Oral GLP agonist pharmaceutical composition with high bioavailability

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 medium-chain fatty acid-based penetration enhancer comprising an aromatic functional group, and one or more medium-chain fatty acid-based penetration enhancer not comprising an aromatic functional group. The pharmaceutical composition may also optionally include an alkalizing agent.

Description

Technical Field

[0001] This invention relates to an oral pharmaceutical composition comprising a GLP receptor agonist or a pharmaceutically acceptable salt or derivative thereof, one or more medium-chain fatty acid-based permeation enhancers containing aromatic functional groups, and one or more medium-chain fatty acid-based permeation enhancers not containing aromatic functional groups. The pharmaceutical composition may also optionally comprise an alkalizing agent. Background Technology

[0002] Peptides are large molecules primarily composed of interconnected amino acids (AAs). They are key therapeutic compounds used to treat various diseases or disorders, mainly administered via injection. However, this method of administration, requiring repeated doses, presents significant challenges to patient compliance.

[0003] Numerous attempts have been made to administer peptides orally. However, most have been unsuccessful, primarily because peptides are susceptible to the effects of gastrointestinal (GIT) enzymes. The permeability of these macromolecules in the gastrointestinal tract presents further challenges to the development of oral therapies for such macromolecules.

[0004] Therefore, there is an urgent need for pharmaceutical compositions containing peptides or pharmaceutically acceptable salts or derivatives thereof to improve oral therapy. Surprisingly, the compositions of the present invention can efficiently deliver peptides via the oral route. Summary of the Invention

[0005] To address the aforementioned problems, the present invention aims to provide an oral pharmaceutical composition comprising a GLP receptor agonist or a pharmaceutically acceptable salt or derivative thereof, one or more medium-chain fatty acid-based permeation enhancers containing aromatic functional groups, and one or more medium-chain fatty acid-based permeation enhancers without aromatic functional groups. The pharmaceutical composition may also optionally comprise an alkalizing agent.

[0006] "Therapeutic effective amount" or "effective amount" refers to the amount of active pharmaceutical ingredient that, when administered, is sufficient to affect prevention or treatment. Therapeutic effective amounts vary depending on the disease and its severity, the age, weight, and other conditions of the patient to be treated. The pharmaceutical compositions of the present invention can be used to treat diseases related to GLP receptors, including but not limited to type 2 diabetes and obesity.

[0007] Medium-chain fatty acids are fatty acids with carbon chains ranging from C6 to C12. Examples of medium-chain fatty acids include hexanoic acid (C6), caprylic acid (C8), capric acid (C10), and lauric acid (C10).

[0008] In some embodiments, the present invention also provides an oral pharmaceutical composition comprising: a. a therapeutically effective amount of a GLP receptor agonist or a pharmaceutically acceptable salt or derivative thereof; b. one or more medium-chain fatty acid-based penetration enhancers containing aromatic functional groups; and c. one or more medium-chain fatty acid-based penetration enhancers not containing aromatic functional groups.

[0009] In some embodiments, the present invention also provides an oral pharmaceutical composition comprising: a. a therapeutically effective amount of a GLP receptor agonist or a pharmaceutically acceptable salt or derivative thereof; b. one or more medium-chain fatty acid-based penetration enhancers containing aromatic functional groups; c. one or more medium-chain fatty acid-based penetration enhancers not containing aromatic functional groups; and d. one or more alkalizing agents.

[0010] In some embodiments, the present invention also provides an oral pharmaceutical composition comprising: a. a therapeutically effective amount of semaglutide; b. one or more medium-chain fatty acid-based penetration enhancers containing aromatic functional groups; c. one or more medium-chain fatty acid-based penetration enhancers not containing aromatic functional groups; and d. one or more alkalizing agents.

[0011] In some embodiments, the medium-chain fatty acid-based penetration enhancer containing aromatic functional groups is sodium 8-(2-hydroxybenzamido)octanoate. In a more specific embodiment, the content of sodium 8-(2-hydroxybenzamido)octanoate is from 25 mg to 200 mg.

[0012] In some embodiments, the present invention also provides an oral pharmaceutical composition comprising: a. a therapeutically effective amount of semaglutide; b. sodium 8-(2-hydroxybenzamido)octanoate; c. sodium decanoate, sodium caprylate, or a combination thereof; and d. calcium carbonate.

[0013] In another embodiment, the pharmaceutical composition of the present invention is in the form of tablets, and is prepared by direct compression of powder. In some embodiments, the tablets do not contain a binder.

[0014] In some embodiments, in single-dose fasting studies in human volunteers, the AUC of one or more pharmaceutical compositions of the present invention is... 0-t (ngxh / mL) is the AUC of the reference substance Rybelsus. 0-t More than 1.5 times (ngxh / mL). In one or more embodiments, in single-dose fasting studies in human volunteers, the AUC of one or more pharmaceutical compositions of the present invention... 0-t (ngxh / mL) is the AUC of the reference substance Rebecca. 0-tMore than twice the (ngxh / mL) of the reference substance Replenish. In one or more embodiments, in single-dose fasting studies in human volunteers, the AUC of Replenish is used. 0-t (ngxh / mL) and the AUC of one or more pharmaceutical compositions of the present invention 0-t The ratio of (ngxh / mL) is 1:1.5 to 1:6.

[0015] In some embodiments, in single-dose fasting studies in human volunteers, the C of one or more pharmaceutical compositions of the present invention max (ng / mL) is the reference value for Rebecca's C max More than 1.5 times (ng / mL). In one or more embodiments, in single-dose fasting studies in human volunteers, the C of one or more pharmaceutical compositions of the present invention max (ng / mL) is the reference value for Rebecca's C max More than twice the amount (ng / mL). In one or more embodiments, in single-dose fasting studies in human volunteers, the reference substance C... max (ng / mL) and the C of one or more pharmaceutical compositions of the present invention max The ratio of (ng / mL) is 1:1.5 to 1:6.

[0016] Glucagon-like peptide (GLP) receptor agonists

[0017] Glucagon-like peptide (GLP) receptor agonists are GLP receptor agonists. GLP receptor agonists are a class of compounds primarily used to treat type 2 diabetes. GLP receptor agonists also have many other applications, including weight management therapy. GLP receptor agonists include semaglutide, exenatide, liraglutide, tirzepatide, alphaglutide, dulaglutide, and lixisenatide. The pharmaceutical compositions of the present invention contain a therapeutically effective amount of a GLP receptor agonist.

[0018] Semaglutide

[0019] Smegglutide is a glucagon-like peptide (GLP) receptor agonist suitable for use in conjunction with diet and exercise to improve glycemic control in adults with type 2 diabetes. Currently, the drug is approved as a solution for subcutaneous injection and as an oral tablet. Approved oral tablets are 3 mg, 7 mg, and 14 mg (Rebex) tablets containing inactive ingredients magnesium stearate, microcrystalline cellulose, povidone, and 8-(2-hydroxybenzamide) (SNAC). The pharmaceutical compositions of the present invention contain a therapeutically effective amount of smegglutide. The content of smegglutide is from 1 mg to 50 mg. Preferably, the content of smegglutide is from 1 mg to 20 mg. In some embodiments, the pharmaceutical compositions of the present invention contain 3 mg, 7 mg, or 14 mg of smegglutide.

[0020] Penetration enhancer

[0021] Permeation enhancers are used to improve the absorption of poorly permeable active pharmaceutical ingredients by the gastrointestinal tract. The permeation enhancers used in the compositions of this invention include one or more medium-chain fatty acid-based permeation enhancers containing aromatic functional groups and one or more medium-chain fatty acid-based permeation enhancers containing aromatic functional groups.

[0022] Permeation enhancers based on medium-chain fatty acids and containing aromatic functional groups include, but are not limited to, sodium 8-(2-hydroxybenzoamide)octanoate, N-(10-[2-hydroxybenzoyl]amino)decanoic acid, and N-(5-chlorosalicyloyl)-8-aminooctanoic acid. Sodium 8-(2-hydroxybenzoamide)octanoate, also known as sodium hexanoate hydrochloride, is the sodium salt form of hexanoic acid hydrochloride.

[0023] The content of the medium-chain fatty acid-based penetration enhancer containing aromatic functional groups is from 25 mg to 500 mg. In some embodiments, the content of the medium-chain fatty acid-based penetration enhancer containing aromatic functional groups is from 25 mg to 200 mg. In some embodiments, the medium-chain fatty acid-based penetration enhancer containing aromatic functional groups is sodium 8-(2-hydroxybenzamido)octanoate. The content of sodium 8-(2-hydroxybenzamido)octanoate is from 25 mg to 500 mg. In a more specific embodiment, the content of sodium 8-(2-hydroxybenzamido)octanoate is from 25 mg to 200 mg.

[0024] Permeation enhancers based on medium-chain fatty acids and free of aromatic functional groups include, but are not limited to, sodium caprylate / sodium octanoate, sodium caprate / sodium decanoate, sodium hexanoate, and sodium dodecanoate.

[0025] The content of the aromatic-functionalized, medium-chain fatty acid-based penetration enhancer is from 25 mg to 800 mg. In some embodiments, the aromatic-functionalized, medium-chain fatty acid-based penetration enhancer is sodium decanoate or sodium octanoate. The content of sodium decanoate or sodium octanoate is from 25 mg to 800 mg. In some more specific embodiments, the content of sodium decanoate or sodium octanoate is from 200 mg to 500 mg.

[0026] In some embodiments, the ratio of "a medium-chain fatty acid-based penetration enhancer containing aromatic functional groups" to "a medium-chain fatty acid-based penetration enhancer without aromatic functional groups" in the pharmaceutical composition is from 1:1 to 1:20. In some preferred embodiments, the ratio of "a medium-chain fatty acid-based penetration enhancer containing aromatic functional groups" to "a medium-chain fatty acid-based penetration enhancer without aromatic functional groups" in the pharmaceutical composition is from 1:1 to 1:5.

[0027] Alkalizing agent

[0028] An alkalizing agent is a compound that provides an alkaline environment during and / or after the dissolution of the active ingredient. Alkaliizing agents include, but are not limited to, calcium carbonate, sodium carbonate, sodium bicarbonate, magnesium hydroxide, and aluminum hydroxide, or combinations thereof. The content of the alkalizing agent can be between 25 mg and 600 mg. In one embodiment, the alkalizing agent is calcium carbonate.

[0029] The oral pharmaceutical compositions of the present invention may 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, and linagliptin; SGLT2 inhibitors, such as dapagliflozin, canagliflozin, empagliflozin, and ertugliflozin; rosiglitazone or pioglitazone; and repaglinide.

[0030] The oral pharmaceutical composition may be in the form of tablets, capsules, powders and granules, multi-compartment dosage forms, etc. Multi-compartment dosage forms may be double-layer tablets, capsule-in-capsule, tablet-in-capsule, and any other dosage form. The pharmaceutical composition may be formulated using any technique known or understood by those skilled in the art. In some specific embodiments, the pharmaceutical composition of the present invention is prepared using a direct powder compression method.

[0031] The oral pharmaceutical composition may 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. Diluents may be selected from microcrystalline cellulose, lactose, mannitol, modified starch, dibasic calcium phosphate, any other diluent, or combinations thereof. Disintegrants may be selected from croscarmellose, sodium carboxymethyl starch, any other disintegrant, or combinations thereof. Binders may be selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, any other binder, or combinations thereof. Lubricants may be selected from calcium stearate, magnesium stearate, sodium stearate fumarate, talc, any other lubricant, or combinations thereof.

[0032] After the invention has been described with reference to different embodiments thereof, other embodiments will be apparent to those skilled in the art from the content of the specification.

[0033] The innovations of this invention will be further illustrated by the following examples. It will be apparent to those skilled in the art that many modifications can be made to the composition without departing from the scope of this invention. Attached Figure Description

[0034] Figure 1 This is a time curve of plasma concentration in human volunteers for Example 1 of the present invention and 7 mg of Rebex tablets.

[0035] Figure 2 This is a solubility curve of the composition of Example 1 of the present invention in phosphate buffer solution with a pH of 6.8. Detailed Implementation

[0036] Example

[0037] Example 1

[0038] Composition

[0039] serial number Element Content per tablet (mg) 1 Smegglutide 7 2 SNAC 150 3 Sodium decanoate 450 4 Calcium carbonate 100 5 Sodium carboxymethyl starch (SSG) 100 6 magnesium stearate 20 Total weight 827

[0040] step:

[0041] 1. Weigh all ingredients accurately.

[0042] 2. Place SNAC, sodium decanoate, calcium carbonate, and sodium carboxymethyl starch in a polymerization bag and mix for 3 minutes.

[0043] 3. Add smegglutinin powder to the mixture.

[0044] 4. Pass the mixture through a 40-mesh sieve.

[0045] 5. Lubricate the mixture with magnesium stearate for 3 minutes.

[0046] 6. Use a suitable punch for compression.

[0047] 7. The tablets are packaged in ALU-ALU blister packs.

[0048] Reference Figure 2 The solubility curve of the composition of Example 1 was determined in phosphate buffer at pH 6.8.

[0049] A cross-biological study was conducted in human volunteers under a single-dose fasting state, comparing the components of Example 1 with Rebecca (reference) tablets. Results are referenced. Figure 1 The results showed that the plasma concentration of the composition in Example 1 was surprisingly high compared to the reference compound Resveratrol.

[0050]

[0051] Example 2

[0052] serial number Element Content per tablet (mg) 1 Smegglutide 7 2 SNAC 150 3 Sodium decanoate 300 4 Calcium carbonate 80 5 Cross-linked polyvinylpyrrolidone 80 6 magnesium stearate 10 Total weight 627

[0053] Steps: The composition was prepared using similar steps as in Example 1.

[0054] Example 3

[0055] serial number Element Content per tablet (mg) 1 Smegglutide 7 2 SNAC 100 3 Sodium decanoate 250 4 Calcium carbonate 60 5 Sodium carboxymethyl starch (SSG) 50 6 magnesium stearate 10 Total weight 477

[0056] Steps: The composition was prepared using similar steps as in Example 1.

[0057] Comparative Example A

[0058] Composition

[0059]

[0060] step:

[0061] 1. Weigh all ingredients accurately.

[0062] 2. Pass components 1 to 5 through a 40# sieve.

[0063] 3. Mix the powder mixture in the polymerization bag for 5 minutes.

[0064] 4. Add approximately 3 mL of water to reach the granulation endpoint.

[0065] 5. Dry the obtained wet granules in a hot air oven at 45 degrees Celsius for 10 hours.

[0066] 6. Pass the dried granules through a 40# sieve.

[0067] 7. Add magnesium stearate and sodium carboxymethyl starch as an extra granular portion and mix for 5 minutes.

[0068] 8. Use a suitable punch to compress and obtain the mixture.

[0069] A crossover biostudy was conducted in human volunteers under a single-dose fasting state, comparing the composition of Comparative Example A with that of Rebecca (reference) tablets. Results are shown in Figure 3. The results indicated that the plasma concentration of the composition of Comparative Example A was significantly lower than that of the 7 mg reference Rebecca.

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 based on medium-chain fatty acids containing aromatic functional groups; and c. One or more medium-chain fatty acid-based penetration enhancers that do not contain aromatic functional groups.

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 content of the medium-chain fatty acid-based penetration enhancer containing aromatic functional groups is from 25 mg to 200 mg.

4. The pharmaceutical composition according to claim 1, characterized in that, The medium-chain fatty acid-based penetration enhancer containing aromatic functional groups is sodium 8-(2-hydroxybenzamido)octanoate.

5. The pharmaceutical composition according to claim 1, characterized in that, The medium-chain fatty acid-based penetration enhancer that does not contain aromatic functional groups is selected from the group consisting of sodium decanoate, sodium octanoate, or combinations thereof.

6. The pharmaceutical composition according to claim 5, characterized in that, The content of sodium decanoate, sodium octanoate, or a combination thereof is 200 mg to 500 mg.

7. The pharmaceutical composition according to claim 1, characterized in that, The composition does not contain adhesives.

8. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition is in the form of tablets.

9. The pharmaceutical composition according to claim 8, characterized in that, The tablets are prepared by direct compression of powder into tablets.

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

11. The pharmaceutical composition according to claim 1, characterized in that, In a single-dose fasting study in human volunteers, the AUC compared to the reference substance Resveratrol was... 0-t Compared to (ngxh / mL), the AUC of the pharmaceutical composition 0-t (ngxh / mL) is more than 1.5 times.

12. The pharmaceutical composition according to claim 1, characterized in that, In a single-dose fasting study in human volunteers, compared with the reference compound Resveratrol, C max Compared to (ng / mL), the C of the pharmaceutical composition max The concentration (ng / mL) was more than 1.5 times higher.

13. 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 based on medium-chain fatty acids containing aromatic functional groups; and c. One or more medium-chain fatty acid-based penetration enhancers that do not contain aromatic functional groups d. One or more alkalizing agents.

14. The pharmaceutical composition according to claim 13, characterized in that, The GLP receptor agonist is smegglutinin.

15. The pharmaceutical composition according to claim 13, characterized in that, The content of the medium-chain fatty acid-based penetration enhancer containing aromatic functional groups is from 25 mg to 200 mg.

16. The pharmaceutical composition according to claim 13, characterized in that, The medium-chain fatty acid-based penetration enhancer containing aromatic functional groups is sodium 8-(2-hydroxybenzamido)octanoate.

17. The pharmaceutical composition according to claim 13, characterized in that, The medium-chain fatty acid-based penetration enhancer that does not contain aromatic functional groups is selected from the group consisting of sodium decanoate, sodium octanoate, or combinations thereof.

18. The pharmaceutical composition according to claim 17, characterized in that, The content of sodium decanoate, sodium octanoate, or a combination thereof is 200 mg to 500 mg.

19. The pharmaceutical composition according to claim 13, characterized in that, The composition does not contain adhesives.

20. The pharmaceutical composition according to claim 13, characterized in that, The pharmaceutical composition is in the form of tablets.

21. The pharmaceutical composition according to claim 20, characterized in that, The tablets are prepared by direct compression.

22. The pharmaceutical composition according to claim 13, characterized in that, The alkalizing agent is calcium carbonate.

23. The pharmaceutical composition according to claim 13, characterized in that, In a single-dose fasting study in human volunteers, the AUC compared to the reference substance Resveratrol was... 0-t Compared to (ngxh / mL), the AUC of the pharmaceutical composition 0-t (ngxh / mL) is more than 1.5 times.

24. The pharmaceutical composition according to claim 13, characterized in that, In a single-dose fasting study in human volunteers, the C-value compared to the reference substance Resveratrol was... max Compared to (ng / mL), the C of the pharmaceutical composition max The concentration (ng / mL) was more than 1.5 times higher.

25. An oral pharmaceutical composition, characterized in that, Include: a. A therapeutically effective dose of semaglutide; b. Sodium 8-(2-hydroxybenzamido)octanoate, ranging from 25 mg to 200 mg; and c. 200 mg to 500 mg of sodium decanoate, sodium octanoate, or a combination thereof.

26. An oral pharmaceutical composition, characterized in that, Include: a. A therapeutically effective dose of semaglutide; b. Sodium 8-(2-hydroxybenzamido)octanoate; c. Sodium decanoate, sodium octanoate, or combinations thereof; and d. Calcium carbonate.

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