Pharmaceutical compositions of oral GLP agonists

Abstract

The present invention relates to a pharmaceutical composition for oral administration comprising a GLP receptor agonist or a pharmaceutically acceptable salt or derivative thereof, one or more penetration enhancers, one or more mucous membrane adhesives, and one or more basifying agents. More preferably, the penetration enhancer is a penetration enhancer based on medium chain fatty acids.

Description

TECHNICAL FIELD

[0001] The present invention relates to a pharmaceutical composition for oral administration comprising a GLP receptor agonist or a pharmaceutically acceptable salt or derivative thereof, one or more permeation enhancer, one or more mucoadhesive agent and one or more alkalizing agent. More preferably, the permeation enhancer is a medium chain fatty acid based permeation enhancer. BACKGROUND

[0002] Peptides are large macromolecules mainly composed of amino acids (AA) connected to each other. Peptides are the main therapeutic compounds used to treat various diseases or disorders, which are mainly administered by injection, however, this mode of administration poses a great inconvenience to the patient's compliance as the patient needs to be repeatedly administered.

[0003] Several attempts have been made to administer polypeptides via oral route. However, most of the attempts were unsuccessful mainly because peptides are susceptible to gastrointestinal tract (GIT) enzymes and pH. The permeability of these macromolecules in the gastrointestinal tract poses further challenges to the development of oral therapy of such macromolecules.

[0004] Therefore, there is an urgent need to use a pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt or derivative thereof to improve oral therapy. Surprisingly, the composition of the present invention can effectively deliver peptides via oral route. SUMMARY

[0005] The present invention relates to a pharmaceutical composition for oral administration comprising a GLP receptor agonist or a pharmaceutically acceptable salt or derivative thereof, one or more permeation enhancer, one or more mucoadhesive agent and one or more alkalizing agent.

[0006] "Therapeutically effective amount" or "effective amount" means the amount of a pharmaceutically active agent that, when administered, is sufficient to affect prevention or treatment. The therapeutically effective amount varies with the disease and its severity, the age, weight, and other conditions of the patient to be treated. The pharmaceutical composition of the present invention can be used to treat diseases related to GLP receptor, including but not limited to type 2 diabetes and obesity.

[0007] "Medium chain fatty acid" means a fatty acid with a carbon chain of C6 to C12. Examples of medium chain fatty acids include caproic acid (C6), caprylic acid (C8), capric acid (C10) and lauric acid (C10).

[0008] In one embodiment, the present invention relates to a pharmaceutical composition for oral administration comprising:

[0009] a therapeutically effective amount of a GLP receptor agonist or a pharmaceutically acceptable salt or derivative thereof;

[0010] one or more penetration enhancers;

[0011] one or more mucoadhesive agents; and

[0012] one or more basifying agents.

[0013] In another embodiment, the present application relates to a pharmaceutical composition for oral administration, comprising:

[0014] a therapeutically effective amount of a GLP receptor agonist or a pharmaceutically acceptable salt or derivative thereof;

[0015] one or more penetration enhancers based on medium chain fatty acids;

[0016] one or more mucoadhesive agents; and

[0017] one or more basifying agents.

[0018] In another embodiment, the present application relates to a pharmaceutical composition for oral administration, comprising:

[0019] a therapeutically effective amount of semaglutide;

[0020] one or more penetration enhancers based on medium chain fatty acids;

[0021] one or more mucoadhesive agents; and

[0022] one or more basifying agents.

[0023] In a specific embodiment, the penetration enhancer based on medium chain fatty acids is a penetration enhancer based on medium chain fatty acids without aromatic functional groups. In some embodiments, the pharmaceutical composition comprises a combination of sodium caprate, sodium caprylate.

[0024] In another embodiment, the present application relates to a pharmaceutical composition for oral administration, comprising:

[0025] a therapeutically effective amount of semaglutide;

[0026] sodium caprate, sodium caprylate, or a combination thereof;

[0027] Carbopol 934P; and

[0028] calcium carbonate.

[0029] In another embodiment, the pharmaceutical composition of the present application is a tablet and is prepared using a direct compression powder.

[0030] a glucagon-like peptide (GLP) receptor agonist

[0031] Glucagon-like peptide (GLP) receptor agonists are agonists of the GLP receptor. GLP receptor agonists are a class of compounds that are primarily used to treat type 2 diabetes. GLP receptor agonists have many other applications, including weight management therapy. GLP receptor agonists include semaglutide, exenatide, liraglutide, tirzepatide, albiglutide, dulaglutide, and lixisenatide. The pharmaceutical compositions of the present invention contain a therapeutically effective amount of a GLP receptor agonist.

[0032] Semaglutide

[0033] Semaglutide is a glucagon-like peptide (GLP) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Currently, the drug is approved as a solution for subcutaneous injection as well as a tablet for oral use. The approved oral tablet is a 3 mg, 7 mg, and 14 mg (Rybelsus) tablet containing the inactive ingredients magnesium stearate, microcrystalline cellulose, povidone, and 8-(2-hydroxybenzamidyl) (SNAC). The pharmaceutical compositions of the present invention contain a therapeutically effective amount of semaglutide. The amount of semaglutide is from 1 mg to 50 mg. Preferably, the amount of semaglutide is from 1 mg to 20 mg. In one embodiment, the pharmaceutical compositions of the present invention contain 3 mg, 7 mg, or 14 mg of semaglutide.

[0034] Permeation enhancer

[0035] Permeation enhancers are used to improve the absorption of poorly permeable active pharmaceutical ingredients from the gastrointestinal tract. The permeation enhancers used in the compositions of the present invention include one or more medium-chain fatty acid-based permeation enhancers containing an aromatic functional group and one or more medium-chain fatty acid-based permeation enhancers containing an aromatic functional group.

[0036] Medium-chain fatty acid-based permeation enhancers containing an aromatic functional group include, but are not limited to, sodium 8-(2-hydroxybenzamidyl) octanoate, N-(10-[2-hydroxybenzoyl]amino) decanoic acid, N-(5-chlorosalicyloyl)-8-aminooctanoic acid. Sodium 8-(2-hydroxybenzamidyl) octanoate, also known as sodium salt hexanoate, is the sodium salt form of salt hexanoate.

[0037] The content of the aromatic functional group-containing medium-chain fatty acid-based penetration enhancer is 25 mg to 500 mg. In one embodiment, the content of the aromatic functional group-containing medium-chain fatty acid-based penetration enhancer is 25 mg to 200 mg. In one embodiment, the aromatic functional group-containing medium-chain fatty acid-based penetration enhancer is sodium 8-(2-hydroxybenzamido)octanoate. The content of sodium 8-(2-hydroxybenzamido)octanoate is 25 mg to 500 mg. In a more specific embodiment, the content of sodium 8-(2-hydroxybenzamido)octanoate is 25 mg to 200 mg.

[0038] The medium-chain fatty acid-based penetration enhancer without aromatic functional group includes, but is not limited to, sodium caprylate / sodium octanoate, sodium caprate / sodium decanoate, sodium hexanoate, and sodium dodecanoate.

[0039] The content of the medium-chain fatty acid-based penetration enhancer without aromatic functional group is 25 mg to 800 mg. In one embodiment, the medium-chain fatty acid-based penetration enhancer without aromatic functional group is sodium caprate or sodium caprylate. The content of sodium caprate or sodium caprylate is 25 mg to 800 mg. In a more specific embodiment, the content of sodium caprate or sodium caprylate is 150 mg to 500 mg.

[0040] Alkalizing agent

[0041] The alkalizing agent is a compound that provides an alkaline environment during and / or after the dissolution of the active ingredient. The alkalizing agent includes, but is not limited to, calcium carbonate, sodium carbonate, sodium bicarbonate, magnesium hydroxide, and aluminum hydroxide, or a combination thereof. The content of the alkalizing agent can be between 25 mg and 600 mg. In one embodiment, the alkalizing agent is calcium carbonate.

[0042] Mucosal adhesive

[0043] Adhesion refers to the ability of a material to attach to the surface of a living being. Adhesion agents improve gastrointestinal retention by promoting bioadhesion of the pharmaceutical composition to the walls of the gastrointestinal tract. Non-limiting examples of adhesion agents include polyacrylates (Carbopol), chitosan, and gums like alginates, and the like. The amount of adhesion agent can be optimized depending on the degree of adhesion desired. The amount of adhesion agent can range from 5 mg to 100 mg. More specifically, the amount of adhesion agent can range from 20 mg to 60 mg. In some preferred embodiments, the mucosal adhesion agent is a polyacrylate typically marketed under the brand name Carbopol. More specifically, the mucosal adhesion agent is Carbopol 934P.

[0044] The oral pharmaceutical composition of the present application can further comprise one or more additional active ingredients. Non-limiting examples of additional active ingredients include biguanides such as metformin; glipizide or glyburide; DPP4 inhibitors such as sitagliptin, alogliptin, linagliptin; SGLT2 inhibitors such as dapagliflozin, canagliflozin, empagliflozin, ertugliflozin; rosiglitazone or pioglitazone; and repaglinide.

[0045] The oral pharmaceutical composition can be a tablet, a capsule, a powder and granules, a granular dosage form, and the like. The multi-chambered dosage form can be a bilayer tablet, a capsule-in-capsule, a tablet-in-capsule, and any other dosage form. The pharmaceutical composition can be formulated by any technique known or understood by one skilled in the art. In a specific embodiment, the pharmaceutical composition of the present application is prepared using a direct compression powder.

[0046] The oral pharmaceutical composition can also optionally include one or more pharmaceutically acceptable excipients such as, but not limited to, diluents, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and solubility enhancers. The diluents can be selected from microcrystalline cellulose, lactose, mannitol, modified starch, dibasic calcium phosphate, any other diluents, or combinations thereof. The disintegrants can be selected from cross-linked polyvinyl pyrrolidone, sodium starch glycolate, any other disintegrants, or combinations thereof. The binders can be selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, any other binders, or combinations thereof. The lubricants can be selected from calcium stearate, magnesium stearate, sodium stearyl fumarate, talc, any other lubricants, or combinations thereof.

[0047] Having described the application with regard to the various embodiments thereof which have been presented for purposes of illustration and not limitation, further embodiments will become apparent to those skilled in the art from consideration of the description and the contents of the specification as a whole.

[0048] The novel features of the application will be further understood from the following examples. It will be apparent to those skilled in the art that numerous modifications can be made to the compositions without departing from the scope of the application. BRIEF DESCRIPTION OF DRAWINGS

[0049] Figure 1 A plot of plasma concentration versus time for 7 mg Rybelsus tablets in human volunteers for Example 1 and 7 of the present application.

[0050] Figure 2 A plot of dissolution of the composition of Example 1 of the present application in phosphate buffer at pH 6.8. DETAILED DESCRIPTION

[0051] EXAMPLE

[0052] Example 1

[0053] COMPOSITION

[0054] No. Ingredient Content per tablet (mg) 1 Semaglutide 7 2 Sodium caprylate 150 3 Sodium caprate 450 4 Calcium carbonate 100 5 Carbomer 934P 25 6 Sodium carboxymethyl starch (SSG) 150 7 Magnesium stearate 20 Total weight 902

[0055] Procedure:

[0056] All ingredients were accurately weighed.

[0057] Sodium caprylate, sodium caprate, calcium carbonate, carbomer, and sodium starch glycolate were placed in a polybag and mixed for 3 minutes.

[0058] Semaglutide powder was added to the mixture.

[0059] The mixture was passed through a 40 mesh sieve.

[0060] The mixture was lubricated with magnesium stearate for 3 minutes.

[0061] Compression is carried out using a suitable punch.

[0062] The lozenges are packed in ALU-ALU blister packs.

[0063] Reference is made to Figure 2 Dissolution profile of the composition of Example 1 was determined in phosphate buffer at pH 6.8.

[0064] A single dose crossover bio-study in human volunteers was carried out in fasted state in three ways to compare the composition of Example 1 with that of Zypitamag (Reference) 7 mg lozenges. The results are referred to Figure 1 The results show that the composition of Example 1 has successfully achieved bioequivalence as compared to the reference Zypitamag 7 mg.

[0065] Example 2

[0066] No. Ingredient Content per tablet (mg) 1 Semaglutide 7 2 Sodium caprylate 150 3 Sodium caprate 250 4 Calcium carbonate 100 5 Carbomer 934P 15 6 Crospovidone 50 7 Magnesium stearate 10 Total weight 582

[0067] Procedure: The composition was prepared using similar procedure as in Example 1.

[0068] Example 3

[0069] No. Ingredient Content per tablet (mg) 1 Semaglutide 7 2 Sodium caprylate 350 3 Sodium caprate 100 4 Calcium carbonate 80 5 Carbomer 934P 20 6 Sodium carboxymethyl starch (SSG) 100 7 Magnesium stearate 10 Total weight 667

[0070] Procedure: The composition was prepared using similar procedure as in Example 1.

[0071] Ratio to A

[0072] Composition

[0073]

[0074]

[0075] Procedure:

[0076] All the ingredients were accurately weighed.

[0077] Ingredients 1 to 5 were passed through 40# sieve.

[0078] The powder mixture was mixed in a polybag for 5 minutes.

[0079] About 3 mL of water was added drop wise to reach the granulation end point.

[0080] The resulting wet granules were dried in a hot air oven at 45°C for 10 hours.

[0081] The dried granules were passed through 40# sieve.

[0082] Magnesium stearate and sodium starch glycolate were added as extra granulation portion and mixed for 5 minutes.

[0083] Compressing with a suitable punch to obtain a mixture.

[0084] A single-dose, fasted-state, three-way crossover bioavailability study comparing the composition of Comparative Example A to 7 mg tablets of Zyprexa® (reference) was conducted in human volunteers. The results are referenced in Figure 3. The results show that the plasma concentrations of the composition of Comparative Example A are very low compared to the 7 mg reference Zyprexa® tablets.

Claims

1. An oral pharmaceutical composition, characterized in that, include: a. A therapeutically effective amount of a GLP receptor agonist or a pharmaceutically acceptable salt or derivative thereof; b. One or more penetration enhancers; c. One or more mucosal adhesives; and d. One or more alkalizing agents.

2. The pharmaceutical composition according to claim 1, characterized in that, The GLP receptor agonist is smegglutinin.

3. The pharmaceutical composition according to claim 1, characterized in that, The one or more penetration enhancers are penetration enhancers based on medium-chain fatty acids.

4. The pharmaceutical composition according to claim 3, characterized in that, The medium-chain fatty acid-based penetration enhancer is sodium 8-(2-hydroxybenzamido)octanoate.

5. The pharmaceutical composition according to claim 4, characterized in that, The content of the sodium 8-(2-hydroxybenzamido)octanoate is from 25 mg to 200 mg.

6. The pharmaceutical composition according to claim 3, characterized in that, The medium-chain fatty acid-based penetration enhancer is sodium decanoate, sodium octanoate, or a combination thereof.

7. The pharmaceutical composition according to claim 6, characterized in that, The content of sodium decanoate, sodium octanoate, or a combination thereof is from 25 mg to 800 mg.

8. The pharmaceutical composition according to claim 1, characterized in that, The adhesive for the mucosa is a polyacrylate.

9. The pharmaceutical composition according to claim 1, characterized in that, The alkalizing agent is selected from the group consisting of calcium carbonate, sodium carbonate, sodium bicarbonate, magnesium hydroxide, aluminum hydroxide, or combinations thereof.

10. The pharmaceutical composition according to claim 1, characterized in that, The composition is in the form of an ingot.

11. The pharmaceutical composition according to claim 1, characterized in that, The tablets are prepared by direct compression.

12. The pharmaceutical composition according to claim 1, characterized in that, The composition further includes one or more additional active ingredients.

13. An oral pharmaceutical composition, characterized in that, include: a. A therapeutically effective dose of semaglutide; b. Sodium decanoate, sodium octanoate, or a combination thereof; c. Polyacrylate carbomer 934P; and d. Calcium carbonate.

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