Pharmaceutical composition for oral administration.
The combination of GLP receptor agonists with medium-chain fatty acid permeation enhancers and optional basifying agents addresses the oral delivery challenges of peptides, enhancing their bioavailability and plasma concentrations.
Patent Information
- Authority / Receiving Office
- BR · BR
- Patent Type
- Applications
- Current Assignee / Owner
- ANYA BIOPHARM INC
- Filing Date
- 2024-03-06
- Publication Date
- 2026-07-07
AI Technical Summary
Peptides are challenging to administer orally due to their susceptibility to enzymes in the gastrointestinal tract and low permeability, making injection the primary mode of administration cumbersome for patients.
A pharmaceutical composition comprising a GLP receptor agonist or its pharmacologically acceptable salt, combined with permeation enhancers based on medium-chain fatty acids with and without aromatic functional groups, optionally with a basifying agent, to enhance oral delivery.
The composition achieves significantly higher plasma concentrations and bioavailability of peptides compared to existing oral formulations, demonstrating improved oral administration efficacy.
Smart Images
Figure 00000000_0000_ABST
Abstract
Description
/ 11 PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION
[001] The present invention relates to a pharmaceutical composition for oral administration comprising a GLP receptor agonist or pharmacologically acceptable salt or its derivatives, one or more permeation enhancers based on medium-chain fatty acids with an aromatic functional group and one or more permeation enhancers based on medium-chain fatty acids without an aromatic functional group. The pharmaceutical composition may optionally further comprise a basifying agent. BACKGROUND OF THE INVENTION
[002] Peptides are large macromolecules composed primarily of amino acids (AAs) linked together. Peptides are the main therapeutic compounds used to treat various diseases or disorders. Peptides are mainly administered by injection, which presents a major challenge for patient adherence, as this is complicated for patients who require repeated administration.
[003] There have been several attempts to administer peptides orally. However, most of them have been unsuccessful, largely due to the susceptibility of the peptide to enzymes in the gastrointestinal tract (GIT). The permeability of these large GIT macromolecules represents an additional challenge for the development of oral therapy for these macromolecules.
[004] Therefore, there is an urgent need to improve oral administration therapy with a pharmaceutical composition composed of pharmacologically acceptable peptides or salts or derivatives. It has been surprisingly found that the composition according to the invention can effectively deliver peptides orally. DESCRIPTION OF THE DRAWINGS
[005] Figure 1: Plasma concentration-time profile curve for example 1 vs. Rybelsus 7 mg tablets in human volunteers. Petition 870250073315, dated 08 / 19 / 2025, page 21 / 41 / 11
[006] Figure 2: Dissolution profile of the composition as per example 1 performed in Phosphate Buffer with pH 6.8. DETAILED DESCRIPTION OF THE INVENTION
[007] The present invention relates to a pharmaceutical composition for oral administration comprising a GLP receptor agonist or pharmacologically acceptable salt or its derivatives, one or more permeation enhancers based on medium-chain fatty acids with an aromatic functional group and one or more permeation enhancers based on medium-chain fatty acids without an aromatic functional group. The pharmaceutical composition may optionally further comprise a basifying agent.
[008] Therapeutically effective amount or effective amount refers to the amount of an active pharmaceutical agent, when administered, that is sufficient to effect such prevention or treatment. The therapeutically effective amount varies according to the disease and its severity, and the age, weight, and other conditions of the patient to be treated. The pharmaceutical composition according to the present invention is useful for the treatment of diseases involving GLP receptors, including, but not limited to, type 2 diabetes and obesity.
[009] Medium-chain fatty acid refers to fatty acids 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).
[0010] In one embodiment, the present invention relates to a pharmaceutical composition for oral administration comprising a. a therapeutically effective amount of GLP receptor agonist or salt or pharmacologically acceptable derivatives thereof b. one or more permeation enhancers based on medium-chain fatty acids with an aromatic functional group, and Petition 870250073315, dated 08 / 19 / 2025, p. 22 / 41 / 11 c. one or more permeation enhancers based on medium-chain fatty acids without an aromatic functional group.
[0011] In another embodiment, the present invention relates to a pharmaceutical composition for oral administration comprising a. a therapeutically effective amount of GLP receptor agonist or salt or pharmacologically acceptable derivatives thereof, b. one or more permeation enhancers based on medium-chain fatty acids with an aromatic functional group, c. one or more permeation enhancers based on medium-chain fatty acids without an aromatic functional group, and d. one or more basifying elements.
[0012] In another embodiment, the present invention relates to a pharmaceutical composition for oral administration comprising a. a therapeutically effective amount of semaglutide, b. one or more permeation enhancers based on medium-chain fatty acids with an aromatic functional group, c. one or more permeation enhancers based on medium-chain fatty acids without an aromatic functional group, and d. one or more basifying elements.
[0013] In one specific embodiment, permeation enhancers based on medium-chain fatty acids with an aromatic functional group are sodium salcaprozate. In a more specific embodiment, sodium salcaprozate is present in amounts of 25 mg to 200 mg.
[0014] In another specific embodiment, the present invention relates to a pharmaceutical composition for oral administration comprising a. a therapeutically effective amount of semaglutide, b. sodium salcaprizate, c. Sodium caprate or sodium caprylate, or combinations thereof, and Petition 870250073315, dated 08 / 19 / 2025, p. 23 / 41 / 11 d. calcium carbonate.
[0015] In another embodiment, the pharmaceutical composition according to the present invention is a tablet and is prepared by the direct compression method. In one embodiment, the tablet does not contain a binder.
[0016] In one or more embodiments, the AUC0-t (ngxh / ml) for one or more pharmaceutical compositions according to the present invention is 1.5 times or more compared to the AUC0-t (ngxh / ml) for the Rybelsus reference product in a single-dose fasting study in human volunteers. In one or more embodiments, the AUC0-t (ngxh / ml) for one or more pharmaceutical compositions according to the present invention is 2 times or more compared to the AUC0-t (ngxh / ml) for the Rybelsus reference product in a single-dose fasting study in human volunteers. In one or more embodiments, the ratio of AUC0-t (ngxh / ml) of the Rybelsus reference product to AUC0-t (ngxh / 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.
[0017] In one or more embodiments, Cmax (ng / ml) for one or more pharmaceutical compositions according to the present invention is 1.5 times or more compared to Cmax (ng / ml) for the reference product Rybelsus in a single-dose fasting study in human volunteers. In one or more embodiments, Cmax (ng / ml) for one or more pharmaceutical compositions according to the present invention is 2 times or more compared to Cmax (ng / ml) for the reference product Rybelsus in a single-dose fasting study in human volunteers. In one or more embodiments, the ratio of Cmax (ng / ml) of the reference product Rybelsus to 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. A-like peptide receptor agonist Petition 870250073315, dated 08 / 19 / 2025, page 24 / 41 / 11 GLUCAGON (GLP)
[0018] Glucagon-like peptide (GLP) receptor agonists are GLP receptor agonists. GLP receptor agonists are a class of compounds primarily used for the treatment of type 2 diabetes. There are many other applications of GLP receptor agonists, including weight management therapy. Without limitation, examples of GLP receptor agonists include 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. SEMAGLUTE
[0019] Semaglutide is a glucagon-like peptide (GLP) receptor agonist and is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. It is currently approved as a solution for subcutaneous administration and as a tablet for oral administration. The oral tablets are approved as 3 mg, 7 mg, and 14 mg tablets (Rybelsus) containing the inactive ingredients magnesium stearate, microcrystalline cellulose, povidone, and salcaprozate sodium (SNAC). 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. More preferably, the amount of semaglutide may range from 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. Permeation enhancers
[0020] Permeation enhancers are used to improve the absorption of poorly permeable active pharmaceutical ingredients throughout the gastrointestinal tract. The permeation enhancer used in the composition according to the present invention includes one or more permeation enhancers. Petition 870250073315, dated 08 / 19 / 2025, p. 25 / 41 / 11 permeation based on medium-chain fatty acids with an aromatic functional group and one or more permeation enhancers based on medium-chain fatty acids with an aromatic functional group.
[0021] Permeation enhancers based on medium-chain fatty acids with an aromatic functional group may include, but are not limited to, sodium 8-(2-hydroxybenzamido)caprylate, N-(10-[2-hydroxybenzoyl]amino)decanoic acid, N-(5-chlorosalicyloyl)-8-aminocaprylic acid. Sodium 8-(2-hydroxybenzamido)caprylate is also known as sodium salcaprozate and is the sodium salt form of salcaprozate.
[0022] The amount of permeation enhancers based on medium-chain fatty acids with an aromatic functional group can range from 25 mg to 500 mg. In one embodiment, the amount of permeation enhancers based on medium-chain fatty acids with an aromatic functional group is 25 mg to 200 mg. In one embodiment, the permeation enhancers based on medium-chain fatty acids with an aromatic functional group are sodium 8-(2-hydroxybenzamido)caprylate (sodium salcaprozate). The amount of sodium 8-(2-hydroxybenzamido)caprylate (sodium salcaprozate) can range from 25 mg to 500 mg. In a more specific embodiment, the amount of sodium 8-(2-hydroxybenzamido)caprylate (sodium salcaprozate) is 25 mg to 200 mg.
[0023] Permeation enhancers based on medium-chain fatty acids without an aromatic functional group may include, but are not limited to, sodium caprylate, sodium caprate, sodium hexanoate, sodium octanoate, sodium decanoate, and sodium dodecanoate.
[0024] The amount of permeation enhancers based on medium-chain fatty acids without an aromatic functional group can range from 25 mg to 800 mg. In one embodiment, the permeation enhancers based on medium-chain fatty acids without an aromatic functional group are sodium caprate or sodium caprylate. The amount of Petition 870250073315, dated 08 / 19 / 2025, p. 26 / 41 / 11 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 from 200 mg to 500 mg.
[0025] In one or more embodiments, the ratio of permeation enhancers based on medium-chain fatty acids with an aromatic functional group to permeation enhancers based on medium-chain fatty acids without an aromatic functional group in a pharmaceutical composition is 1:1 to 1:20. In one or more preferred embodiments, the ratio of permeation enhancers based on medium-chain fatty acids with an aromatic functional group to permeation enhancers based on medium-chain fatty acids without an aromatic functional group in a pharmaceutical composition is 1:1 to 1:5. BASIFICANTES
[0026] Basifying agents are compounds that provide an alkaline environment during and / or after the dissolution of the active ingredient. Basifying agents may include, among others, calcium carbonate, sodium carbonate, sodium bicarbonate, magnesium hydroxide, and aluminum hydroxide, or a combination thereof. The amount of basifying agent may range from 25 mg to 600 mg. In one embodiment, the basifying agent is calcium carbonate.
[0027] The oral pharmaceutical composition according to the present invention may additionally include one or more additional active ingredients. Non-limiting examples of additional active ingredients include biguanides such as metformin; glipizide or glibenclamide; DPP4 inhibitors such as sitagliptin, alogliptin, linagliptin; SGLT2 inhibitors such as dapagliflozin, canagliflozin, empagliflozin, ertugliflozin; rosiglitazone or pioglitazone; and repaglinide.
[0028] Oral pharmaceutical compositions may be tablets, capsules, powders and granules, multi-particulate pharmaceutical forms and the like. Multi-compartmental pharmaceutical forms may be bilayer tablets, capsules in Petition 870250073315, dated 08 / 19 / 2025, page 27 / 41 / 11 capsule, tablet in capsule and any other pharmaceutical form. Pharmaceutical compositions may be formulated by any techniques known or verified by a person skilled in the art. In a specific embodiment, the pharmaceutical composition of the present invention is prepared by the direct compression method.
[0029] The oral pharmaceutical composition may additionally and optionally include any one or a combination of one or more pharmacologically acceptable excipients, such as, but not limited to, diluents, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and solubility enhancers. The diluent may be selected from microcrystalline cellulose, lactose, mannitol, modified starches, dibasic calcium phosphate, any other diluent, or a combination thereof. The disintegrant may be selected from cross-linked polyvinylpyrrolidone, sodium starch glycolate, any other disintegrant, or a combination thereof. The binder may be selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, any other binder, or a combination thereof.Lubricants may be selected from calcium stearate, magnesium stearate, sodium stearyl fumarate, talc, any other lubricant, or a combination thereof.
[0030] Having described the invention with reference to the different embodiments of the invention, other embodiments will become apparent to a person skilled in the art from consideration of the specifications.
[0031] The innovation is further defined by way of reference to the following examples. It will be evident to those skilled in the art that many modifications to the composition can be made without departing from the scope of this invention. EXAMPLES Petition 870250073315, dated 08 / 19 / 2025, page 28 / 41 / 11 EXAMPLE - 1 Compositions: Serial Number | Ingredient | Amount per tablet (mg) | 1 | Semaglutide | 7 | 2 | Sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC) | 150 | 3 | Sodium caprate | 450 | 4 | Calcium carbonate | 100 | 5 | Sodium starch glycolate (SSG) | 100 | 6 | Magnesium stearate | 20 | Total | 827 Procedure:
[0032] 1. All ingredients were weighed accurately.
[0033] 2. SNAC, sodium caprate, calcium carbonate and SSG were mixed in a plastic bag for 3 min.
[0034] 3. Semaglutide powder added to the above mixture.
[0035] 4. The mixture above was passed through a 40 mesh sieve.
[0036] 5. The mixture was lubricated with magnesium stearate for 3 min.
[0037] 6. Compression was performed using appropriate punctures.
[0038] 7. The tablets were packaged in ALU-ALU blister packs.
[0039] The dissolution profile of the composition as per example 1 was performed in phosphate buffer with pH 6.8 and is shown in figure 2.
[0040] A single-dose, fasting, 3-way crossover biostudy was conducted for the Example 1 composition versus Rybelsus tablet (reference) in human volunteers. The results are shown in Figure 1. The results show a surprisingly higher plasma concentration for the Example 1 composition compared to the Rybelsus reference product. Formulation Results of the pilot study (in healthy volunteers) Rybelsus AUC 0-t values (ng x h / ml) are 978.0±1239.6 AUC 0.® values (ng x h / ml) are 1470.9±1822.5 Cmax values (ng / ml) are 18.562±25.549 Tmax values (h) are 1.44±0.72 T1 - (Ex-1) AUC 0-t values (ng x h / ml) are 3438.7±4349.0 AUC 0-® values (ng x h / ml) are 5007.6±6375.7 Cmax values (ng / ml) are 54.944±67.907 Tmax values (h) are 2.09±1.54 EXAMPLE - 2 Petition 870250073315, dated 08 / 19 / 2025, page 29 / 41 / 11 Serial Number | Ingredient | Amount per tablet (mg) | 1 | Semaglutide | 7 | 2 | Sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC) | 150 | 3 | Sodium caprate | 300 | 4 | Calcium carbonate | 80 | 5 | Crospovidone | 80 | 6 | Magnesium stearate | 10 | Total | 627
[0041] Procedure - The composition was prepared using a procedure analogous to example 1. EXAMPLE - 3 Serial Number | Ingredient | Amount per tablet (mg) | 1 | Semaglutide | 7 | 2 | Sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC) | 100 | 3 | Sodium caprate | 250 | 4 | Calcium carbonate | 60 | 5 | Sodium starch glycolate | 50 | 6 | Magnesium stearate | 10 | Total | 477
[0042] Procedure - The composition was prepared using a procedure analogous to example 1. COMPARATIVE EXAMPLE OF COMPOSITION Serial Number | Ingredient | Quantity per tablet (mg) | Intragranular | 1 Sodium caprate 450 | 2 Sodium lauryl sulfate (SLS) 10 | 3 Sodium starch glycolate (SSG) 150 | 4 Povidone 30 | 5 Semaglutide 7 | 6 Water qss | Extragranular | 6 Sodium starch glycolate (SSG) 100 | 7 Magnesium stearate 10 | Total 757 Procedure
[0043] a. All ingredients were weighed accurately.
[0044] b. Ingredients 1 to 5 were sifted through a 40 # sieve.
[0045] c. The powder mixture was mixed in polyethylene bags for min.
[0046] d. Approximately 3 ml of water added drop by drop to reach the final granulation point.
[0047] e. The resulting moist granules were dried in an air oven. Petition 870250073315, dated 08 / 19 / 2025, page 30 / 41 / 11 hot for 10 hours at 45 degrees Celsius.
[0048] f The dry granules were passed through a 40 # sieve.
[0049] g. Mg of sodium stearate and starch glycolate were added as an extra granular component and mixed for 5 minutes.
[0050] h. The resulting mixture was compressed using suitable punches.
[0051] A single-dose, fasting, three-way crossover biostudy was conducted for the comparative sample composition A versus Rybelsus tablet (reference) in human volunteers. The results are shown in Figure 3. The results show a very low plasma concentration for the comparative sample composition A compared to the Rybelsus 7 mg reference product. Petition 870250073315, dated 08 / 19 / 2025, pp. 31 / 41
Claims
1 / 4 CLAIMS 1. Pharmaceutical composition for oral administration, characterized in that it comprises a. a therapeutically effective amount of GLP receptor agonist or salt or pharmacologically acceptable derivatives thereof, b. one or more permeation enhancers based on medium-chain fatty acids with an aromatic functional group, and c. one or more permeation enhancers based on medium-chain fatty acids without an aromatic functional group.
2. Pharmaceutical composition according to claim 1, characterized in that the GLP receptor agonist is semaglutide.
3. Pharmaceutical composition according to claim 1, characterized in that the permeation enhancers based on medium-chain fatty acids with an aromatic functional group are in the amount of 25 mg to 200 mg.
4. Pharmaceutical composition according to claim 1, characterized in that the permeation enhancers based on medium-chain fatty acids with an aromatic functional group are sodium salcaprozate.
5. Pharmaceutical composition according to claim 1, characterized in that permeation enhancers based on medium-chain fatty acids without an aromatic functional group are selected from the group consisting of sodium caprate or sodium caprylate or combinations thereof.
6. Pharmaceutical composition according to claim 5, characterized in that the sodium caprate or sodium caprylate or combinations thereof is from 200 mg to 500 mg.
7. Pharmaceutical composition according to claim 1, characterized in that said composition does not contain a binder. Petition 870250073315, dated 19 / 08 / 2025, page 32 / 41 2 / 4 8. Pharmaceutical composition according to claim 1, characterized in that said pharmaceutical composition is a tablet.
9. Pharmaceutical composition according to claim 8, characterized in that said tablet is prepared by the direct compression method.
10. Pharmaceutical composition according to claim 1, characterized in that said composition additionally comprises one or more additional active ingredients.
11. Pharmaceutical composition according to claim 1, characterized in that the AUC 0-t (ng x h / ml) for said pharmaceutical composition is 1.5 times or more compared with the AUC 0-t (ng x h / ml) for the Rybelsus reference product in a single-dose fasting study in human volunteers.
12. Pharmaceutical composition according to claim 1, characterized in that Cmax (ng / ml) for said pharmaceutical composition is 1.5 times or more compared with Cmax (ng / ml) for the reference product Rybelsus in a single-dose fasting study in human volunteers.
13. Pharmaceutical composition for oral administration, characterized in that it comprises: a. a therapeutically effective amount of GLP receptor agonist or salt or pharmacologically acceptable derivatives thereof, b. one or more permeation enhancers based on medium-chain fatty acids with an aromatic functional group, c. one or more permeation enhancers based on medium-chain fatty acids without an aromatic functional group, and d. one or more basifying agents.
14. Pharmaceutical composition according to claim 13, characterized in that the GLP receptor agonist is Petition 870250073315, dated 08 / 19 / 2025, page 33 / 41 3 / 4 semaglutide.
15. Pharmaceutical composition according to claim 13, characterized in that permeation enhancers based on medium-chain fatty acids with an aromatic functional group are present in amounts ranging from 25 mg to 200 mg.
16. Pharmaceutical composition according to claim 13, characterized in that the permeation enhancers based on medium-chain fatty acids with an aromatic functional group are sodium salcaprozate.
17. Pharmaceutical composition according to claim 13, characterized in that the permeation enhancers based on medium-chain fatty acids without an aromatic functional group are selected from the group consisting of sodium caprate or sodium caprylate or combinations thereof.
18. Pharmaceutical composition according to claim 17, characterized in that sodium caprate or sodium caprylate or combinations thereof is in an amount of 200 mg to 500 mg.
19. Pharmaceutical composition according to claim 13, characterized in that said composition does not contain a binder.
20. Pharmaceutical composition according to claim 13, characterized in that said pharmaceutical composition is a tablet.
21. Pharmaceutical composition according to claim 20, characterized in that said tablet is prepared by the direct compression method.
22. Pharmaceutical composition according to claim 13, characterized in that the basifying agent is calcium carbonate.
23. Pharmaceutical composition according to claim 13, characterized in that the AUC 0-t (ng x h / ml) for said pharmaceutical composition is 1.5 times or more compared with the AUC 0-t (ng x h / ml) for the reference product Rybelsus in a single-dose fasting study in human volunteers.
24. Pharmaceutical composition according to claim 13, characterized in that Cmax (ng / ml) for said pharmaceutical composition is 1.5 times or more compared with Cmax (ng / ml) for the reference product Rybelsus in a single-dose fasting study in human volunteers.
25. Pharmaceutical composition for oral administration, characterized in that it comprises a. a therapeutically effective amount of semaglutide, b. 25 mg to 200 mg of sodium salcaprozate, and c. 200 mg to 500 mg of sodium caprate or sodium caprylate or combinations thereof.
26. Pharmaceutical composition for oral administration, characterized in that it comprises: a. a therapeutically effective amount of semaglutide, b. sodium salcaprizate, c. sodium caprate or sodium caprylate, or combinations thereof, and d. calcium carbonate. Petition 870250073315, dated 19 / 08 / 2025, pp. 35 / 41