000 mg/tab.
Similarly, Semaglutide 3 mg and 7 mg Tablets can be manufactured using similar excipients in appropriate amount.
Example 7- Analytical, dissolution and stability studies
The semaglutide 14mg tablet formed in Example 6B were subjected to analytical, dissolution and stability studies and the results were compared with existing semaglutide 14mg tablet, Rybelsus (manufactured by Novo Nordisk).
The analytical comparison is shown in Table 7 below:
Test Reference Product: Rybelsus
Mfg. by: Novo Nordisk
Batch No.: PS6KX29 Test Product:
Mfg.by: Alkem Laboratories
Batch No.: A1946-009
Description White to off white coloured, oval shaped, biconvex, tablets having debossed “14” on one side and “novo” on other side Light pink to pink coloured, Capsule shaped, biconvex, uncoated tablets, plain surfaces on both sides with mottled appearance.
Assay (% label Claim) 103.7 100.9
Dissolution (% Release) 101 (99 – 105) 88 (80 – 90)
Related Substances (By HPLC)
i) Back bone impurity*
ii) Di-Gly impurity*
iii) Aspartimide impurity*
iv) Des-Thr impurity*
v) Des Aib-His impurity
vi) Mono PEG impurity*
vii) Single highest unknown impurity
viii) Total Impurity
0.13
0.45
0.18
0.48
0.09
0.00
0.55
1.34
0.15
0.58
0.23
0.16
0.08
0.09
0.58
1.58

Stability studies: The stability of the Semaglutide tablets is tested over six months.
Table 8: Stability data of Semaglutide tablet
Sr.
No. TEST SPECIFICATION Initial 6M
1 Description Light Pink to Pink coloured, oval shaped, biconvex, uncoated tablets, plain surfaces on both sides with mottled appearance. Complies Complies
4 Dissolution
Not less than 75 % (Q) of labelled amount of Semaglutide (C187H291N45O59) is dissolved in 60 minutes. Mean- 88
Min- 80
Max- 90 Mean – 83
Min – 79
Max - 86
5 Assay (% Label Claim):
Semaglutide Content
Claim: 14 mg/Tablet Not less than 90.0% and Not more than 110.0% of labelled amount of Semaglutide (C187H291N45O59) 100.9 98.0
6 Related Substance
(By HPLC, w/w)
Back bone impurity* Not more than 1.0 % 0.15 0.20
Di-Gly impurity* Not more than 1.0 % 0.58 0.76
Aspartimide impurity* Not more than 1.0 % 0.23 0.32
Des-Thr impurity* Not more than 1.0 % 0.16 0.29
Des Aib-His impurity Not more than 1.0 % 0.08 0.15
Mono PEG impurity* Not more than 1.0 % 0.09 0.19
Single highest unknown impurity Not more than 1.0 % 0.58 0.98
Total impurity Not more than 8.0 % 1.58 2.52
7 Microbial Limit Test a. Total Aerobic Microbial Count Not more than 103 cfu/g <10 cfu/g <10 cfu/g
b. Total Combined Yeasts & Moulds count Not more than 102 cfu/g <10 cfu/g
<10 cfu/g

c. Escherichia Coli Absent/g Absent/g Absent/g

As observed from Table 8, the semaglutide tablets manufactured in the present invention are stable over a period of six months.
Although the inventions herein have been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described.
All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.
,CLAIMS:
1. A pharmaceutical composition comprising semaglutide and one or more permeation enhancers selected from soyabean lecithin, lysine, phenyl alanine, tryptophan, sodium caprylate, sodium caprate, capsaicin analogue, sodium laurate, sodium chenodeoxycholate, propyl gallate, sodium octanoate, sodium nonanoate, sodium decanoate, sodium undecanoate, sodium dodecanoate, sodium tridecanoate, dodecyl maltoside, tridecyl maltoside, tetradecyl maltoside, sucrose mono-dodecanoate, sucrose mono-tridecanoate, sucrose mono-tetradecanoate, sodium dodecyl sulfate, sodium hexanoate, sodium heptanoate, sodium tetradecanoate, and combinations thereof.

2. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition comprises about 0.1 to about 10 % w/w of semaglutide.

3. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition comprises about 40 % w/w to about 80 % w/w of permeation enhancer.

4. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition further comprises pharmaceutically acceptable excipients selected from the group consisting of binders, solubilizer, diluents, disintegrants, lubricants, glidants, antioxidants, pH adjusting agents, flavouring agent, colorants, sweetening agent, and combinations thereof.

5. The pharmaceutical composition as claimed in claim 1-4, wherein the pharmaceutical composition comprises a) about 0.1 to about 10 % w/w of semaglutide, b) about 40 % w/w to about 80 % w/w of permeation enhancer, c) about 1 % w/w to about 20 % w/w of binders, d) about 0.05 % w/w to about 2 % w/w of solubilizer, e) about 5 % w/w to about 30 % w/w of diluents, f) about 2 % w/w to about 20 % w/w of disintegrant, g) about 0.2 % w/w to about 5 % w/w of lubricants, h) about 0.2 % w/w to about 5 % w/w of glidants, i) optionally about 0.02 % w/w to about 0.5 % w/w of colorants, and optionally other pharmaceutically acceptable excipients.

6. The pharmaceutical composition as claimed in claim 1, wherein the permeation enhancer is sodium caprylate.

7. A pharmaceutical composition comprising a) semaglutide from about 0.1 to about 10 % w/w; b) a permeation enhancer, sodium caprylate from about 40 % w/w to about 80 % w/w; c) a pH adjusting agent, disodium hydrogen phosphate from about 0.05% w/w to about 0.20% w/w; d) disintegrant, crospovidone and/or sodium starch glycolate from about 1%w/w to about 10% w/w; and e) optionally, other pharmaceutically acceptable excipients selected from the group consisting of binders, solubilizer, diluents, disintegrants, lubricants, glidants, antioxidants, flavouring agent, colorants, sweetening agent, and combinations thereof.

8. The pharmaceutical composition as claimed in claim 7, wherein pharmaceutical composition comprises a) about 1 to about 20 mg of semaglutide, and b) about 200 to about 400mg of sodium caprylate.

9. A pharmaceutical composition comprising a) about 0.1 to about 10 % w/w of semaglutide, b) about 40 % w/w to about 80 % w/w of permeation enhancer, c) about 1 % w/w to about 20 % w/w of binders, d) about 0.05 % w/w to about 2 % w/w of solubilizer, e) about 5 % w/w to about 30 % w/w of diluents, f) about 2 % w/w to about 20 % w/w of disintegrant, g) about 0.2 % w/w to about 5 % w/w of lubricants, h) about 0.2 % w/w to about 5 % w/w of glidants, i) about 0.05% w/w to about 0.20% w/w of pH adjusting agents, j) optionally about 0.02 % w/w to about 0.5 % w/w of colorants, and optionally other pharmaceutically acceptable excipients, wherein the composition contains total impurity less than 8% w/w.

10. A process for preparing the pharmaceutical composition of claim 1, the process comprising the steps of:
a. sifting the permeation enhancer through a sieve;
b. preparing a binder component;
c. adding the binder component of step (b) to the permeation enhancer of step (a) to obtain a granule;
d. adding semaglutide and diluent, disintegrant, glidant, binder, colorant to the granule of step (c);
e. adding lubricant to the mixture of step (d) to obtain the pharmaceutical composition.