DESC:TECHNICAL FIELD:
The present subject matter relates to stable pharmaceutical compositions comprising an incretin analog with activity at glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide- 1 (GLP-1) receptor. The present subject matter relates to a stable pharmaceutical composition, comprising tirzepatide or pharmaceutically acceptable salts thereof as an active ingredient and a suitable buffer. Further, provided does a process for preparing the stable pharmaceutical composition comprise tirzepatide or pharmaceutically acceptable salts thereof.
BACKGROUND:
Tirzepatide is an incretin analog and a GIP receptor and GLP-1 receptor co-agonist or dual receptor agonist. Tirzepatide is based on the GIP sequence and contains 2 non-coded amino acids (aminoisobutyric acid, Aib) in positions 2 and 13, a C-terminal amide, and Lys residue at position 20 that is attached to 1,20-eicosanedioic acid via a linker. It is a 39 amino acid linear synthetic peptide where out of the 39 amino acids, 37 are naturally occurring and two are modified amino acid residues present at position 2 and 13, conjugated to a C20 fatty diacid moiety and is reported to have the following chemical structure:

Tirzepatide selectively binds to and activates both the GIP and GLP-1 receptors, the targets for native GIP and GLP-1. GLP-1 is a physiological regulator of appetite and caloric intake. Nonclinical studies suggested that the addition of GIP activity may further contribute to the regulation of food intake. tirzepatide is currently marketed under the tradename Mounjaro®, for the treatment of type 2 diabetes and Zepbound®, for weight loss or Obesity treatment. tirzepatide is administered through subcutaneous injection. Mounjaro® and Zepbound® both are given as subcutaneously once weekly and are available as single-dose pens in 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg per 0.5 ml. Mounjaro® also available as vials in the same strengths 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg per 0.5 ml.

U.S. Pat. No. 9,474,780 discloses tirzepatide and in Example 1 describes with the following sequence:
YX1EGTFTSDYSIX2LDKIAQKAFVQWLMGGPSSGAPPPS
wherein X1 is Aib; X2 is Aib; K at position 20 is chemically modified through conjugation to the epsilon-amino group of the K side-chain with (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(?Glu)1-CO—(CH2)18—CO2H; and the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO: 1).
U.S. Pat. No. 11,357,820 discloses a subcutaneous injectable pharmaceutical composition of tirzepatide containing NaCl, propylene glycol and dibasic sodium phosphate.

There remains a desire for compositions of tirzepatide addressing problems encountered by a peptide containing composition, e.g., process simplicity, storage and stability. Stability of such compositions during the stress conditions encountered during their distribution and storage pose a major challenge. The inventors of the present subject matter developed a composition of tirzepatide, which may in part address the above-mentioned challenges.

SUMMARY OF THE SUBJECT MATTER:
The present subject matter aims to provide a stable pharmaceutical composition comprising incretin analogue having GLP/GIP agonist activity or pharmaceutically acceptable salts thereof and a buffer.
In one aspect, the present subject matter aims to provide a stable pharmaceutical composition comprising tirzepatide or pharmaceutically acceptable salts thereof and a buffer.
In one aspect, the present subject matter aims to provide a stable pharmaceutical composition comprising tirzepatide or pharmaceutically acceptable salts thereof, isotonicity agent and a buffer.
In another aspect, the present subject matter aims to provide a stable pharmaceutical composition comprising tirzepatide or pharmaceutically acceptable salts thereof and a buffer, which can be administered by oral, parenteral, sublingual and buccal and intramuscular route.
In another aspect, the present subject matter aims to provide a stable pharmaceutical composition comprising tirzepatide or pharmaceutically acceptable salts thereof and buffer, which can be administered by parenteral route comprising subcutaneous, intravenous or intramuscular route.
In a specific aspect, the present subject matter aims to provide a stable pharmaceutical composition comprising tirzepatide or pharmaceutically acceptable salts thereof and a buffer, which can be administered by subcutaneous route.
In an embodiment, the composition is administered about once weekly. In an embodiment, the composition is administered once every seven days.
In an embodiment, the stable pharmaceutical composition is in liquid form for subcutaneous administration.
In one embodiment, the stable liquid pharmaceutical composition comprises tirzepatide concentration in an amount of about 2.5 mg/ml to about 60 mg/ml, isotonicity agent and a buffer, wherein the pharmaceutical composition is for subcutaneous administration.
In one embodiment, the stable liquid pharmaceutical composition comprises tirzepatide concentration in an amount of about 2.5 mg/ml to about 50 mg/ml and a buffer, wherein the pharmaceutical composition is for subcutaneous administration.
In an embodiment, the stable liquid pharmaceutical composition comprises tirzepatide in an amount of about 5 mg/ml to about 30 mg/ml. More specifically, the stable liquid pharmaceutical composition comprises tirzepatide in an amount of about 5 mg/ml, 10 mg/mL, 15 mg/ml, 20 mg/ml, 25 mg/ml and 30 mg/ml.
In an embodiment, the stable liquid pharmaceutical composition comprises tirzepatide in an amount of about 2.5 mg/ml to about 60 mg/ml. More specifically, the stable liquid pharmaceutical composition comprises tirzepatide in an amount of about 2.5 mg/ml, 5 mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml & 60 mg/ml.
In an embodiment, the stable liquid pharmaceutical composition comprises sodium chloride and a buffer selected from Tris, Tris HCl , glycine, glycine HCl, phosphate buffer (Sodium dihydrogen phosphate dihydrate), acetic acid, citric acid, sodium citrate, citrate buffer, tartrate buffer, sodium tartarate dihydrate, histidine, L-histidine, sodium carbonate, sodium bicarbonate, carbonate buffer, tartarate, benzoate, sodium acetate, aspartic acid, ascorbic acid, succinic acid, lactic acid, Sodium lactate, glutaric acid, malic acid, boric acid, orthophosphoric acid, sodium acetate, glycine, tartaric acid, cysteine, tyrosine, phenylalanine, praline, arginine, threonine, serine, valine, isoleucine, lysine, glutamine, dibasic sodium phosphate, phosphate buffer and carbonic acid, alkali or alkaline earth salt of one of these acids.
In an additional embodiment, the stable liquid pharmaceutical composition comprises a buffer selected from citrate buffer, tartarate buffer, histidine, acetic acid, citric acid, ascorbic acid, succinic acid, carbonate buffer, tris buffer, lactic acid, Sodium lactate and phosphate buffer or combinations thereof.
In an additional embodiment, the stable liquid pharmaceutical composition comprises a buffer selected from citrate buffer, tartarate buffer, tris buffer and histidine or combinations thereof.
In an additional embodiment, the stable liquid pharmaceutical composition comprises phosphate buffer and pH adjusting agent hydrochloric acid and optionally sodium hydroxide.
In an embodiment, the stable liquid pharmaceutical composition comprises a buffer in an amount of between about 0.01% w/v to about 0.5 % w/v, specifically, the stable liquid pharmaceutical composition comprises a buffer in an amount of between about 0.02 %w/v to about 0.3% w/v, more specifically, the stable liquid pharmaceutical composition comprises a buffer in an amount of about 0.02%, about 0.03 about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09% w/v, about 0.1% w/v, about 0.13% w/v, about 0.14% w/v, about 0.15% w/v, about 0.16% w/v, about 0.18% w/v, about 0.20% w/v, about 0.22% w/v, about 0.23% w/v, about 0.24% w/v, about 0.25% w/v, about 0.26% w/v, about 0.27% w/v, about 0.3% w/v, about 0.35% w/v, about 0.4% w/v, about 0.45% w/v or about 0.5% w/v .
In an embodiment, the stable liquid pharmaceutical composition comprises a buffer in an amount of between about 0.1 mg/ml to about 5 mg/ml, specifically the stable liquid pharmaceutical composition comprises a buffer in an amount of between about 0.2 mg/ml to about 0.8mg/ml, more specifically the stable liquid pharmaceutical composition comprises a buffer in an amount of about 0.2, about 0.3 about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, or about 0.9 mg/ml, about 1.0 mg/ml, about 1.2 mg/ml, about 1.3 mg/ml, about 1.4mg/ml, about 1.5mg/ml, about 1.6 mg/ml, about 1.7 mg/ml, about 1.8 mg/ml, about 2.0 mg/ml, about 2.2 mg/ml, about 2.3 mg/ml, about 2.4 mg/ml, about 2.5 mg/ml, about 2.6 mg/ml, about 2.8 mg/ml, about 3.0 mg/ml, about 3.5 mg/ml, about 4.0 mg/ml, about 4.5 mg/ml or about 5.0 mg/ml.
In another embodiment, the stable liquid pharmaceutical composition has adjusted pH between about 5.0 to about 9.0, specifically the stable liquid pharmaceutical composition has adjusted pH between about 6.0 to about 8.0 or about 6.5 to about 7.5, and more. Specifically the stable liquid pharmaceutical composition has adjusted pH about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, or about 8.0.
In one embodiment, the stable liquid pharmaceutical composition further comprises pharmaceutically acceptable ingredients.
In an embodiment, the stable liquid pharmaceutical composition further comprises pharmaceutically acceptable ingredients as buffers, pH adjusting agents, isotonicity agents, vehicles, preservatives etc.
In one embodiment, the stable liquid pharmaceutical composition further comprises as pH adjusting agents selected from sodium hydroxide, hydrochloric acid, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, potassium hydroxide, Tris, sodium bicarbonate, sodium carbonate, trolamine or combinations thereof.
In an embodiment, the stable liquid pharmaceutical composition further comprises sodium hydroxide and/or hydrochloric acid as pH adjusting agents.
In an embodiment, the stable liquid pharmaceutical composition further comprises hydrochloric acid as pH adjusting agents.
In an embodiment, the stable liquid pharmaceutical composition further comprises sodium hydroxide as pH adjusting agents.
In an embodiment, the stable liquid pharmaceutical composition further comprises hydrochloric acid as pH adjusting agents without use of sodium hydroxide.
In an embodiment, the stable liquid pharmaceutical composition does not comprise preservative.
In an embodiment, the stable liquid pharmaceutical composition comprises a suitable preservative selected from benzyl alcohol, parabens (methyl, propyl, butyl), benzalkonium chloride, chlorobutanol, and thiomersal or combination thereof.
In an embodiment, the stable liquid pharmaceutical composition comprises a suitable isotonicity agent e.g., Sodium chloride (NaCl), propylene glycol or combination thereof.
In an embodiment, the stable liquid pharmaceutical composition comprises suitable vehicles e.g., water for injection, ethanol, glycerin, corn oil, peanut oil, and cotton seed oil or combination thereof.
In an embodiment, the stable liquid pharmaceutical composition comprises water for injection as a vehicle.
In an embodiment, the stable liquid pharmaceutical composition can be stored in or supplied in single dose vial, multiple dose vial, single dose pre-filled syringe, multiple dose pre-filled syringe (PFS), single dose autoinjector/pen or multiple dose autoinjector/pen.
In an embodiment, the stable liquid pharmaceutical composition can be stored in or supplied in single dose vial, single dose pre-filled syringe (PFS) or single dose autoinjector/pen.
In an embodiment, the stable liquid pharmaceutical composition is for subcutaneous administration.
In another embodiment, the stable liquid pharmaceutical composition can be supplied or stored in any suitable volume for subcutaneous administration. In one or more embodiments, the composition volume is between about 0.1 ml and about 1000 ml. For example, the composition volume can be about 0.1 ml to about 10 ml, about 0.5 ml to about 5 ml, or about 1 ml. In some embodiments, the composition volume is about 0.1 ml, about 0.2 ml, about 0.3 ml, about 0.4 ml, about 0.5 ml, about 0.6 ml, about 0.7 ml or about 0.8 ml, about 0.9 ml or about 1.0 ml.
In one embodiment of, the stable liquid pharmaceutical composition can be supplied or stored in any suitable container. For example, the composition can be in a container that includes, but is not limited to, a vial, cartridge, ampoule, bag (IV bag), bottle, or syringe (e.g., pre-filled syringe or component of an auto-injector), disposable pen, reusable pen, or prefilled, disposable pen, reusable pen, or automatic pen injector.
In one embodiment, the stable liquid pharmaceutical composition can be supplied or stored in a vial.
In another embodiment, the stable liquid pharmaceutical composition can be supplied as single dose vial or multiple dose vial.
In an embodiment, the stable liquid pharmaceutical composition can be supplied as single dose vial in volume of 0.5 ml having tirzepatide in an amount of 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg and 30 mg.
In an embodiment, the stable liquid pharmaceutical composition can be supplied as single dose or multiple dose pre-filled syringe in volume of 0.5 ml having tirzepatide in an amount of 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg and 30 mg.
In an embodiment, the stable liquid pharmaceutical composition can be supplied as single dose or multiple dose autoinjector/pen in volume of 0.5 ml having tirzepatide in an amount of 1.25 mg, 2.5 mg, 5mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg and 30 mg.
In an embodiment, the stable liquid pharmaceutical composition can be supplied as single dose or multiple dose autoinjector/pen in volume of 0.6 ml having tirzepatide in an amount of 1.25 mg, 2.5 mg, 5mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg and 30 mg.
In an embodiment, the stable liquid pharmaceutical composition can be prepared as part of an article of manufacture comprising the composition, wherein the article of manufacture can be a single or multi-dose vial, a reusable auoinjector pen, a pre-filled syringe, disposable pen, an autoiniector or a pump.
In another embodiment, the stable liquid pharmaceutical composition may be administered intravenously, intramuscularly or subcutaneously. The stable liquid pharmaceutical compositions typically are administered using a prefilled, disposable pen, reusable pen, or autoinjector pen. Alternatively, the stable liquid pharmaceutical compositions may be administered using a vial or a pump device. In preferably, the device is an autoinjector pen.
In one embodiment, the stable liquid pharmaceutical composition may be presented in a pre-filled syringe or vial or autoinjector pen. Such pre-filled syringe or vial or autoinjector pen may be able to administer about 0.5 ml to about 1 ml of the composition per patient per dose.
In one embodiment, the stable liquid pharmaceutical composition may be presented in a pre-filled syringe or vial or autoinjector pen as strengths of 1.25 mg/0.5ml, 2.5 mg/0.5ml, 5 mg/0.5ml, 7.5 mg/0.5ml, 10 mg/0.5ml, 12.5 mg/0.5ml and 15 mg/0.5ml, 20 mg/0.5ml, 25 mg/0.5ml and 30 mg/0.5ml. Such pre-filled syringe or vial or autoinjector pen may be able to administer about 0.5 ml to about 1 ml of the composition per patient per dose.
In another embodiment, the stable liquid pharmaceutical composition of the present subject matter is stable for about 1 month or more, about 3 months or more, about 6 months or more, about 9 months or more, about 12 months or more, or about 18 months or more, about 24 months or more, about 36 months or more when stored at a temperature of about 2-8°C, 25° C / 60% RH or about 30° C /65% RH.
In an embodiment, the present subject matter is related to a process for preparation of the stable pharmaceutical composition comprising tirzepatide or pharmaceutically acceptable salts thereof as an active ingredient and a suitable buffer, wherein the composition is for subcutaneous use.
In an embodiment, the present subject matter is related to a process of preparation of the stable liquid pharmaceutical composition comprising,
(a) taking 80% of vehicle,
(b) adding isotonicity agent to vehicle of step (a) under continuous stirring until it is completely dissolved,
(c) adding required quantity of buffer to step (b) solution and stirring well to dissolve completely,
(d) optionally adjusting pH using pH adjusting agents,
(e) optionally sparging the solution with nitrogen until dissolved oxygen level is achieved below 0.5 ppm.
(f) adding tirzepatide under continuous stirring until it get dissolved,
(g) optionally adjusting the pH of the solution to desired level and volume adjustment,
(h) filtering the solution followed by filling in vial/PFS in autoinjector and purging with nitrogen.

DETAILED DESCRIPTION OF THE SUBJECT MATTER:

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of skill in the art to which the disclosure pertains.
In this specification, the term "a" or "an" means one or more unless otherwise specified and does not exclude the possibility that more than one element is present.
In this specification, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

In this specification, the term “comprising” or “comprise” or “comprises” describes components that must be present, but leaves open the possibility that other unspecified components may also be present within the scope of the relevant term.

In this specification, the term "stable" and "stability" as used herein refers to both the physical form and the chemical purity of the active pharmaceutical ingredient or the pharmaceutical active dosage form.

In this specification, the term “about” means that amounts, sizes, compositions, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors.
In this specification, the term “buffer” means a compound or mixture of compounds that by their presence in the solution resist changes in the pH upon the addition of small quantities of acid or base.
In this specification, the term “tirzepatide” is intended to encompass tirzepatide and salts thereof. In some instances, pharmaceutically acceptable salts for use herein may be selected from sodium, trifluoroacetate, hydrochloride and/or acetate salts.
In this specification, the term, “treat,” “treating,” “to treat” and the like mean restraining, slowing, stopping or reversing the progression or severity of an existing condition, disease, disorder or symptom.
In this specification, the term, “effective amount/dose” means an amount, concentration or dose of tirzepatide, or a pharmaceutically acceptable salt thereof which, upon single or multiple dose administration to an individual in need thereof, provides a desired pharmacological effect in such an individual who is under diagnosis or treatment.
In this specification, the term “pharmaceutically acceptable salt” is well known to one of skill in the art. Pharmaceutically acceptable salts and common techniques for preparing them are well known in the art. In some instances, pharmaceutically acceptable salts for use herein may be selected from sodium, trifluoroacetate, hydrochloride and/or acetate salts.
In this specification the term GIP or GLP-1 receptors, “activity,” “activate,” “activating” and the like means a capacity of a compound, such as the incretin analogs herein, to bind to and induce a response at the receptor(s), as measured using assays known in the art, such as the in vitro assays.
An embodiment of the present subject matter is directed to provide a stable pharmaceutical composition comprising incretin analog with activity GLP/GIP agonist or pharmaceutically acceptable salts thereof and buffer.
In one aspect, the present subject matter aims to provide a stable pharmaceutical composition comprising tirzepatide or pharmaceutically acceptable salts thereof and buffer.
In another aspect, the present subject matter aims to provide a stable pharmaceutical composition comprising tirzepatide or pharmaceutically acceptable salts thereof and a buffer which can be administered by oral, parenteral, sublingual and buccal and intramuscular route.
In another aspect, the present subject matter aims to provide a stable pharmaceutical composition comprising tirzepatide or pharmaceutically acceptable salts thereof and a buffer which can be administered by parenteral route comprising subcutaneous, intravenous or intramuscular route.
In another aspect, the present subject matter aims to provide a stable pharmaceutical composition comprising tirzepatide or pharmaceutically acceptable salts thereof and a buffer which can be administered by subcutaneous route.
In an embodiment, the stable pharmaceutical composition is in liquid form.
In one embodiment, the stable liquid pharmaceutical composition comprises tirzepatide concentration in an amount of about 2.5 mg/ml to about 60 mg/ml, isotonicity agent and a buffer, wherein the pharmaceutical composition is for subcutaneous administration.
In one embodiment, the stable liquid pharmaceutical composition comprises tirzepatide concentration in an amount of about 2.5 mg/ml to about 60 mg/ml, sodium chloride and a buffer, wherein the pharmaceutical composition is for subcutaneous administration.
In one embodiment, the stable liquid pharmaceutical composition comprises tirzepatide concentration in an amount of about 2.5 mg/ml to about 50 mg/ml, sodium chloride and a buffer, wherein the pharmaceutical composition is for subcutaneous administration.
In an embodiment of the present subject matter, the stable pharmaceutical composition may be administered subcutaneously and contains a therapeutically effective amount of tirzepatide. As described herein, a therapeutically effective amount can be present in a composition at a concentration of tirzepatide, about 1 mg/ml to about 60 mg/ml, more preferably 1.25 mg/ml, to about 60 mg/ml, more specifically for example, about 1.0 mg/ml, 1.25 mg/ml, about 1.5 mg/ml , about 2.0 mg/ml, about 2.5 mg/ml, about 3.0 mg/ml, about 3.5 mg/ml, about 4.0 mg/ml, about 4.5 mg/ml, about 5 mg/ml, about 5.5 mg/ml, about 6.0 mg/ml, about 6.5 mg/ml, about 7.0 mg/ml, about 7.5 mg/ml, about 8.0 mg/ml, about 8.5 mg/ml, about 9.0 mg/ml, about 9.5 mg/ml, about 10 mg/ml, about 10.5 mg/ml, about 11.0 mg/ml, about 11.5 mg/ml, about 12.0 mg/ml, about 12.5 mg/ml, about 13.0 mg/ml, about 13.5 mg/ml, about 14.0 mg/ml, about 14.5 mg/ml, about 15.0 mg/ml, about 15.5 mg/ml, about 16.0 mg/ml, about 16.5 mg/ml, about 17.0 mg/ml, about 17.5 mg/ml, about 18.0 mg/ml, about 18.5 mg/ml, about 19.0 mg/ml, about 19.5 mg/ml, about 20 mg/ml, about 20.5 mg/ml, about 21.5 mg/ml, about 22.0 mg/ml, about 22.5 mg/ml, about 23.0 mg/ml, about 23.5 mg/ml, about 24.0 mg/ml, about 24.5 mg/ml, about 25.0 mg/ml, about 25.5 mg/ml, about 26.0 mg/ml, about 26.5 mg/ml, about 27.0 mg/ml, about 27.5 mg/ml, about 28.0 mg/ml, about 28.5 mg/ml, about 29.0 mg/ml, about 29.5 mg/ml, about 30.0 mg/ml, about 30.5 mg/ml, about 31.0 mg/ml, about 31.5 mg/ml, about 32.0 mg/ml, about 32.5 mg/ml, about 33.0 mg/ml, about 33.5 mg/ml, about 34.0 mg/ml, about 34.5 mg/ml, about 35.0 mg/ml, about 36 mg/ml, about 37.0 mg/ml, about 40 mg/ml, 45.0 mg/ml, about 50 mg/ml about 55 mg/ml or about 60 mg/ml.
In an embodiment, the stable liquid pharmaceutical composition comprises a buffer selected from Tris, Tris HCl, phosphate buffer (Sodium dihydrogen phosphate dihydrate), acetic acid, citric acid, sodium citrate, citrate buffer, tartrate buffer, sodium tartarate dihydrate, histidine, sodium carbonate, sodium bicarbonate, carbonate buffer, tartarate, benzoate, sodium acetate, aspartic acid, ascorbic acid, succinic acid, lactic acid, Sodium lactate, glutaric acid, malic acid, boric acid, orthophosphoric acid, sodium acetate, glycine, tartaric acid, cysteine, tyrosine, phenylalanine, praline, arginine, threonine, serine, valine, isoleucine, lysine, glutamine, dibasic sodium phosphate, phosphate buffer and carbonic acid, alkali or alkaline earth salt of one of these acids.
In an embodiment, the stable liquid pharmaceutical composition comprises a buffer selected from citrate buffer, tartarate buffer, histidine, acetic acid, citric acid, ascorbic acid, succinic acid, carbonate buffer, tris buffer, lactic acid, Sodium lactate and phosphate buffer or combinations thereof.
In an embodiment, the stable liquid pharmaceutical composition comprises a buffer selected from citrate buffer, tartarate buffer, tris buffer and histidine or combinations thereof.
In an embodiment, the stable liquid pharmaceutical composition comprises phosphate buffer.
In an embodiment, the stable liquid pharmaceutical composition comprises histidine buffer.
In an embodiment, the stable liquid pharmaceutical composition comprises citrate buffer.
In an embodiment, the stable liquid pharmaceutical composition comprises tris buffer.
In an embodiment, the stable liquid pharmaceutical composition comprises a buffer in an amount of between about 0.01%w/v to about 0.5 % w/v, specifically the stable liquid pharmaceutical composition comprises buffer in an amount of between about 0.02 %w/v to about 0.3 % w/v, more specifically the stable liquid pharmaceutical composition comprises buffer in an amount of about 0.02%, about 0.03 about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, or about 0.09% w/v, about 0.1% w/v, about 0.13% w/v, about 0.14% w/v, about 0.15% w/v, about 0.16% w/v, about 0.18% w/v, about 0.20% w/v, about 0.22% w/v, about 0.23% w/v, about 0.24% w/v, about 0.25% w/v, about 0.26% w/v, about 0.27% w/v, about 0.3% w/v, about 0.35% w/v, about 0.4% w/v, about 0.45% w/v or about 0.5% w/v .
In an embodiment, the stable liquid pharmaceutical composition comprises a buffer in an amount of between about 0.1 mg/ml to about 5 mg/ml, specifically the stable liquid pharmaceutical composition comprises a buffer in an amount of between about 0.2 mg/ml to about 0.8mg/ml, more specifically the stable liquid pharmaceutical composition comprises a buffer in an amount of about 0.2, about 0.3 about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, or about 0.9 mg/ml, about 1.0 mg/ml, about 1.2 mg/ml, about 1.3 mg/ml, about 1.4mg/ml, about 1.5mg/ml, about 1.6 mg/ml, about 1.7 mg/ml, about 1.8 mg/ml, about 2.0 mg/ml, about 2.2 mg/ml, about 2.3 mg/ml, about 2.4 mg/ml, about 2.5 mg/ml, about 2.6 mg/ml, about 2.8 mg/ml, about 3.0 mg/ml, about 3.5 mg/ml, about 4.0 mg/ml, about 4.5 mg/ml or about 5.0 mg/ml.
The buffer for use with the compositions disclosed herein can be a premixed buffer or can be formed in situ as part of the composition process.
In another embodiment, the stable liquid pharmaceutical composition has adjusted pH between about 5.0 to about 9.0, specifically the stable liquid pharmaceutical composition has adjusted pH between about 6.0 to about 8.0 or about 6.5 to about 7.5, and more specifically the stable liquid pharmaceutical composition has adjusted pH about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, or about 8.0.
In an embodiment, the stable liquid pharmaceutical composition can further include ingredients, such as diluents, pH adjusting agents, salts, isotonicity agents, antioxidants, and preservatives, vehicles etc.
In an embodiment, the stable liquid pharmaceutical composition can further include a pH adjusting agent, for example, an acid or a base. The pH adjusting agents to aid in adjusting the pH of the composition. In one or more embodiments, the pH adjusting agent may be sodium hydroxide, hydrochloric acid, acetic acid, citric acid, fumaric acid, tris buffer, nitric acid, phosphoric acid, sulfuric acid, potassium hydroxide, sodium bicarbonate, sodium carbonate, trolamine or combinations thereof.
In an embodiment, the stable liquid pharmaceutical composition further comprises sodium hydroxide and/or hydrochloric acid as pH adjusting agents.
In another embodiment, the stable liquid pharmaceutical composition further comprises hydrochloric acid as pH adjusting agents.
In another embodiment, the stable liquid pharmaceutical composition further comprises sodium hydroxide as pH adjusting agents.
In another embodiment, the stable liquid pharmaceutical composition further comprises hydrochloric acid as pH adjusting agents without use of sodium hydroxide.
In an embodiment, the stable liquid pharmaceutical composition does not comprises preservative.
In an embodiment, the stable liquid pharmaceutical composition comprises suitable preservative such as benzyl alcohol, phenol, parabens (methyl, propyl, butyl), benzalkonium chloride, chlorobutanol, and thiomersal or combination thereof.
In an embodiment, the stable liquid pharmaceutical composition comprises suitable vehicles. The examples of such vehicles are water for injection, ethanol, glycerin, propylene glycol, corn oil, peanut oil, and cotton seed oil or combination thereof.
In an embodiment, the stable liquid pharmaceutical composition comprises water for injection as a vehicle.
In an embodiment, the stable liquid pharmaceutical composition comprises a suitable isotonicity agent. The examples include dextrose, glycerol, sodium chloride (NaCl), potassium chloride, glycerine, propylene glycol and mannitol.
In an embodiment, the stable liquid pharmaceutical composition comprises sodium chloride as isotonicity agent.
In an embodiment, the stable liquid pharmaceutical composition comprises sodium chloride in an amount of about 6.0 mg/ml to about 10 mg/ml. Specifically the stable liquid pharmaceutical composition comprises sodium chloride in an amount of about 6.2 mg/ml, about 6.4 mg/ml, about 6.5 mg/ml, about 6.8 mg/ml, about 7.0 mg/ml, about 7.0 mg/ml, about 7.5 mg/ml, about 8.0 mg/ml, about 8.1 mg/ml, about 8.2 mg/ml, about 8.3 mg/ml, 8.4 mg/ml, about 8.5 mg/ml, about 9.0 mg/ml, about 9.5 mg/ml or about 10.0 mg/ml.
In another embodiment of the present subject matter, the stable liquid pharmaceutical composition may be formulated for single or multiple dosage administration. Multiple dosage composition may include preservatives or antimicrobial agents. All compositions must be sterile, as known and practiced in the art.
In another embodiment, the stable liquid pharmaceutical composition of the present subject matter comprises a composition that is stable for about 1 month or more, about 3 months or more, about 6 months or more, about 9 months or more, about 12 months or more, or about 18 months or more, about 24 months or more or about 36 months or more when stored at an accelerated temperature of about 2-8°C, 25° C / 60% RH or about 30° C /65% RH.
In another embodiment, the stable liquid pharmaceutical composition can be supplied or stored in any suitable volume for subcutaneous administration. In one or more embodiments, the composition volume is between about 0.1 ml and about 1000 ml. For example, the composition volume can be about 0.1 ml to about 10 ml, about 0.5 ml to about 5 ml, or about 1 ml. In some embodiments, the composition volume is about 0.1 ml, about 0.2 ml, about 0.3 ml, about 0.4 ml, about 0.5 ml, about 0.6 ml, about 0.7 ml or about 0.8 ml, about 0.9 ml or about 1.0 ml.
In another embodiment, the stable liquid pharmaceutical composition can be supplied or stored in volume of about 0.5 ml, about 1.0 ml, about 1.5 ml or about 3.0 ml for subcutaneous administration.
In one embodiment of, the stable liquid pharmaceutical composition can be supplied or stored in any suitable container. For example, the composition can be in a container that includes, but is not limited to, a vial, cartridge, ampoule, bag (IV bag), bottle, or syringe (e.g., pre-filled syringe or component of an auto-injector), disposable pen, reusable pen, or prefilled, disposable pen, reusable pen, or automatic pen injector.
In one embodiment, the stable liquid pharmaceutical composition can be supplied or stored in a vial.
In another embodiment, the stable liquid pharmaceutical composition can be supplied as a single dose vial or multiple dose vial.
In an embodiment, the stable liquid pharmaceutical composition can be supplied as a single dose vial in volume of 0.5 ml having tirzepatide in amount of 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg and 30 mg.
In an embodiment, the stable liquid pharmaceutical composition can be supplied as a single dose or multiple dose pre-filled syringe in volume of 0.5 ml having tirzepatide in amount of 1.25 mg, 2.5 mg, 5mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg and 30 mg.
In an embodiment, the stable liquid pharmaceutical composition can be supplied as single dose or multiple dose autoinjector/pen in volume of 0.5 ml having tirzepatide in amount of 1.25 mg, 2.5 mg, 5mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg and 30 mg.
In an embodiment, the stable liquid pharmaceutical composition can be prepared as part of an article of manufacture comprising the composition, where the article of manufacture can be a single or multi-dose vial, a reusable autoinjector pen, a pre-filled syringe, disposable pen, an autoinjector or a pump.
In another embodiment, the stable liquid pharmaceutical composition may be administered intravenously, intramuscularly or subcutaneously. The stable liquid pharmaceutical compositions typically are administered using a prefilled, disposable pen, reusable pen, or autoinjector pen. Alternatively, the stable liquid pharmaceutical compositions may be administered using a vial or a pump device. In preferably, the device is an autoinjector pen.
In one embodiment, the stable liquid pharmaceutical composition may be presented in a pre-filled syringe or vial or autoinjector pen. Such pre-filled syringe or vial or autoinjector pen may be able to administer about 0.5 ml to about 1 ml of the composition per patient per dose.
In one embodiment, the stable liquid pharmaceutical composition may be presented in a pre-filled syringe or vial or autoinjector pen as strengths of 1.25 mg/0.5ml, 2.5 mg/0.5ml, 5 mg/0.5ml, 7.5 mg/0.5ml, 10 mg/0.5ml, 12.5 mg/0.5ml, 15 mg/0.5ml, 20 mg/0.5ml, 25 mg/0.5ml and 30 mg/0.5ml. Such pre-filled syringe or vial or autoinjector pen may be able to administer about 0.5 ml to about 1 ml of the composition per patient per dose.
In an embodiment, the composition of the tirzepatide is administered about once weekly. In an embodiment, the composition of a tirzepatide is administered once every seven days.
In an embodiment, the stable liquid pharmaceutical composition prior to filling the composition in a container, the container is preferably sterile and has been subjected to a sterilization process prior to filing with the sterile compositions of the subject matter. Compositions may also be subject to sterilization after filling of the vials or other containers.
In an embodiment, the stable liquid pharmaceutical composition of the present subject matter contain tirzepatide or any pharmaceutically acceptable salt thereof as the active ingredient, In some embodiments, the composition preferably contain tirzepatide or any pharmaceutically acceptable salt thereof as the sole active ingredient.
In an embodiment, the stable liquid pharmaceutical composition comprising tirzepatide or a pharmaceutically-acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is in the form of ready to use composition.
In an embodiment, the stable liquid pharmaceutical composition, comprising tirzepatide or a pharmaceutically-acceptable salt thereof and pharmaceutically acceptable excipients, wherein the pharmaceutical composition is in the form of aqueous solution or a lyophilized powder, which can be diluted or reconstituted just prior to use.
In an embodiment, the stable liquid pharmaceutical composition comprises tirzepatide in an amount of about 2.5 mg/ml to about 60 mg/ml, a buffer selected from citrate buffer , sodium citrate, tartarate buffer, sodium tartarate dihydrate, histidine, acetic acid, citric acid, ascorbic acid, succinic acid, carbonate buffer, tris buffer, lactic acid, sodium lactate and phosphate buffer or combinations thereof, a pH adjuster selected from hydrochloric acid and/or sodium hydroxide, wherein the pH is adjusted in-between about 6.0 to about 8.0 and supplied as single dose vial in 0.5 ml volume as strengths 1.25 mg/0.5ml, 2.5 mg/0.5ml, 5 mg/0.5ml, 7.5 mg/0.5ml, 10 mg/0.5ml, 12.5 mg/0.5ml, 15 mg/0.5ml, 20 mg/0.5ml, 25 mg/0.5ml and 30 mg/0.5ml.
In an embodiment, the stable liquid pharmaceutical composition comprises tirzepatide in an amount of about 2.5 mg/ml to about 60 mg/ml, a buffer selected from citrate buffer, tartarate buffer, tris buffer and histidine or combinations thereof, sodium chloride as isotonicity agent, a pH adjuster selected from hydrochloric acid and/or sodium hydroxide, wherein the pH is adjusted in-between about 6.0 to about 8.0, and is supplied as single dose vial in 0.5 ml volume as strengths 1.25 mg/0.5ml, 2.5 mg/0.5ml, 5 mg/0.5ml, 7.5 mg/0.5ml, 10 mg/0.5ml, 12.5 mg/0.5ml, 15 mg/0.5ml, 20 mg/0.5ml, 25 mg/0.5ml and 30 mg/0.5ml.
In another embodiment, the stable liquid pharmaceutical composition comprises tirzepatide in an amount of about 2.5 mg/ml to about 60 mg/ml, a phosphate buffer, hydrochloric acid, sodium chloride as isotonicity agent, optionally sodium hydroxide as pH adjuster, wherein the pH is adjusted in-between about 6.0 to about 8.0, and is supplied as single dose vial in 0.5 ml volume as strengths 1.25 mg/0.5ml, 2.5 mg/0.5ml, 5 mg/0.5ml, 7.5 mg/0.5ml, 10 mg/0.5ml, 12.5 mg/0.5ml, 15 mg/0.5ml, 20 mg/0.5ml, 25 mg/0.5ml and 30 mg/0.5ml.
In an embodiment, the stable liquid pharmaceutical composition comprises tirzepatide in an amount of about 2.5 mg/ml to about 60 mg/ml, a buffer selected from citrate buffer, sodium citrate, tartarate buffer, sodium tartarate dihydrate, histidine, acetic acid, citric acid, ascorbic acid, succinic acid, lactic acid, sodium lactate, carbonate buffer, tris buffer and phosphate buffer or combinations thereof, a pH adjuster selected from hydrochloric acid and/or sodium hydroxide, wherein the pH is adjusted in-between about 6.0 to about 8.0 and is supplied as single dose autoinjector/pre-filled syringe in 0.5 ml volume as strengths 1.25 mg/0.5ml, 2.5 mg/0.5ml, 5 mg/0.5ml, 7.5 mg/0.5ml, 10 mg/0.5ml, 12.5 mg/0.5ml, 15 mg/0.5ml, 20 mg/0.5ml, 25 mg/0.5ml and 30 mg/0.5ml.
In an embodiment, the stable liquid pharmaceutical composition comprises tirzepatide in an amount of about 2.5 mg/ml to about 60 mg/ml, a buffer selected from citrate buffer, tartarate buffer, tris buffer and histidine or combinations thereof, sodium chloride as isotonicity agent, a pH adjuster selected from hydrochloric acid and/or sodium hydroxide, wherein the pH is adjusted in-between about 6.0 to about 8.0, and is supplied as single dose autoinjector/pre-filled syringe in 0.5 ml volume as strengths 1.25 mg/0.5ml, 2.5 mg/0.5ml, 5 mg/0.5ml, 7.5 mg/0.5ml, 10 mg/0.5ml, 12.5 mg/0.5ml, 15 mg/0.5ml, 20 mg/0.5ml, 25 mg/0.5ml and 30 mg/0.5ml.
In another embodiment, the stable liquid pharmaceutical composition comprises tirzepatide in an amount of about 2.5 mg/ml to about 60 mg/ml, a phosphate buffer, hydrochloric acid optionally sodium hydroxide as pH adjuster, wherein the pH is adjusted in-between about 6.0 to about 8.0, and is supplied as single dose autoinjector/pre-filled syringe in 0.5 ml volume as strengths of 1.25 mg/0.5ml, 2.5 mg/0.5ml, 5 mg/0.5ml, 7.5 mg/0.5ml, 10 mg/0.5ml, 12.5 mg/0.5ml, 15 mg/0.5ml, 20 mg/0.5ml, 25 mg/0.5ml and 30 mg/0.5ml.
In an embodiment, the stable liquid pharmaceutical composition comprises tirzepatide in an amount of about 2.5 mg/ml to about 60 mg/ml, a buffer selected from citrate buffer , sodium citrate, tartarate buffer, sodium tartarate dihydrate, histidine, acetic acid, citric acid, ascorbic acid, succinic acid, carbonate buffer, tris buffer, lactic acid, sodium lactate and phosphate buffer or combinations thereof, a pH adjuster selected from hydrochloric acid and/or sodium hydroxide, wherein the pH is adjusted in-between about 6.0 to about 8.0, sodium chloride as isotonicity agent and is supplied as single dose vial or single dose autoinjector/pre-filled syringe in 0.5 ml volume as strengths 1.25 mg/0.5ml, 2.5 mg/0.5ml, 5 mg/0.5ml, 7.5 mg/0.5ml, 10 mg/0.5ml, 12.5 mg/0.5ml, 15 mg/0.5ml, 20 mg/0.5ml, 25 mg/0.5ml and 30 mg/0.5ml.
In an embodiment, the stable liquid pharmaceutical composition comprises tirzepatide in an amount of about 2.5 mg/ml to about 60 mg/ml, a buffer selected from citrate buffer, tartarate buffer, tris buffer and histidine or combinations thereof, a pH adjuster selected from hydrochloric acid and/or sodium hydroxide, wherein the pH is adjusted in-between about 6.0 to about 8.0, sodium chloride as isotonicity agent and is supplied as single dose vial or single dose autoinjector/pre-filled syringe in 0.5 ml volume as strengths 1.25 mg/0.5ml, 2.5 mg/0.5ml, 5 mg/0.5ml, 7.5 mg/0.5ml, 10 mg/0.5ml, 12.5 mg/0.5ml, 15 mg/0.5ml, 20 mg/0.5ml, 25 mg/0.5ml and 30 mg/0.5ml.
In an embodiment, the stable liquid pharmaceutical composition comprises tirzepatide in an amount of about 2.5 mg/ml to about 60 mg/ml, a phosphate buffer, a pH adjuster selected from hydrochloric acid and/or sodium hydroxide, wherein the pH is adjusted in-between about 6.0 to about 8.0, sodium chloride as isotonicity agent and is supplied as single dose vial or single dose autoinjector/pre-filled syringe in 0.5 ml volume as strengths 1.25 mg/0.5ml, 2.5 mg/0.5ml, 5 mg/0.5ml, 7.5 mg/0.5ml, 10 mg/0.5ml, 12.5 mg/0.5ml, 15 mg/0.5ml, 20 mg/0.5ml, 25 mg/0.5ml and 30 mg/0.5ml.
In an embodiment, the stable liquid pharmaceutical composition as described herein is administered with an intent of treatment or prevention of a disease or condition to an individual in need of an effective amount/dose. In an embodiment, the stable liquid pharmaceutical composition is suitable for subcutaneous administration, for example, to a mammal to treat or prevent a disease or condition. Preferably, the mammal is a human. The disclosure further describes a composition herein for use as a medicament. The disease or condition that is treatable by the administration of an effective amount/dose of a composition herein example, diabetes, type 2 diabetes mellitus (“T2D”), refractory type 2 diabetes, high blood pressure, raising HDL-C, hyperglycemia, glycemic control, weight loss treat, weight management, obesity, obstructive sleep apnea, chronic kidney disease, preventing or delaying HFpEF or cognitive decline or combinations thereof. In particular, the compositions of the present disclosure can be administered to patients with type 2 diabetes mellitus (“T2D”) and obesity.
The present subject matter also relates to a process for preparation of the stable pharmaceutical composition comprising tirzepatide or pharmaceutically acceptable salts thereof as an active ingredient, isotonicity agent and a suitable buffer, wherein the compositions for subcutaneous use.
In an embodiment, the present subject matter is related to a process of preparation of the stable liquid pharmaceutical composition comprising,
(a) taking 80% of the vehicle,
(b) adding isotonicity agent to vehicle of step (a) under continuous stirring until it is completely dissolved,
(c) adding required quantity of buffer to step (b) solution and stirring well to dissolve completely,
(d) optionally adjusting pH using pH adjusting agents,
(e) optionally sparging the solution with nitrogen until dissolved oxygen level is achieved below 0.5 ppm.
(f) adding tirzepatide under continuous stirring until it get dissolved,
(g) optionally adjusting the pH of the solution to desired level and volume adjustment,
(h) filtering the solution followed by filling in vial/ PFS in autoinjector and purging with nitrogen.

The present subject matter is further illustrated by the following examples, which are provided merely to be exemplary of the subject matter and are not intended to limit the scope of the subject matter. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present subject matter.
Examples
Examples 1 to 14
Table 1 – Tirzepatide 2.5mg/0.5ml Injectable Composition
Ingredients Concentration %w/v
Examples 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Tirzepatide 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
Sodium Chloride 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82
Histidine 0.05 - - - - - - - - - - 0.15 - -
Sodium citrate - 0.05 - - - - - - - - - - 0.25 -
Sodium tartrate dihydrate - - 0.05 - - - - - - - - - - -
citric acid - - - 0.06 - - - - - - - - - -
succinic acid - - - - 0.08 - - - - - - - - -
lactic acid - - - - - 0.04 - - - - - - - -
Sodium lactate - - - - - - 0.07 - - - - - - -
Phosphate buffer - - - - - - - 0.05 0.05 - - - - -
Carbonate buffer - - - - - - - - 0.05 - - - -
Tris buffer - - - - - - - - - - 0.05 - - 0.06
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Examples 15- 28
Table 2 - Tirzepatide 5mg/0.5ml Injectable Composition
Ingredients Concentration %w/v
Examples 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Tirzepatide 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
Sodium Chloride 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82
Histidine 0.05 - - - - - - - - - - 0.15 - -
Sodium citrate - 0.05 - - - - - - - - - - 0.25 -
Sodium tartrate dihydrate - - 0.05 - - - - - - - - - - -
citric acid - - - 0.06 - - - - - - - - - -
succinic acid - - - - 0.08 - - - - - - - - -
lactic acid - - - - - 0.04 - - - - - - - -
Sodium lactate - - - - - - 0.07 - - - - - - -
Phosphate buffer - - - - - - - 0.05 0.05 - - - - -
Carbonate buffer - - - - - - - - 0.05 - - - -
Tris buffer - - - - - - - - - - 0.05 - - 0.06
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Examples 29-42
Table 3 - Tirzepatide 7.5 mg/0.5ml Injectable Composition
Ingredients Concentration %w/v
Examples 29 30 31 32 33 34 35 36 37 38 39 40 41 42
Tirzepatide 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5
Sodium Chloride 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82
Histidine 0.05 - - - - - - - - - - 0.15 - -
Sodium citrate - 0.05 - - - - - - - - - - 0.25 -
Sodium tartrate dihydrate - - 0.05 - - - - - - - - - - -
citric acid - - - 0.06 - - - - - - - - - -
succinic acid - - - - 0.08 - - - - - - - - -
lactic acid - - - - - 0.04 - - - - - - - -
Sodium lactate - - - - - - 0.07 - - - - - - -
Phosphate buffer - - - - - - - 0.05 0.05 - - - - -
Carbonate buffer - - - - - - - - 0.05 - - - -
Tris buffer - - - - - - - - - - 0.05 - - 0.06
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Examples 43-56
Table 4 - Tirzepatide 10 mg/0.5ml Injectable Composition
Ingredients Concentration %w/v
Examples 43 44 45 46 47 48 49 50 51 52 53 54 55 56
Tirzepatide 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0
Sodium Chloride 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82
Histidine 0.05 - - - - - - - - - - 0.15 - -
Sodium citrate - 0.05 - - - - - - - - - - 0.25 -
Sodium tartrate dihydrate - - 0.05 - - - - - - - - - - -
citric acid - - - 0.06 - - - - - - - - - -
succinic acid - - - - 0.08 - - - - - - - - -
lactic acid - - - - - 0.04 - - - - - - - -
Sodium lactate - - - - - - 0.07 - - - - - - -
Phosphate buffer - - - - - - - 0.05 0.05 - - - - -
Carbonate buffer - - - - - - - - 0.05 - - - -
Tris buffer - - - - - - - - - - 0.05 - - 0.06
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Examples 57-70
Table 5 - Tirzepatide 12.5 mg/0.5ml Injectable Composition
Ingredients Concentration %w/v
Examples 57 58 59 60 61 62 63 64 65 66 67 68 69 70
Tirzepatide 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5
Sodium Chloride 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82
Histidine 0.05 - - - - - - - - - - 0.15 - -
Sodium citrate - 0.05 - - - - - - - - - - 0.25 -
Sodium tartrate dihydrate - - 0.05 - - - - - - - - - - -
citric acid - - - 0.06 - - - - - - - - - -
succinic acid - - - - 0.08 - - - - - - - - -
lactic acid - - - - - 0.04 - - - - - - - -
Sodium lactate - - - - - - 0.07 - - - - - - -
Phosphate buffer - - - - - - - 0.05 0.05 - - - - -
Carbonate buffer - - - - - - - - 0.05 - - - -
Tris buffer - - - - - - - - - - 0.05 - - 0.06
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Examples 71-84
Table 6 - Tirzepatide 15 mg/0.5ml Injectable Composition
Ingredients Concentration %w/v
Examples 71 72 73 74 75 76 77 78 79 80 81 82 83 84
Tirzepatide 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0
Sodium Chloride 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82
Histidine 0.05 - - - - - - - - - - 0.15 - -
Sodium citrate - 0.05 - - - - - - - - - - 0.25 -
Sodium tartrate dihydrate - - 0.05 - - - - - - - - - - -
citric acid - - - 0.06 - - - - - - - - - -
succinic acid - - - - 0.08 - - - - - - - - -
lactic acid - - - - - 0.04 - - - - - - - -
Sodium lactate - - - - - - 0.07 - - - - - - -
Phosphate buffer - - - - - - - 0.05 0.05 - - - - -
Carbonate buffer - - - - - - - - 0.05 - - - -
Tris buffer - - - - - - - - - - 0.05 - - 0.06
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Examples 85-98
Table 7- Tirzepatide 1.25 mg/0.5ml Injectable Composition
Ingredients Concentration %w/v
Examples 85 86 87 88 89 90 91 92 93 94 95 96 97 98
Tirzepatide 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25
Sodium Chloride 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82
Histidine 0.05 - - - - - - - - - - 0.15 - -
Sodium citrate - 0.05 - - - - - - - - - - 0.25 -
Sodium tartrate dihydrate - - 0.05 - - - - - - - - - - -
citric acid - - - 0.06 - - - - - - - - - -
succinic acid - - - - 0.08 - - - - - - - - -
lactic acid - - - - - 0.04 - - - - - - - -
Sodium lactate - - - - - - 0.07 - - - - - - -
Phosphate buffer - - - - - - - 0.05 0.05 - - - - -
Carbonate buffer - - - - - - - - 0.05 - - - -
Tris buffer - - - - - - - - - - 0.05 - - 0.06
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Examples 99-112
Table 8 - Tirzepatide 20 mg/0.5ml Injectable Composition
Ingredients Concentration %w/v
Examples 99 100 101 102 103 104 105 106 107 108 109 110 111 112
Tirzepatide 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0
Sodium Chloride 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82
Histidine 0.05 - - - - - - - - - - 0.15 - -
Sodium citrate - 0.05 - - - - - - - - - - 0.25 -
Sodium tartrate dihydrate - - 0.05 - - - - - - - - - - -
citric acid - - - 0.06 - - - - - - - - - -
succinic acid - - - - 0.08 - - - - - - - - -
lactic acid - - - - - 0.04 - - - - - - - -
Sodium lactate - - - - - - 0.07 - - - - - - -
Phosphate buffer - - - - - - - 0.05 0.05 - - - - -
Carbonate buffer - - - - - - - - 0.05 - - - -
Tris buffer - - - - - - - - - - 0.05 - - 0.06
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Examples 113-126
Table 9- Tirzepatide 25 mg/0.5ml Injectable Composition
Ingredients Concentration %w/v
Examples 113 114 115 116 117 118 119 120 121 122 123 124 125 126
Tirzepatide 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0
Sodium Chloride 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82
Histidine 0.05 - - - - - - - - - - 0.15 - -
Sodium citrate - 0.05 - - - - - - - - - - 0.25 -
Sodium tartrate dihydrate - - 0.05 - - - - - - - - - - -
citric acid - - - 0.06 - - - - - - - - - -
succinic acid - - - - 0.08 - - - - - - - - -
lactic acid - - - - - 0.04 - - - - - - - -
Sodium lactate - - - - - - 0.07 - - - - - - -
Phosphate buffer - - - - - - - 0.05 0.05 - - - - -
Carbonate buffer - - - - - - - - 0.05 - - - -
Tris buffer - - - - - - - - - - 0.05 - - 0.06
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Examples 127-140
Table 9- Tirzepatide 30 mg/0.5ml Injectable Composition
Ingredients Concentration %w/v
Examples 127 128 129 130 131 132 133 134 135 136 137 138 139 140
Tirzepatide 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0
Sodium Chloride 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82 0.82
Histidine 0.05 - - - - - - - - - - 0.15 - -
Sodium citrate - 0.05 - - - - - - - - - - 0.25 -
Sodium tartrate dihydrate - - 0.05 - - - - - - - - - - -
citric acid - - - 0.06 - - - - - - - - - -
succinic acid - - - - 0.08 - - - - - - - - -
lactic acid - - - - - 0.04 - - - - - - - -
Sodium lactate - - - - - - 0.07 - - - - - - -
Phosphate buffer - - - - - - - 0.05 0.05 - - - - -
Carbonate buffer - - - - - - - - 0.05 - - - -
Tris buffer - - - - - - - - - - 0.05 - - 0.06
Sodium hydroxide q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Hydrochloric acid q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH q.s. to pH
Water for injection q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

Example 141 - Stability Experiments:
The concentration of tirzepatide and degradation products in compositions was analyzed by HPLC method. The results of the experiment are illustrated in Table 10 below.
Table 10: Stability data set-A-
Tests Example 1 Example 2 Example 3 Example 8 Example 11
Initial
Description Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution
Assay of tirzepatide (%) 97.6
101.0
102.2
102.2
100.6

Total degradation products (%) 0.07
0.08
0.12
0.14
0.1

1 Month 2-8°C
Description Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution
Assay of tirzepatide (%) 98.4
102.4
101.2
101.2
100.8

Total degradation products (%) 0.15
0.12
0.06
0.11
0.07

2 Month 2-8°C
Description Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution
Assay of tirzepatide (%) 98.0 100.0 94.2 98.6 97.4
Total degradation products (%) 0.17 0.95 0.92 0.75 0.21

Table 11: Stability data set-B-
Tests Example 12 Example 13 Example 40 Example 41 Example
82 Example
83
Initial
Description Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution
Assay of tirzepatide (%) 108.2 103.8 97.8 96.3 97.1 104.8
Total degradation products (%) 0.26 0.22 0.12 0.36 0.43 0.19
1 Month 2-8°C
Description Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution
Assay of tirzepatide (%) 98.4 99.0 NA 98.9 98.9 96.6
Total degradation products (%) 0.13 0.44 0.22 0.89 0.8 0.25
3 Month 2-8°C
Description Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution
Assay of tirzepatide (%) 101.6 98.2 NA 97.3 96.0 103.8
Total degradation products (%) 0.68 1.13 0.75 1.06 0.98 1.58
6 Month 2-8°C
Description Clear, colorless solution Clear, colorless solution Clear, colorless solution NA NA Clear, colorless solution
Assay of tirzepatide (%) 100.6 97.6 100.3 NA 95.8 100.8
Total degradation products (%) 0.72 1.02 0.98 NA 1.93
1.31

Above experiments’ result demonstrated that the compositions of the present subject matter are stable.

We Claim:

1. A stable liquid pharmaceutical composition comprising tirzepatide or a pharmaceutically acceptable salt thereof, a isotonicity agent and a buffer in in an amount of about 0.01% w/v to about 0.5 % w/v, wherein the pharmaceutical composition is for parenteral use.

2. The stable liquid pharmaceutical composition according to claim 1, comprising tirzepatide in an amount of about 2.5 mg/ml to about 60 mg/ml, sodium chloride as isotonicity agent in an amount of 6.0 mg/ml to 10 mg/ml and a buffer selected from citrate buffer, histidine, tartarate buffer, tris buffer, lactic acid, carbonate buffer and succinic acid or combinations thereof.

3. The stable liquid pharmaceutical composition according to claim 2, comprising tirzepatide in an amount of about 2.5 mg/ml, about 5 mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml, 40 mg/ml, 30 mg/ml, 50 mg/ml or 60 mg/ml, sodium chloride and buffer selected from citrate buffer, histidine, tartarate buffer, tris buffer, lactic acid, carbonate buffer and succinic acid or combinations thereof.

4. The stable liquid pharmaceutical composition according to claim 3, wherein the buffer comprises citrate buffer.

5. The stable liquid pharmaceutical composition according to claim 3, wherein the buffer comprises histidine buffer.

6. The stable liquid pharmaceutical composition according to claim 3, wherein the buffer comprises tris buffer.

7. The stable liquid pharmaceutical composition according to claim 1, wherein the composition is supplied as single dose vials or multiple dose vials, single dose or multiple dose pre-filled syringe (PFS) or autoinjector/pen.
8. The stable liquid pharmaceutical composition according to claim 7, wherein the pre-filled syringe (PFS) or autoinjector/pen is able to administer about 0.5 ml to about 1 ml of the composition per patient per dose.

9. The stable liquid pharmaceutical composition according to claim 1, for use in the treatment of diabetes, obesity, refractory type 2 diabetes or obstructive sleep apnea, preventing , delaying HFpEF or chronic kidney disease.

10. The stable liquid pharmaceutical composition according to claim 1, wherein the composition is administered in effective dose once weekly.
,CLAIMS:We Claim:

1. A stable liquid pharmaceutical composition comprising tirzepatide or a pharmaceutically acceptable salt thereof, a isotonicity agent and a buffer in in an amount of about 0.01% w/v to about 0.5 % w/v, wherein the pharmaceutical composition is for parenteral use.

2. The stable liquid pharmaceutical composition according to claim 1, comprising tirzepatide in an amount of about 2.5 mg/ml to about 60 mg/ml, sodium chloride as isotonicity agent in an amount of 6.0 mg/ml to 10 mg/ml and a buffer selected from citrate buffer, histidine, tartarate buffer, tris buffer, lactic acid, carbonate buffer and succinic acid or combinations thereof.

3. The stable liquid pharmaceutical composition according to claim 2, comprising tirzepatide in an amount of about 2.5 mg/ml, about 5 mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml, 40 mg/ml, 30 mg/ml, 50 mg/ml or 60 mg/ml, sodium chloride and buffer selected from citrate buffer, histidine, tartarate buffer, tris buffer, lactic acid, carbonate buffer and succinic acid or combinations thereof.

4. The stable liquid pharmaceutical composition according to claim 3, wherein the buffer comprises citrate buffer.

5. The stable liquid pharmaceutical composition according to claim 3, wherein the buffer comprises histidine buffer.

6. The stable liquid pharmaceutical composition according to claim 3, wherein the buffer comprises tris buffer.

7. The stable liquid pharmaceutical composition according to claim 1, wherein the composition is supplied as single dose vials or multiple dose vials, single dose or multiple dose pre-filled syringe (PFS) or autoinjector/pen.
8. The stable liquid pharmaceutical composition according to claim 7, wherein the pre-filled syringe (PFS) or autoinjector/pen is able to administer about 0.5 ml to about 1 ml of the composition per patient per dose.

9. The stable liquid pharmaceutical composition according to claim 1, for use in the treatment of diabetes, obesity, refractory type 2 diabetes or obstructive sleep apnea, preventing , delaying HFpEF or chronic kidney disease.

10. The stable liquid pharmaceutical composition according to claim 1, wherein the composition is administered in effective dose once weekly.