Pharmaceutical composition
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Patents
- Current Assignee / Owner
- MEDINCELL SA
- Filing Date
- 2021-07-02
- Publication Date
- 2026-06-25
Smart Images
Figure 0007880319000045 
Figure 0007880319000046 
Figure 0007880319000047
Abstract
Claims
1. A branched copolymer comprising at least three polyester arms, wherein the polyester is poly(ε-caprolactone-co-lactic acid) and is bonded to a central core, the central core being a branched polyether derivable from poly(ethylene glycol) (PEG) and polyols, and the branched copolymer is of formula A(B) ｎ The formula is such that A represents the central core, B represents the polyester arm, n represents the number of polyester arms and is at least an integer of 3, the polyol is pentaerythritol (PE), dipentaerythritol (DPE), trimethylolpropane (TMP), trimethylolmethane, glycerol, hexaglycerol, erythritol, xylitol, di(trimethylolpropane) (diTMP), sorbitol, or inositol, and the branched copolymer has a solubility of less than 15 mg / mL in water at 37°C. A pharmaceutical composition for use in forming a depot ex vivo or in situ, comprising: At least one pharmaceutically active ingredient, and at least 20% (w / w%) of the total composition of a pharmaceutically acceptable organic solvent. A pharmaceutical composition further comprising the above.
2. The composition according to claim 1, wherein the molecular weight of the polyether is 10 kDa or less, 5 kDa or less, preferably 4 kDa or less, preferably 3 kDa or less, preferably 2 kDa or less, preferably 1 kDa or less, or preferably 0.5 kDa or less, and optionally at least 0.2 kDa.
3. A branched copolymer comprising at least three polyester arms, wherein the polyester is poly(ε-caprolactone-co-lactic acid) and is bonded to a central core, the central core being a branched polyether derivable from poly(ethylene glycol) (PEG) and polyols, and the branched copolymer is of formula A(B) ｎ The polyol is a branched copolymer in which, in the formula, A represents the central core, B represents the polyester arm, n represents the number of polyester arms and is at least an integer of 3, the polyol is pentaerythritol (PE), dipentaerythritol (DPE), trimethylolpropane (TMP), trimethylolmethane, glycerol, hexaglycerol, erythritol, xylitol, di(trimethylolpropane) (diTMP), sorbitol, or inositol, and the molecular weight of the polyether is 10 kDa or less, 5 kDa or less, preferably 4 kDa or less, 3 kDa or less, or 2 kDa or less, or 1 kDa or less, or 0.5 kDa or less. A pharmaceutical composition for use in forming a depot ex vivo or in situ, comprising: At least one pharmaceutically active ingredient, and at least 20% (w / w%) of the total composition of a pharmaceutically acceptable organic solvent. A pharmaceutical composition further comprising the above.
4. The composition according to claim 3, wherein the branched copolymer has a solubility of less than 15 mg / mL in water at 37°C.
5. The composition according to any one of claims 1 to 4, wherein the branched copolymer has a solubility of less than 10 mg / mL, less than 5 g / mL, less than 2 mg / mL, or less than 1 mg / mL in water at 37°C.
6. A composition according to any one of claims 1 to 5, suitable for forming an in situ depot.
7. The composition according to any one of claims 1 to 6, wherein n is 3, 4, 5, 6, or 8, preferably 3 or 4.
8. The composition according to any one of claims 1 to 7, wherein each branch of the multi-branched polyether has a terminal reactive group that can react with a polyester or its monomer or precursor.
9. The composition according to claim 8, wherein the terminal reactive group is a hydroxyl group.
10. The multi-branched polyether is a composition according to any one of claims 1 to 9, having any one of formulas 1 to 4: Formula 1 【Chemistry 1】 (In the formula, R １ teeth 【Chemistry 2】 (where x is H or alkyl, x is 0 or 1, and m is an integer between 2 and 76.) Formula 2 【Transformation 3】 (In the formula, m is an integer between 5 and 40.) Formula 3 【Chemistry 4】 (In the formula, m is an integer between 5 and 40.) Formula 4 【Transformation 5】 (In the formula, m is an integer between 25 and 30, and v is 6.)
11. The aforementioned multibranched polyether has formula 1, where x is 1, and R １ The composition according to claim 10, wherein is alkyl, and optionally ethyl.
12. The aforementioned multibranched polyether has formula 1, where x is 1, and R １ teeth 【Transformation 6】 The composition according to claim 10.
13. The multibranched polyether has formula 1, where x is 0 and R １ The composition according to claim 10, wherein is H.
14. The composition according to any one of claims 1 to 13, wherein the branched copolymer can be obtained by reacting the branched polyether with D,L-lactide and ε-caprolactone.
15. The composition according to claim 14, wherein the branched copolymer can be obtained by ring-opening polymerization of the D,L-lactide and ε-caprolactone initiated by the branched polyether.
16. The composition according to any one of claims 1 to 15, wherein the number of ester repeating units in each arm is independently in the range of 5 to 230, optionally 10 to 115, and optionally 10 to 90, and the ratio of lactic acid repeating units to hexanoate repeating units is in the range of 25 / 75 to 99 / 1.
17. The multi-branched copolymer is a composition according to any one of claims 1 to 16, having any of formulas 5 to 8: Formula 5 【Transformation 7】 (In the formula, R ３ teeth 【Transformation 8】 (where x is H or alkyl, m is an integer between 2 and 76, n is an integer between 5 and 230, and q is between 0.25 and 0.99.) Formula 6 【Chemistry 9】 (In the formula, m is an integer between 5 and 40, n is an integer between 10 and 115, and q is an integer between 0.25 and 0.99.) Formula 7 【Chemistry 10】 (In the formula, m is an integer between 5 and 40, n is an integer between 10 and 115, and q is an integer between 0.25 and 0.99.) Formula 8 【Chemistry 11】 (In the formula, m is an integer between 25 and 30, n is an integer between 10 and 90, q is between 0.25 and 0.99, and v is 6.)
18. The aforementioned branched copolymer has formula 5, where x is 1, and R ３ The composition according to claim 17, wherein is alkyl, and optionally ethyl.
19. The multi-branched copolymer has Formula 5, x is 1, and R ３ is 【Chemistry 12】 The composition according to claim 17, wherein m is an integer between 2 and 76, n is an integer between 5 and 230, and q is between 0.25 and 0.
99.
20. The aforementioned branched copolymer has formula 5, where x is 0 and R ３ The composition according to claim 17, wherein is H.
21. The composition according to claim 17, wherein the branched copolymer has formula 5, the polyether core has a molecular weight of 2 kDa, and the molar ratio of the ester repeating unit to ethylene oxide is 4 or 6.
22. The composition according to any one of claims 1 to 21, wherein the at least one pharmaceutically active ingredient is in the form of a suspension at a temperature between 10°C and 37°C.
23. The composition according to any one of claims 1 to 22, wherein the molecular weight of the polyether is in the range of 0.5 kDa to 10 kDa, optionally 1 kDa to 10 kDa, preferably 2 kDa to 10 kDa, preferably 2 kDa to 5 kDa, or most preferably 0.5 kDa to 2 kDa.
24. The composition according to any one of claims 1 to 23, wherein the molar ratio of the ester repeating units to the ethylene oxide of the multibranched copolymer is 1 to 10, preferably 2 to 6.
25. The composition according to any one of claims 1 to 24, wherein the pharmaceutically acceptable organic solvent is a biocompatible organic solvent, and optionally the amount of the solvent is at least 25% or at least 35% (w / w%) of the total composition.
26. The pharmaceutically acceptable organic solvent is selected from the following group for the composition according to claim 25: benzyl alcohol, benzyl benzoate, dimethyl isosorbide (DMI), dimethyl sulfoxide (DMSO), ethyl acetate, ethyl benzoate, ethyl lactate, glycerol formal, methyl ethyl ketone, methyl isobutyl ketone, N-ethyl-2-pyrrolidone, N-methyl-2-pyrrolidinone (NMP), pyrrolidone-2, tetraglycol, triacetin, triptyline, trippropionine, glycoflor, and mixtures thereof.
27. The composition according to any one of claims 1 to 26, wherein the pharmaceutically active ingredient is hydrophobic.
28. The composition according to any one of claims 1 to 27, wherein the pharmaceutically active ingredient is meloxicam, tamsulosin, or a combination thereof.
29. The composition according to any one of claims 1 to 28, wherein the at least one pharmaceutically active ingredient is present in an amount of 0.05% to 60%, optionally 0.05% to 40%, optionally 5% to 30%, optionally 5% to 25%, optionally 5% to 20%, or optionally 10% to 20% (w / w%) of the whole composition.
30. The composition according to any one of claims 1 to 29, which is an injectable liquid.
31. The composition according to any one of claims 1 to 30, wherein the multi-branched copolymer is present in an amount of 20% to 70%, optionally 20% to 60%, optionally 30% to 60%, or optionally 30% to 50% (w / w%) of the entire composition.
32. A composition according to any one of claims 1 to 31, suitable for delivering a pharmaceutically active ingredient to a target for at least one day, optionally at least three days, optionally at least seven days, optionally at least thirty days, optionally at least ninety days, optionally at least 180 days, or optionally at least one year.
33. A method for producing a pharmaceutical composition according to any one of claims 1 to 32, comprising dissolving a polybranched copolymer according to any one of claims 1 to 32 in a pharmaceutically acceptable organic solvent, and subsequently adding a pharmaceutically active ingredient to the composition.
34. A composition according to any one of claims 1 to 32 for use as a pharmaceutical agent, wherein the use optionally includes administering the composition to a subject and forming an in situ depot in vivo.