Pharmaceutical compositions of orally administered GLP agonists

Abstract

The present invention relates to a pharmaceutical composition for oral administration, comprising a GLP receptor agonist, a pharmacoagulably salt thereof, or a derivative thereof, one or more penetration enhancers, one or more mucosal adhesives, and one or more basicizing agents. Preferably, the penetration enhancer is a medium-chain fatty acid-based penetration enhancer.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition for oral administration, comprising a GLP receptor agonist, a pharmacologically acceptable salt thereof, or a derivative thereof, one or more penetration enhancers, one or more mucoadhesives, and one or more basifying agents. Preferably, the penetration enhancer is a medium-chain fatty acid-based penetration enhancer.

Background Art

[0002] Peptides are mainly macromolecules composed of amino acids (AAs) bonded to each other. Peptides are used as major therapeutic agents for the treatment of various diseases and disorders. Peptides are mainly administered by injection, but repeated administration is required, which is cumbersome for patients, and there is a major problem with patient medication compliance.

Summary of the Invention

Problems to be Solved by the Invention

[0003] Attempts have been made to deliver peptides through the oral route. However, most of these attempts have not been successful mainly because peptides are sensitive to gastrointestinal (GIT) enzymes. A further problem for the development of oral therapies with such macromolecules is the penetration of many of these macromolecules from the GIT.

[0004] Therefore, there is an urgent need for a pharmaceutical composition containing a peptide, a pharmacologically acceptable salt thereof, or a derivative thereof, with improved oral delivery therapy. It has unexpectedly been found that the composition according to the invention can effectively deliver peptides through the oral route.

Means for Solving the Problems

[0005] The present invention relates to a pharmaceutical composition for oral administration, comprising a GLP receptor agonist, a pharmacoagulably salt thereof, or a derivative thereof, one or more penetration enhancers, one or more mucosal adhesives, and one or more basicizing agents.

[0006] The "therapeutic effective dose" or "effective dose" refers to a sufficient amount of pharmacologically active substance, upon administration, to exert an effect in such prevention or treatment. The therapeutic effective dose varies depending on the disease and its severity, as well as the age, weight, and other conditions of the patient being treated. The pharmaceutical compositions according to the present invention are useful for the treatment of GLP receptor-related diseases, including, but not limited to, type 2 diabetes and obesity.

[0007] Medium-chain fatty acids are fatty acids that have a carbon chain with 6 to 12 carbon atoms. 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 is a pharmaceutical composition for oral administration, a therapeutically effective dose of a GLP receptor agonist, a pharmacologically acceptable salt thereof, or a derivative thereof, b. A penetration enhancer of 1 or more units, c 1 or higher mucosal adhesive, d A basicizing agent of 1 or higher, This relates to a pharmaceutical composition containing [a specific ingredient / component].

[0009] In one embodiment, the present invention is a pharmaceutical composition for oral administration, a therapeutically effective dose of a GLP receptor agonist, a pharmacologically acceptable salt thereof, or a derivative thereof, b. A medium-chain fatty acid-based penetration enhancer of 1 or more units, c 1 or higher mucosal adhesive, d A basicizing agent of 1 or higher, This relates to a pharmaceutical composition containing [a specific ingredient / component].

[0010] In one embodiment, the present invention is a pharmaceutical composition for oral administration, a therapeutically effective dose of semaglutide, b. A medium-chain fatty acid-based penetration enhancer of 1 or more units, c 1 or higher mucosal adhesive, d A basicizing agent of 1 or higher, This relates to a pharmaceutical composition containing [a specific ingredient / component].

[0011] In a specific embodiment, the medium-chain fatty acid-based penetration enhancer is a medium-chain fatty acid-based penetration enhancer that does not have aromatic functional groups. In one embodiment, the pharmaceutical composition includes a combination of sodium caprate and sodium caprylate.

[0012] In one embodiment, the present invention is a pharmaceutical composition for oral administration, a therapeutically effective dose of semaglutide, b. Sodium caprate, sodium caprylate, or a combination thereof, c. Polyacrylate (Carbopol 934P), d Calcium carbonate and, This relates to a pharmaceutical composition containing [a specific ingredient / component].

[0013] In one embodiment, the pharmaceutical composition according to the present invention is a tablet and is manufactured by a direct compression method.

[0014] <Glucagon-like peptide (GLP) receptor agonists> Glucagon-like peptide (GLP) receptor agonists are agonists of the GLP receptor. GLP receptor agonists are a group of compounds primarily used to treat type 2 diabetes. GLP receptor agonists have many other uses, including weight management therapy. Examples of GLP receptor agonists include, but are not limited to, semaglutide, exenatide, liraglutide, tirzepatide, albiglutide, dulaglutide, and lixisenatide. The pharmaceutical composition according to the present invention may contain a therapeutically effective amount of GLP receptor agonist.

[0015] <Semaglutide> Semaglutide is a glucagon-like peptide (GLP) receptor agonist. Semaglutide has also been indicated as a diet and exercise adjunct to improve glycemic control in adult patients with type 2 diabetes, and is currently approved as a subcutaneous solution and oral tablets. Oral tablets are approved in 3 mg, 7 mg, and 14 mg (Rybelsus) doses, containing magnesium stearate, microcrystalline cellulose, povidone, and sodium salcaprozate (SNAC) as inactive ingredients. The pharmaceutical composition according to the present invention may contain a therapeutically effective amount of semaglutide. The amount of semaglutide may range from 1 mg to 50 mg. Preferably, the amount of semaglutide is in the range of 1 mg to 20 mg. In one embodiment, the pharmaceutical composition of the present invention contains 3 mg, 7 mg, or 14 mg of semaglutide.

[0016] <Penetration enhancer> Penetration enhancers are used to improve the absorption of active pharmaceutical ingredients with low permeability through the digestive tract. The penetration enhancers used in the pharmaceutical composition according to the present invention may be selected from the group consisting of one or more medium-chain fatty acid-based penetration enhancers having aromatic functional groups, and one or more medium-chain fatty acid-based penetration enhancers having aromatic functional groups.

[0017] Medium-chain fatty acid penetration enhancers having an aromatic functional group may include, without limitation, sodium 8-(2-hydroxybenzamido) caprylate, N-(10-[2-hydroxybenzoyl] amino) decanoic acid, and N-(5-chlorosalicyloyl)-8-aminocaprylic acid. Sodium 8-(2-hydroxybenzamido) caprylate is also known as Salcaprozate Sodium and is the sodium salt of Salcaprozate.

[0018] The amount of the medium-chain fatty acid penetration enhancer having an aromatic functional group may be in the range of 25 mg to 500 mg. In one embodiment, the amount of the medium-chain fatty acid penetration enhancer having an aromatic functional group may be in the range of 25 mg to 200 mg. In one embodiment, the medium-chain fatty acid penetration enhancer having an aromatic functional group may be sodium 8-(2-hydroxybenzamido) caprylate (Salcaprozate Sodium). The amount of sodium 8-(2-hydroxybenzamido) caprylate (Salcaprozate Sodium) may be in the range of 25 mg to 500 mg. In a more specific embodiment, the amount of sodium 8-(2-hydroxybenzamido) caprylate (Salcaprozate Sodium) is in the range of 25 mg to 200 mg.

[0019] Medium-chain fatty acid penetration enhancers having no aromatic functional group may include, without limitation, sodium caprylate, sodium caprate, sodium hexanoate, sodium octanoate, sodium decanoate, and sodium dodecanoate.

[0020] The amount of the medium-chain fatty acid-based penetration enhancer having no aromatic functional group may be in the range of 25 mg to 800 mg. In one embodiment, the medium-chain fatty acid-based penetration enhancer having no aromatic functional group is sodium caprate or sodium caprylate. The amount of sodium caprate or sodium caprylate may be in the range of 25 mg to 800 mg. In a more specific embodiment, the amount of sodium caprate or sodium caprylate is in the range of 150 mg to 500 mg.

[0021] <Basic agent> The basic agent is a compound that provides a basic environment during and / or after dissolution of the active ingredient. The basic agent may include, without limitation, calcium carbonate, sodium carbonate, sodium bicarbonate, magnesium hydroxide, and aluminium hydroxide, or combinations thereof. The amount of the basic agent may be in the range of 25 mg to 600 mg. In one embodiment, the basic agent is calcium carbonate.

[0022] <Mucoadhesive> Mucoadhesion is the ability of a substance to adhere to a biological surface. Mucoadhesion improves gastrointestinal retention by promoting the biological adhesion of pharmaceutical compositions to the gastrointestinal tract wall. Examples of mucoadhesion that are not limited to mucoadhesion include polyacrylates (Carbopol), chitosan, and gums such as alginic acid. The amount of mucoadhesion may be optimized according to the required amount of adhesion. The amount of mucoadhesion may be in the range of 5 mg to 100 mg. More specifically, the amount of mucoadhesion may be in the range of 20 mg to 60 mg. In a preferred embodiment, the mucoadhesion is polyacrylates commonly sold under the brand name Carbopol. A more specific example of mucoadhesion is Carbopol 934P.

[0023] The oral pharmaceutical composition according to the present invention may further contain one or more additional active ingredients. Examples of additional active ingredients that are not limited to these 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.

[0024] Oral pharmaceutical compositions may be tablets, capsules, powders, granules, multi-particle dosage forms, etc. Multilayer dosage forms may be two-layer tablets, capsule-in-capsules, tablet-in-capsules, or any other dosage form. Pharmaceutical compositions may be formulated by any technique known or understood by those skilled in the art. In one specific embodiment, the pharmaceutical composition of the present invention is manufactured by a direct compression method.

[0025] Oral pharmaceutical compositions may optionally further contain any, but not limited to, pharmacologically acceptable excipients such as diluents, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and dissolution accelerators, or one or more combinations thereof. Diluents may be selected from microcrystalline cellulose, lactose, mannitol, modified starches, dibasic calcium phosphate, other diluents, or combinations thereof. Disintegrants may be selected from the group consisting of cross-linked polyvinylpyrrolidone, sodium starch glycolate, other disintegrants, or combinations thereof. Binders may be selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, other binders, and combinations thereof. The lubricant may be selected from calcium stearate, magnesium stearate, sodium stearyl fumarate, talc, other lubricants, or combinations thereof.

[0026] Although the present invention has been described with reference to different embodiments, other embodiments will become apparent to those skilled in the art by examining the specification.

[0027] The technical concept of the present invention is further defined by reference to the following embodiments. Those skilled in the art will see that various modifications can be made within the scope of the present invention. [Brief explanation of the drawing]

[0028] [Figure 1] This is the plasma concentration-time profile curve from Example 1, compared to 7 mg of Rybelsus tablets, in human volunteers. [Figure 2] This is the dissolution profile of the composition according to Example 1, performed in phosphate buffer at pH 6.8. [Modes for carrying out the invention]

[0029] Example 1

[0030] composition [Table 1]

[0031] procedure: 1. All ingredients were accurately weighed. 2. Sodium caprylate, sodium caprate, calcium carbonate, carbomer, and SSG were mixed in a plastic bag for 3 minutes. 3. Semaglutide powder was added to the above mixture. 4. The above mixture was sieved through a 40-mesh sieve. 5. The mixture was lubricated with magnesium stearate for 3 minutes. 6. Compression was carried out using an appropriate punch. 7. The tablets were packaged in ALU-ALU blister packs.

[0032] The solubility profile of the composition according to Example 1 was performed in phosphate buffer at pH 6.8 and is shown in Figure 2.

[0033] A single-dose, fasted, three-way crossover biostudies were conducted in human volunteers using the composition of Example 1, which was compared to the reference product Rybelsus 7 mg tablets. The results are shown in Figure 1. The results indicate that the composition of Example 1 successfully achieved bioequivalence with the reference product, Rybelsus 7 mg.

[0034] Example 2 [Table 2]

[0035] procedure: The compositions were prepared using the same procedure as in Example 1.

[0036] Example 3 [Table 3]

[0037] procedure: The compositions were prepared using the same procedure as in Example 1.

[0038] Comparative example A

[0039] composition [Table 4]

[0040] procedure: 1. All ingredients were accurately weighed. 2. Components numbered 1-5 were sieved through a 40-mesh sieve. 3. The powder mixture was mixed in a plastic bag for 5 minutes. 4. Once the granulation endpoint was reached, approximately 3 mL of water was added dropwise. 5. The resulting wet granules were dried in a hot air oven at 45°C for 10 hours. 6. The dried granules were sieved through a 40-mesh sieve. 7. Magnesium stearate and sodium starch glycolate were added as extra-granular components and mixed for 5 minutes. 8. The resulting mixture was compressed using a suitable punch.

[0041] A single-dose, fasted, three-way crossover biostudies were conducted in human volunteers using the composition of Comparative Example A, which was compared to the reference product Rybelsus 7 mg tablets. The results are shown in Figure 3. The results indicate that the plasma concentrations of the composition of Comparative Example A were significantly lower than those of the reference product, Rybelsus 7 mg tablets.

Claims

1. A pharmaceutical composition for oral administration, a. A therapeutically effective dose of a GLP receptor agonist, or a pharmacologically acceptable salt or derivative thereof, b. A penetration enhancer of 1 or more units, c. A mucosal adhesive of 1 or more, d A basicizing agent of 1 or more units, A pharmaceutical composition containing the following:

2. The pharmaceutical composition according to claim 1, wherein the GLP receptor agonist is semaglutide.

3. The pharmaceutical composition according to claim 1, wherein the one or more penetration enhancers are chain fatty acid-based penetration enhancers.

4. The pharmaceutical composition according to claim 3, wherein the medium-chain fatty acid-based penetration enhancer is sodium salcaprozate.

5. The pharmaceutical composition according to claim 4, wherein the amount of sodium salcaprozate is 25 mg to 200 mg.

6. The pharmaceutical composition according to claim 3, wherein the medium-chain fatty acid-based penetration enhancer is sodium caprate or sodium caprylate, or a combination thereof.

7. The pharmaceutical composition according to claim 6, wherein the amount of sodium caprate or sodium caprylate, or a combination thereof, is 25 mg to 800 mg.

8. The pharmaceutical composition according to claim 1, wherein the mucosal adhesive is polyacrylate.

9. The pharmaceutical composition according to claim 1, wherein the basicizing agent is selected from the group consisting of calcium carbonate, sodium carbonate, sodium bicarbonate, magnesium hydroxide, aluminum hydroxide, or a combination thereof.

10. The pharmaceutical composition according to claim 1, wherein the composition is in the form of a tablet.

11. The pharmaceutical composition according to claim 1, wherein the tablets are manufactured by a direct compression method.

12. The pharmaceutical composition according to claim 1, wherein the composition further comprises one or more additional active ingredients.

13. A pharmaceutical composition for oral administration, a. A therapeutically effective dose of semaglutide, b. Sodium caprate or sodium caprylate, or a combination thereof, c. Polyacrylate (Carbopol 934P), d. Calcium carbonate and, A pharmaceutical composition containing the following:

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