Oral dosage forms of GLP-1 / GIP dual agonists

Abstract

The present invention discloses a stable stable pharmaceutical formulation of GIP / GLP-1 dual agonists and one or more permeation enhances, and process for their preparation. Oral administration of the formulations of the present invention can be used for the treatment of type 2 diabetes as well as a variety of other conditions.

Description

[0001] Oral dosage forms of GLP-l / GIP dual agonists

[0002] CROSS REFERENCE

[0003] This application claims the priority of Indian provisional applications IN202541030314 filed on 28thMarch 2025.

[0004] FIELD OF THE INVENTION

[0005] The present invention is related to oral dosage form of Glucagon like peptide- 1 (GLP-1) and Gastric inhibitory polypeptide (GIP) agonists. In particular, the invention discloses solid oral dosage form of tirzepatide.

[0006] BACKGROUND

[0007] Therapeutic peptide molecules play a crucial role in the treatment of various diseases. Among these peptides, GLP-1 agonists and / or GIP agonists are particularly significant for managing metabolic disorders such as diabetes, weight management, metabolic dysfunction-associated steatohepatitis (MASH), obstructive sleep apnea, and obesity-related morbidity and mortality.

[0008] Most peptide drugs are approved as injectable formulations suitable for the parenteral route of administration. Some of these peptides can be self-administered via the subcutaneous route, enhancing patient adherence and compliance. However, there is a growing need to develop oral dosage forms of these peptide molecules to further improve convenience and patient compliance.

[0009] Oral administration of peptide and / or protein-based pharmaceuticals faces challenges due to the degradation of peptides and proteins in the digestive system and the poor absorption of large molecules. Tirzepatide is a GLP-l / GIP dual agonist that is currently administered via the subcutaneous route, enabling self-administration. An oral dosage form of tirzepatide has not yet been approved. Developing such a formulation could significantly improve patient adherence and ease of administration compared to parenteral options.

[0010] SUMMARY OF THE INVENTION

[0011] The present invention discloses an oral dosage form of peptide molecules which are GLP-1 and / or GIP agonist. In particular, the invention discloses solid oral dosage forms of tirzepatidecomprising tirzepatide or pharmaceutically acceptable thereof and one or more permeation enhancers.

[0012] The permeation enhancers disclosed herein is selected from the group consisting of sodium caprylate (C8), sodium N-[8-2-hydroxybenzoyl)amino] caprylate (SNAC), or 8-(N-2-hydroxy-5-chlorobenzoyl) -amino-caprylic acid (5-CNAC) or combinations thereof. In particular, the invention discloses optimized concentration of permeation enhancer / s to achieve better absorption, optimal permeability and safe on longer use of the same.

[0013] Further, the disclosed solid oral dosage form of tirzepatide or pharmaceutically acceptable thereof comprises enteric / colon- specific release system.

[0014] The solid oral dosage forms of tirzepatide as disclosed in the present invention is either a capsule or tablet and exhibits at least 0.5 % of relative oral bioavailability compared to subcutaneous administration of tirzepatide.

[0015] The disclosed formulations of the invention may be administered with or without food. Further, the disclosed formulations can be administered either daily or alternate days or once in three days or once in four days or once in five days or once in six days or once in seven days.

[0016] DETAILED DESCRIPTION OF THE INVENTION

[0017] The present invention discloses solid oral dosage forms of GIP / GLP1 dual agonist. In particular, the invention discloses solid oral dosage form of tirzepatide or pharmaceutically acceptable thereof.

[0018] In one embodiment, the invention discloses a solid oral dosage form of GIP / GLP dual agonist comprising; GIP / GLP1 dual agonist and one or more permeation enhancers.

[0019] 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 a peptide. The permeation enhancers is selected from the group consisting of zwitter-ionic permeation enhancers, cationic permeation enhancers, non-ionic permeation enhancers or anionic permeation enhancers.

[0020] The zwitter ionic permeation enhancer is selected from betaines, lauroyl carnitine or mysritoyl carnitine or palmitoyl carnitine. The cation permeation enhancer is selected from the group consisting of chitosan, poly-L-lysine, or quaternary ammonium compounds.The anionic permeation enhancers includes Sulfonic Acid Derivatives such as sodium lauryl sulfate, Fatty Acids such as sodium caprate, sodium caprylate, and sodium stearate, sodium palmitate, sodium larureate, Citric Acid Derivatives such as sodium citrate and other citrate salts or Tartaric Acid Derivatives such as sodium tartrate and similar compounds.

[0021] The non-ionic permeation enhancers include polyethylene glycol (PEG) derivatives such as PEG ethers and esters, fatty acid esters such as ethyl oleate and isopropyl myristate, propylene glycol monocaprylate, sucrose esters, alkyl glycosides such as dodecyl maltoside, sarcosinate surfactants such as sodium palmitoyl sarcosinate, azones, and other non-ionic surfactants, which enhance permeability by disrupting lipid bilayers.

[0022] In the above mentioned embodiment, wherein the permeation enhancers is selected from the group consisting of sodium caprylate (C8), sodium N-[8-2-hydroxybenzoyl)amino] caprylate (SNAC), or 8-(N-2-hydroxy-5-chlorobenzoyl)-amino-caprylic acid (5-CNAC)or combinations thereof.

[0023] In another embodiment, the invention discloses a solid oral dosage form of GIP / GLP dual agonist comprising; GIP / GLP1 dual agonist, permeation enhancers and optionally comprising pharmaceutically acceptable excipients.

[0024] In the above mentioned embodiment, the pharmaceutically acceptable excipients include plasticizer, pH modifier, binders, lubricant, glidant, or disintegrant.

[0025] In any of the above mentioned embodiment, the lubricant is selected from the list comprising of magnesium stearate, zinc stearate, sodium stearyl fumarate, calcium stearate, stearic acid, colloidal silica, sodium lauryl sulfate, aluminum or calcium silicate, cutina, PEG 4000-8000, talc and combinations thereof. The 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.

[0026] In any of the above mentioned embodiment, the glidants include, without limitation, colloidal silicon dioxide (e.g., Aerosil 200), magnesium trisilicate, powdered cellulose, starch, talc and 1 combinations thereof. The 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.

[0027] In any of the above mentioned embodiment, the pH modifiers / regulator is selected from 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- 15 hydroxyethyl)amino)-2-(hydroxymethyl)propane-l,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.

[0028] In any of the above mentioned embodiments, the solid oral dosage form of GIP / GLP1 agonist comprises an enteric / colonic release system (distal intestine). The enteric oral dosage formulations as disclosed in the invention is designed to protect active pharmaceutical ingredients (APIs) from the acidic environment of the stomach and ensure targeted release in the intestine. The enteric materials used in this embodiment are selected to provide optimal release profiles based on their solubility characteristics at varying pH levels. The enteric / colonic polymer referred herein includes polymer, combination of fatty acid and plasticizer, plant based polymer, shellac, pH sensitive polymers. The enteric / colonic polymer is selected from the group consisting of cellulose based polymers such as cellulose acetate phthalate, Hydroxypropyl Methylcellulose Phthalate (HPMCP), Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS) or Methacrylic Acid Copolymers such as Eudragit L which is designed to dissolve at pH levels greater than 5.5 for release in the proximal small intestine or Eudragit S which is suitable for dissolution at pH levels greater than 7.0, ensuring release further along the intestinal tract or polyvinyl based polymers such as Polyvinyl Acetate Phthalate (PVAP) which provides effective acid resistance and controlled release in the intestine. The enteric / colonic polymer is selected from the group consisting of methacrylic acid, ethyl acrylate or methylmethacrylate or combinations thereof.

[0029] In any of the above mentioned embodiments, the amount of the GIP / GLP1 dual agonist ranges from 0.5 mg to 50 mg.In any of the above mentioned embodiments of the invention, wherein the permeation enhancer is present in an amount range from about Img to about 1000 mg.

[0030] In certain embodiments, the permeation enhancer is present in an amount of about 25 mg to about 900 mg; from about 100 mg to about 500 mg; and in particularly preferred embodiments, from about 100 mg to about 300 mg.

[0031] In an embodiment, the invention discloses a pharmaceutical composition of solid oral dosage form of GIP / GLP1 dual agonist comprising tirzepatide or pharmaceutically acceptable thereof and one or more permeation enhancer.

[0032] In the above mentioned embodiment, the the permeation enhancers is selected from the group consisting of sodium caprylate (C8), sodium N-[8-2-hydroxybenzoyl)amino] caprylate (SNAC), or 8-(N-2-hydroxy-5-chlorobenzoyl)-amino-caprylic acid (5-CNAC)combinations thereof.

[0033] In another embodiment, the invention discloses a solid oral dosage form of GIP / GLP1 dual agonist comprising; tirzepatide or pharmaceutically acceptable thereof, one or more permeation enhancers and optionally comprising pharmaceutically acceptable excipients.

[0034] In an embodiment, the present invention discloses solid oral dosage form of tirzepatide comprising, tirzepatide or pharmaceutically acceptable thereof, SNAC and sodium caprylate optionally comprises one or more pharmaceutically acceptable excipients.

[0035] In another embodiment, the invention discloses a GIP / GLP1 dual agonist tablet comprising; tirzepatide or pharmaceutically acceptable thereof, one or more permeation enhancers and optionally comprising pharmaceutically acceptable excipients. The tablet as disclosed in the invention is prepared by either wet granulation or dry granulation or direct compression.

[0036] In another embodiment, the present invention disclosed solid oral dosage form of tirzepatide comprising a) tirzepatide or pharmaceutically acceptable thereof, b) combination of following enhancers SNAC and sodium caprylate (C8); c) a pharmaceutically acceptable excipients selected from the group comprising of binder, lubricant or diluent.

[0037] In an embodiment , the present invention disclosed solid oral dosage form of tirzepatide comprising a) 2 mg to 60 mg tirzepatide or pharmaceutically acceptable thereof, b) 10 mg to 300 mg sodium caprylate (C8); c) optionally a pharmaceutically acceptable excipients selected from the group comprising of of binder, lubricant or diluent.In an embodiment , the present invention disclosed solid oral dosage form of tirzepatide comprising a) 2 mg to 60 mg tirzepatide or pharmaceutically acceptable thereof, b) 10 mg to 300 mg sodium caprylate (C8); c) 10 mg to 300 mg SNAC and d) optionally a pharmaceutically acceptable excipients selected from the group comprising of binder, lubricant or diluent.

[0038] In yet another embodiment, the present invention discloses enteric / coloniccapsules of tirzepatide comprising trizepatide or pharmaceutically acceptable thereof and one or permeation enhancers.

[0039] In an embodiment, the invention discloses a solid oral dosage form containing tirzepatide or pharmaceutically acceptable thereof, SNAC, and a lipid-based carrier system comprising C8 triglycerides. The formulation comprises of HPMCAS to ensure delayed release in the small intestine for optimal therapeutic effect. In yet another embodiment, the pharmaceutical composition comprises tirzepatide and one or more permeation enhancers, wherein the tirzepatide and the permeation enhancer(s) are processed together by dry granulation to form granules having improved flowability and uniform distribution, and wherein the granules are filled into capsules.

[0040] In the above mentioned embodiment, tirzepatide is blended with one or more permeation enhancers selected from non-ionic, zwitter-ionic, cationic, or anionic permeation enhancers, optionally in the presence of one or more pharmaceutically acceptable excipients. The blended components are subjected to dry granulation, including roller compaction or slugging, to obtain compacted material that is subsequently milled to form granules comprising tirzepatide uniformly distributed with the permeation enhancer(s).

[0041] In an embodiment, the invention discloses an oral tablet dosage form comprising tirzepatide in combination with one or more permeation enhancers, wherein the tablet is formulated using a tablet-in-tablet (Tab-in-Tab) approach.

[0042] In the above mentioned embodiment, wherein the tablet-in-tablet dosage form comprises a core tablet containing tirzepatide and at least one permeation enhancer, wherein the permeation enhancer is present individually or as a combination of permeation enhancers in predefined ratios.

[0043] In the above mentioned embodiment, the core tablet is sandwiched between one or more outer layers comprising a mixture of microcrystalline cellulose (MCC) and lactose, followed by compression to form a multilayer tablet. The compressed tablet-in-tablet dosage form is coated using an aqueous, alcoholic, or hydro-alcoholic coating system.In the above mentioned embodiment, the coating comprises one or more enteric, distal enteric, or colonic polymers, selected from methacrylate derivatives, phthalate derivatives, or combinations thereof. The enteric, distal enteric, or colonic polymer is present in an amount ranging from about 2.5% to about 70% w / w of the coating composition. Further, the coating is configured to provide pH-dependent release of tirzepatide at a pH ranging from about 5.5 to about 8.0.

[0044] In another embodiment, the invention provides an oral tablet dosage form comprising tirzepatide and one or more permeation enhancers, wherein the dosage form is prepared using a direct coating approach, wherein the core tablet is directly coated with an aqueous, alcoholic, or hydro-alcoholic coating system comprising one or more enteric, distal enteric, or colonic polymers.

[0045] In another embodiment, the invention provides an oral tablet dosage form comprising tirzepatide and one or more permeation enhancers, wherein the dosage form is prepared using a direct coating approach, wherein the core tablet is directly coated with an aqueous, alcoholic, or hydro-alcoholic coating system comprising one or more enteric, distal enteric, or colonic polymers.

[0046] In any of the foregoing embodiments, the permeation enhancer is selected from one or more absorption-enhancing agents suitable for improving gastrointestinal uptake of peptide therapeutics.

[0047] In any of the above mentioned embodiments, the tablet dosage form is configured to enhance oral bioavailability of tirzepatide while minimizing degradation in the gastric environment.

[0048] In any of the above mentioned embodiments, the disclosed solid oral dosage form of GIP / GLP1 dual agonist can be administered with or without food.

[0049] In any of the disclosed embodiments, the solid oral dosage form of tirzepatide or pharmaceutically acceptable thereof is released at a pH range between 5-8 especially at pH greater than 5.5. In particular, the disclosed formulations of tirzepatide absorption is maximum at a pH of greater than 6.

[0050] In any of the above mentioned embodiments, the solid oral dosage form of tirzeptide or pharmaceutically acceptable thereof absorption is maximum between distal part of intestine and colon.In any of the above-mentioned embodiments, the disclosed solid oral dosage form of GIP / GLP1 dual agonist is used for the treatment of a disease condition in the patient wherein the disease condition includes type 2 diabetes mellitus, non-alcoholic steatohepatitis (NASH), weight management, fatty liver disease, and metabolic disorders.

[0051] In yet another embodiment, the invention discloses a method of delivering tirzepatide for the treatment of type 2 diabetes or obesity, wherein the formulation includes tirzepatide or pharmaceutically acceptable thereof and combination of SNAC, C8 triglycerides and pharmaceutically acceptable excipients. to provide sustained release over a 24-hour period.

[0052] In any of the above mentioned embodiments, the disclosed solid oral dosage form of GIP / GLP1 dual agonist is administered once daily, twice daily, thrice daily, alternate days, once weekly, once biweekly or once monthly.

[0053] Certain specific aspects and embodiments of the invention are more fully described by reference to the following examples. However, these examples should not be construed as limiting the scope of the invention in any manner.

[0054] Examples

[0055] Example 1: Preparation of solid oral dosage form of GIP / GLP1 agonist

[0056] Approximately 15 mg of tirzepatide API was mixed with one or more permeation enhancers, with or without pharmaceutically acceptable excipients. The mixed content was then filled into an enteric / colonic capsule. The enteric / colonic capsules were designed to release the API at a pH range of 5.5 to 7.0. Details of the formulation are provided in Table 1.

[0057] Pharmacokinetic study of GIP / GLP1 agonists

[0058] As part of the experimental design to assess the pharmacokinetics of tirzepatide administered via the oral route and subcutaneous route in male beagle dogs, the dogs were divided into six groups, with each group comprising five dogs.

[0059] Five groups of dogs were administered an oral dosage form of tirzepatide, while another group received tirzepatide via subcutaneous injection. Blood samples were periodically collected at the following time intervals: 0 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, 18 h (Day 0), 24 h (Day 1), 48 h (Day 2), 72 h (Day 3), 168 h (Day 7), 240 h (Day 9), and 360 h (Day 14).The drug / tirzepatide concentrations in the plasma samples were measured, and parameters such as the area under the curve (AUC) and maximum concentration (Cmax) were calculated. The relative bioavailability percentage was compared with the reference, and the results are presented in Table 1.

[0060]

[0061] NM-not measured; * -variability has been observed among the subjects

[0062] Table 1: Pharmacokinetic data of tirzepatide oral formulations prepared as per example -1. Example-2 Tirzepatide capsule compositions

[0063] Granules of the following composition are filled into enteric or colon-based capsules.

[0064]

[0065] Table 2: Tirzepatide capsule compositions

[0066] Example-3 Tirzepatide tablet compositionsEnteric- or colon-targeted tablets are prepared from the composition below using known techniques such as enteric polymer coating or tablet-in-tablet methods as described in the specification.

[0067]

[0068] Table 3: Tirzepatide tablet compositions

Claims

Claims1. A solid oral pharmaceutical dosage form of tirzepatide comprising tirzepatide or a pharmaceutically acceptable salt thereof and combination of two permeation enhancers, wherein the first permeation enhancer is sodium caprylate (C8), and second permeation enhancer is sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC).

2. The dosage form according to claim 1, wherein the first permeation enhancer present in an amount ranging from about 25 mg to about 500 mg.

3. The dosage form according to claim 1, wherein the second permeation enhancer present in an amount ranging from about 25 mg to about 500 mg.

4. The dosage form according to claims 1-3, further comprising one or more pharmaceutically acceptable excipients.

5. The dosage form according to claims 1-4, wherein the dosage form is a tablet with enteric / colonic polymer based coating or an enteric / colonic capsule for release greater than 6..

6. The dosage form according to claim 5, wherein the enteric / colonic polymer based system comprises an enteric / colonic polymer selected from cellulose acetate phthalate (CAP), Hydroxypropyl Methylcellulose Phthalate (HPMCP), Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS), Hypromellose acetate succinate (HPMC-AS), methacrylic acid copolymers, Eudragit L, Eudragit S, Polyvinyl Acetate Phthalate (PVAP), and combinations thereof.

7. The dosage form according to claims 1-6, wherein the dosage form is configured to release tirzepatide at a pH greater than 5.

58. The dosage form according to claims 1-7, wherein the dosage form is configured to release tirzepatide at a pH greater than 6.

09. The dosage form according to claims 1-8, wherein (i) tirzepatide is present in an amount of 0.5 mg to 50 mg and (ii) total amount of the permeation enhancers is present in an amount of 1 mg to 1000 mg.

10. A solid oral pharmaceutical dosage form of tirzepatide comprising tirzepatide or a pharmaceutically acceptable salt thereof and sodium caprylate (C8), optionally comprising pharmaceutically acceptable excipients.

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