Pharmaceutical composition for oral administration of a GLP-1 receptor agonist
View Patent ↗The invention relates to a pharmaceutical composition for use as a medicament, in the oral treatment of a disease, in particular a metabolic disease, said pharmaceutical composition comprising a Glucagon-like peptide-1 receptor agonist (GLP-1), and a system that can buffer the pH of the pharmaceutical composition to a value ranging from 4 to 8.
1 . A method for the oral treatment of a disease, comprising administering a pharmaceutical composition, said pharmaceutical composition comprising:
(i) a protein active ingredient selected from the group consisting of GLP-1, semaglutide, liraglutide, dulaglutide, albiglutide, exenatide, and lixisenatide, and
(ii) a system that can buffer the pH of the pharmaceutical composition to a value ranging from 4 to 8, wherein the system that can buffer the pharmaceutical composition comprises:
(a) from 0.5 to 20% by mass monosodium phosphate dihydrate relative to the total mass of the pharmaceutical composition,
(b) from 10 to 60% by mass anhydrous monosodium citrate relative to the total mass of the pharmaceutical composition,
(c) from 20 to 95% by mass sodium bicarbonate relative to the total mass of the system that can buffer the pharmaceutical composition, and
(d) from 0.5 to 20% by mass sodium benzoate relative to the total mass of the pharmaceutical composition.
2 . The method of treatment according to claim 1 , wherein the protein active ingredient is selected from the group consisting of GLP-1, semaglutide, liraglutide, dulaglutide, and albiglutide.
3 . The method of treatment according to claim 1 , wherein the disease is a metabolic disease.
4 . The method of treatment according to claim 1 , wherein the protein active ingredient selected from exenatide and lixisenatide.
5 . The method of treatment according to claim 1 , wherein the composition is in liquid form or in solid form.
6 . The method of treatment according to claim 1 , wherein the pharmaceutical composition is free of additional compound(s) capable of protecting the protein active ingredient against degradation by digestive enzymes.
7 . The method of treatment according to claim 1 , wherein the system that can buffer the pharmaceutical composition allows to obtain a pH ranging from 4.5 to 7.5.
8 . The method of treatment according to claim 1 , wherein the system that can buffer the pharmaceutical composition is capable of protecting at least 70% of the protein active ingredient from degradation by at least one digestive enzyme when the pharmaceutical composition is contacted with said digestive enzyme(s).
9 . The method of treatment according to claim 1 , wherein the system that can buffer the pharmaceutical composition is capable of protecting at least 70% of the protein active ingredient from degradation by pepsin when the pharmaceutical composition is contacted with 2 to 5 mg/ml of pepsin for one hour.
10 . The method of treatment according to claim 1 , wherein the composition does not comprise insulin, a derivative thereof or an analogue thereof and/or wherein the composition does not comprise other protein active ingredient(s).
11 . The method of treatment according to claim 1 , wherein the composition is a composition in solid form which comprises from 0.0001 to 5% by mass of the protein active ingredient relative to the total mass of the pharmaceutical composition.
12 . The method of treatment according to claim 1 , wherein the composition is a solid form composition which comprises:
(i) 120 milligrams (mg) of monosodium phosphate dihydrate,
(ii) 1142 mg of anhydrous monosodium citrate,
(iii) 2076 mg of sodium bicarbonate,
(iv) 157 mg of sodium benzoate, and
(v) from 0.5 to 100 mg of the protein active ingredient.
13 . A method for preparing a composition, said composition comprising:
(i) a protein active ingredient selected from the group consisting of GLP-1, semaglutide, liraglutide, dulaglutide, albiglutide, exenatide, and lixisenatide, and
(ii) a system that can buffer the pH of the pharmaceutical composition to a value ranging from 4 to 8, wherein the system that can buffer the pharmaceutical composition comprises:
(a) from 0.5 to 20% by mass monosodium phosphate dihydrate relative to the total mass of the pharmaceutical composition,
(b) from 10 to 60% by mass anhydrous monosodium citrate relative to the total mass of the pharmaceutical composition,
(c) from 20 to 95% by mass sodium bicarbonate relative to the total mass of the system that can buffer the pharmaceutical composition, and
(d) from 0.5 to 20% by mass sodium benzoate relative to the total mass of the pharmaceutical composition,
the method comprising mixing the protein active ingredient with the system that can buffer the pH of said pharmaceutical composition to a value ranging from 4 to 8.
14 . A method for the oral treatment of a disease comprising administering a kit of reagents to a subject, said kit of reagents comprising:
(i) a pharmaceutical composition in solid form comprising-a protein active ingredient, said protein active ingredient being GLP-1, semaglutide, liraglutide, dulaglutide, albiglutide, exenatide, or lixisenatide, and
(ii) a pharmaceutical composition comprising a buffer system, in which said pharmaceutical composition comprising a buffer system (ii) can buffer the pH of the pharmaceutical composition comprising the protein active ingredient (i) to a value ranging from 4 to 8, when the compositions (i) and (ii) are mixed in solution and wherein the buffer system comprises:
(a) from 0.5 to 20% by mass monosodium phosphate dihydrate relative to the total mass of the pharmaceutical composition,
(b) from 10 to 60% by mass anhydrous monosodium citrate relative to the total mass of the pharmaceutical composition,
(c) from 20 to 95% by mass sodium bicarbonate relative to the total mass of the system that can buffer the pharmaceutical composition, and
(d) from 0.5 to 20% by mass sodium benzoate relative to the total mass of the pharmaceutical composition,
wherein the protein active ingredient is mixed with the buffer system, and wherein said kit of reagents is free of additional compound(s) capable of protecting the protein active ingredient of the pharmaceutical composition (i) against a degradation by digestive enzymes.
15 . The method of treatment according to claim 1 , wherein the protein active ingredient is semaglutide.
16 . The method of treatment according to claim 7 , wherein the system that can buffer the pharmaceutical composition allows to obtain a pH ranging from 5 to 7.
17 . The method of treatment according to claim 16 , wherein the system that can buffer the pharmaceutical composition allows to obtain a pH ranging from 6 to 7.
18 . The method of treatment according to claim 17 , wherein the system that can buffer the pharmaceutical composition is capable of protecting at least 75% of the protein active ingredient from degradation by at least one digestive enzyme when the pharmaceutical composition is contacted with said digestive enzyme(s).
19 . The method of treatment according to claim 18 , wherein the system that can buffer the pharmaceutical composition is capable of protecting at least 80% of the protein active ingredient from degradation by at least one digestive enzyme when the pharmaceutical composition is contacted with said digestive enzyme(s).
20 . The method of treatment according to claim 19 , wherein the system that can buffer the pharmaceutical composition is capable of protecting at least 85% of the protein active ingredient from degradation by at least one digestive enzyme when the pharmaceutical composition is contacted with said digestive enzyme(s).
21 . The method of treatment according to claim 20 , wherein the system that can buffer the pharmaceutical composition is capable of protecting at least 90% of the protein active ingredient from degradation by at least one digestive enzyme when the pharmaceutical composition is contacted with said digestive enzyme(s).
22 . The method of treatment according to claim 21 , wherein the system that can buffer the pharmaceutical composition is capable of protecting at least 95% of the protein active ingredient from degradation by at least one digestive enzyme when the pharmaceutical composition is contacted with said digestive enzyme(s).
23 . The method of treatment according to claim 1 , wherein the composition is a composition in solid form which comprises from 0.0001 to 5% by mass of semaglutide, relative to the total mass of the pharmaceutical composition.
24 . The method of treatment according to claim 1 , wherein the composition is a composition in solid form which comprises from 0.001 to 1.5% by mass of the protein active ingredient relative to the total mass of the pharmaceutical composition.
25 . The method of treatment according to claim 23 , wherein the composition comprises from 0.001 to 1.5% by mass of semaglutide, relative to the total mass of the pharmaceutical composition.
26 . The method of treatment according to claim 1 , wherein the composition is a composition in solid form which comprises from 0.001 to 1% by mass of the protein active ingredient relative to the total mass of the pharmaceutical composition.
27 . The method of treatment according to claim 25 , wherein the composition comprises from 0.001 to 1% by mass of semaglutide, relative to the total mass of the pharmaceutical composition.
28 . The method of treatment according to claim 1 , wherein the composition is a composition in solid form which comprises from 0.01 to 0.5% by mass of the protein active ingredient relative to the total mass of the pharmaceutical composition.
29 . The method of treatment according to claim 27 , wherein the composition comprises from 0.01 to 0.5% by mass of semaglutide, relative to the total mass of the pharmaceutical composition.
30 . The method of treatment according to claim 1 , wherein the composition is a composition in solid form which comprises from 0.05 to 0.5% by mass of the protein active ingredient relative to the total mass of the pharmaceutical composition.
31 . The method of treatment according to claim 29 , wherein the composition comprises from 0.05 to 0.5% by mass of semaglutide, relative to the total mass of the pharmaceutical composition.
32 . The method of treatment according to claim 1 , wherein the composition is a solid form composition which comprises:
(i) 120 milligrams (mg) of monosodium phosphate dihydrate,
(ii) 1142 mg of anhydrous monosodium citrate,
(iii) 2076 mg of sodium bicarbonate,
(iv) 157 mg of sodium benzoate, and
(v) from 0.5 to 100 mg of semaglutide.
33 . The method of treatment according to claim 1 , wherein the composition is a solid form composition which comprises:
(i) 120 milligrams (mg) of monosodium phosphate dihydrate,
(ii) 1142 mg of anhydrous monosodium citrate,
(iii) 2076 mg of sodium bicarbonate,
(iv) 157 mg of sodium benzoate, and
(v) from 0.5 to 40 mg of a protein active ingredient.
34 . The method of treatment according to claim 1 , wherein the composition is a solid form composition which comprises:
(i) 120 milligrams (mg) of monosodium phosphate dihydrate,
(ii) 1142 mg of anhydrous monosodium citrate,
(iii) 2076 mg of sodium bicarbonate,
(iv) 157 mg of sodium benzoate, and
(v) from 0.5 to 40 mg of semaglutide.
35 . The method of treatment according to claim 1 , wherein the composition is a solid form composition which comprises:
(i) 120 milligrams (mg) of monosodium phosphate dihydrate,
(ii) 1142 mg of anhydrous monosodium citrate,
(iii) 2076 mg of sodium bicarbonate,
(iv) 157 mg of sodium benzoate, and
(v) from 1 to 50 mg of a protein active ingredient.
36 . The method of treatment according to claim 1 , wherein the composition is a solid form composition which comprises:
(i) 120 milligrams (mg) of monosodium phosphate dihydrate,
(ii) 1142 mg of anhydrous monosodium citrate,
(iii) 2076 mg of sodium bicarbonate,
(iv) 157 mg of sodium benzoate, and
(v) from 1 to 50 mg of semaglutide.
37 . The method of treatment according to claim 3 , wherein the metabolic disease is type 2 diabetes, non-alcoholic steatohepatitis and/or obesity.