Pharmaceutical composition of orally administered GLP agonist having high bioavailability
The pharmaceutical composition with GLP receptor agonists and fatty acid penetration enhancers addresses oral delivery challenges by enhancing bioavailability, effectively treating type 2 diabetes and obesity through improved gastrointestinal penetration and absorption.
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Filing Date
- 2024-03-06
- Publication Date
- 2026-03-18
AI Technical Summary
Existing oral delivery methods for peptides face challenges due to sensitivity to gastrointestinal enzymes and poor penetration from the gastrointestinal tract, necessitating improved compositions for effective oral administration.
A pharmaceutical composition comprising a GLP receptor agonist, pharmaceutically acceptable salts or derivatives, medium-chain fatty acid penetration enhancers with and without aromatic functional groups, and a basifying agent, formulated using a direct compression method, which may include ingredients like semaglutide, sodium salcaprozate sodium, sodium caprate/caprylate, and calcium carbonate.
The composition achieves a therapeutic effective dose with enhanced bioavailability, demonstrated by AUC and Cmax values up to 1.5 to 2 times higher than existing products, facilitating effective treatment of GLP receptor-related diseases such as type 2 diabetes and obesity.
Smart Images
Figure 2026509387000001_ABST
Abstract
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 medium-chain fatty acid penetration enhancers having an aromatic functional group, and one or more medium-chain fatty acid penetration enhancers having no aromatic functional group. The pharmaceutical composition may further contain a basifying agent.
Background Art
[0002] Peptides are polymers mainly composed of amino acids (AAs) linked 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, so 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 treatments with such polymers is the penetration of many of these polymers 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 treatment. It was unexpectedly 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 pharmaceutically acceptable salt thereof, or a derivative thereof; one or more medium-chain fatty acid-based osmotic enhancers having aromatic functional groups; and one or more medium-chain fatty acid-based osmotic enhancers not having aromatic functional groups. The pharmaceutical composition may further contain a basicizing agent.
[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 medium-chain fatty acid-based penetration enhancer having one or more aromatic functional groups, c. One or more medium-chain fatty acid-based penetration enhancers that do not have aromatic functional groups, 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 having one or more aromatic functional groups, c. One or more medium-chain fatty acid-based penetration enhancers that do not have aromatic functional groups, 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 having one or more aromatic functional groups, c. One or more medium-chain fatty acid-based penetration enhancers that do not have aromatic functional groups, 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 osmosis enhancer having an aromatic functional group is salcaprozate sodium. In a more specific embodiment, the amount of salcaprozate sodium is 25 mg to 200 mg.
[0012] In one embodiment, the present invention is a pharmaceutical composition for oral administration, a therapeutically effective dose of semaglutide, b. Sodium salcaprozate and c. Sodium caprate or sodium caprylate, or a combination thereof, 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 manufactured by a direct compression method. In one embodiment, the tablet does not contain a binder.
[0014] In one or more embodiments, the AUC of one or more pharmaceutical compositions according to the present invention 0-t (ngxh / mL) is the AUC of the reference product Rybelsus in a single-dose fasting study of human volunteers. 0-tThis is 1.5 times or more compared to (ngxh / mL). In one or more embodiments, the AUC of one or more pharmaceutical compositions according to the present invention. 0-t (ngxh / mL) is the AUC of the reference product Rybelsus in a single-dose fasting study of human volunteers. 0-t It is more than twice as high as (ngxh / mL). In one or more embodiments, in a single-dose fasting study of human volunteers, the AUC of the reference product Rybelsus was 0-t AUC of one or more pharmaceutical compositions according to the present invention (ngxh / mL) 0-t The ratio to (ngxh / mL) is 1:1.5 to 1:6.
[0015] In one or more embodiments, the Cmax (ng / mL) of one or more pharmaceutical compositions according to the present invention is 1.5 times or more than that of the reference product Rybelsus in a single-dose fasting study in human volunteers. In one or more embodiments, the Cmax (ng / mL) of one or more pharmaceutical compositions according to the present invention is 2 times or more than that of the reference product Rybelsus in a single-dose fasting study in human volunteers. In one or more embodiments, the ratio of the Cmax (ng / mL) of the reference product Rybelsus to the Cmax (ng / mL) of one or more pharmaceutical compositions according to the present invention in a single-dose fasting study in human volunteers is 1:1.5 to 1:6.
[0016] <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 mainly used for treating 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, Lixisenatide, etc. The pharmaceutical composition according to the present invention may contain a therapeutically effective amount of a GLP receptor agonist.
[0017] 〈Semaglutide〉 Semaglutide is a glucagon-like peptide (GLP) receptor agonist. Also, Semaglutide has been shown as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes and is currently approved as a solution for subcutaneous administration and tablets for oral administration. The oral tablets are approved as 3 mg, 7 mg, and 14 mg (Rybelsus) tablets containing magnesium stearate, microcrystalline cellulose, povidone, and sodium N-(8-[2-hydroxybenzoyl]amino)caprylate (SNAC) as inert ingredients. The pharmaceutical composition according to the present invention may contain a therapeutically effective amount of Semaglutide. The amount of Semaglutide may be in the range of 1 mg to 50 mg. The amount of Semaglutide is preferably 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.
[0018] 〈Penetration enhancer〉 Penetration enhancers are used to improve the absorption of active pharmaceutical ingredients with low permeability through the gastrointestinal tract. The penetration enhancers used in the pharmaceutical composition according to the present invention include one or more medium-chain fatty acid-based penetration enhancers having an aromatic functional group and one or more medium-chain fatty acid-based penetration enhancers having an aromatic functional group.
[0019] 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.
[0020] 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.
[0021] 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.
[0022] The amount of the medium-chain fatty acid-based osmotic enhancer that does not have aromatic functional groups may be in the range of 25 mg to 800 mg. In one embodiment, the medium-chain fatty acid-based osmotic enhancer that does not have aromatic functional groups 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 200 mg to 500 mg.
[0023] In one or more embodiments, the ratio of a medium-chain fatty acid-based penetration enhancer having aromatic functional groups to a medium-chain fatty acid-based penetration enhancer without aromatic functional groups in the pharmaceutical composition is 1:1 to 1:20. In one or more preferred embodiments, the ratio of a medium-chain fatty acid-based penetration enhancer having aromatic functional groups to a medium-chain fatty acid-based penetration enhancer without aromatic functional groups in the pharmaceutical composition is 1:1 to 1:5.
[0024] <Basicizing agent> A basicizing agent is a compound that provides a basic environment during and / or after the dissolution of the active ingredient. The basicizing agent may, without limitation, include calcium carbonate, sodium carbonate, sodium bicarbonate, magnesium hydroxide, aluminum hydroxide, or a combination thereof. The amount of the basicizing agent may range from 25 mg to 600 mg. In one embodiment, the basicizing agent is calcium carbonate.
[0025] 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.
[0026] 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.
[0027] 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.
[0028] 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.
[0029] 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]
[0030] [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]
[0031] Example 1
[0032] composition [Table 1]
[0033] procedure: 1. All ingredients were accurately weighed. 2. SNAC, sodium caprate, calcium carbonate, 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.
[0034] 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.
[0035] 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. The results are shown in Figure 1. The results show that the plasma concentration of the composition of Example 1 was remarkably high compared to the reference product, Rybelsus. [Table 2]
[0036] Example 2 [Table 3]
[0037] procedure: The compositions were prepared using the same procedure as in Example 1.
[0038] Example 3 [Table 4]
[0039] procedure: The compositions were prepared using the same procedure as in Example 1.
[0040] Comparative example A
[0041] composition [Table 5]
[0042] 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. Approximately 3 mL of water was added dropwise until the granulation endpoint was reached. 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.
[0043] A single-dose, fasted, three-way crossover biostudies were performed in human volunteers using the composition of Comparative Example A, which was compared to the reference product Rybelsus 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.
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. One or more medium-chain fatty acid-based penetration enhancers having aromatic functional groups, c. A medium-chain fatty acid-based penetration enhancer that does not have an aromatic functional group, Pharmaceutical composition.
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 amount of the medium-chain fatty acid-based penetration enhancer having the aromatic functional group is 25 mg to 200 mg.
4. The pharmaceutical composition according to claim 1, wherein the medium-chain fatty acid-based penetration enhancer having the aromatic functional group is sodium salcaprozate.
5. The pharmaceutical composition according to claim 1, wherein the medium-chain fatty acid-based penetration enhancer that does not have the aromatic functional group is selected from the group consisting of sodium caprate, sodium caprylate, or a combination thereof.
6. The pharmaceutical composition according to claim 5, wherein the amount of sodium caprate or sodium caprylate, or a combination thereof, is 200 mg to 500 mg.
7. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition does not contain a binder.
8. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a tablet.
9. The pharmaceutical composition according to claim 8, wherein the tablets are manufactured by a direct compression method.
10. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises one or more additional active ingredients.
11. AUC of the aforementioned pharmaceutical composition 0-t (ngxh / mL) was found in a single-dose fasting study of human volunteers, compared to the AUC of the reference product Rybelsus. 0-t The pharmaceutical composition according to claim 1, wherein the concentration is 1.5 times or more compared to (ngxh / mL).
12. The pharmaceutical composition according to claim 1, wherein the Cmax (ng / mL) of the pharmaceutical composition is 1.5 times or more compared to the Cmax (ng / mL) of the reference product Rybelsus in a single-dose fasting study of human volunteers.
13. 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. One or more medium-chain fatty acid-based penetration enhancers having aromatic functional groups, c. One or more medium-chain fatty acid-based penetration enhancers that do not have aromatic functional groups, d A basicizing agent of 1 or more units, A pharmaceutical composition containing the following:
14. The pharmaceutical composition according to claim 13, wherein the GLP receptor agonist is semaglutide.
15. The pharmaceutical composition according to claim 13, wherein the amount of the medium-chain fatty acid-based penetration enhancer having the aromatic functional group is 25 mg to 200 mg.
16. The pharmaceutical composition according to claim 13, wherein the medium-chain fatty acid-based penetration enhancer having the aromatic functional group is sodium salcaprozate.
17. The pharmaceutical composition according to claim 13, wherein the medium-chain fatty acid-based penetration enhancer that does not have the aromatic functional group is selected from the group consisting of sodium caprate, sodium caprylate, or a combination thereof.
18. The pharmaceutical composition according to claim 17, wherein the amount of sodium caprate or sodium caprylate, or a combination thereof, is 200 mg to 500 mg.
19. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition does not contain a binder.
20. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition is a tablet.
21. The pharmaceutical composition according to claim 20, wherein the tablets are manufactured by a direct compression method.
22. The pharmaceutical composition according to claim 13, wherein the basicizing agent is calcium carbonate.
23. AUC of the aforementioned pharmaceutical composition 0-t (ngxh / mL) was found in a single-dose fasting study of human volunteers, compared to the AUC of the reference product Rybelsus. 0-t The pharmaceutical composition according to claim 13, wherein the concentration is 1.5 times or more compared to (ngxh / mL).
24. The pharmaceutical composition according to claim 13, wherein the Cmax (ng / mL) of the pharmaceutical composition is 1.5 times or more compared to the Cmax (ng / mL) of the reference product Rybelsus in a single-dose fasting study of human volunteers.
25. A pharmaceutical composition for oral administration, a. A therapeutically effective dose of semaglutide, b. 25 mg to 200 mg of salcaprozate sodium, c. 200 mg to 500 mg of sodium caprate or sodium caprylate, or a combination thereof, A pharmaceutical composition containing the following:
26. A pharmaceutical composition for oral administration, a. A therapeutically effective dose of semaglutide, b. Sodium salcaprozate and c. Sodium caprate or sodium caprylate, or a combination thereof, d. Calcium carbonate and, A pharmaceutical composition containing the following: