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1. WO2020112655 - PHARMACEUTICAL BIODISSOLVABLE GELS FOR DRUG DELIVERY

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[ EN ]

CLAIMS

1. A pharmaceutical composition comprising a reverse thermal gelation material, wherein the pharmaceutical composition makes a transition from liquid to gel near the body temperature of a mammal.

2. The pharmaceutical composition of claim 1, wherein the mammal is a human being.

3. The pharmaceutical composition of claim 1 or 2, further comprising an active pharmaceutical ingredient.

4. The pharmaceutical composition of claim 3, wherein the active pharmaceutical ingredient is designed for anti-angiogenesis.

5. The pharmaceutical composition of claim 3, wherein the active pharmaceutical ingredient is a multi-kinase inhibitor.

6. The pharmaceutical composition of claim 3, wherein the active pharmaceutical ingredient comprises axitinib, nintedanib, pirfenidone, riociguat, sorafenib, sunitinib, lenvatinib, regorafenib, ponatinib, pazopanib, or a combination thereof.

7. The pharmaceutical composition of claim 1, 2, 3, 4, 5, or 6, wherein the pharmaceutical composition is a liquid at a temperature of about 2 °C to about 8 °C.

8. The pharmaceutical composition of claim 1, 2, 3, 4, 5, 6, or 1, wherein the pharmaceutical composition is a gel at a temperature of about 30 °C to about 40 °C.

9. The pharmaceutical composition of claim 1, 2, 3, 4, 5, 6, 7 , or 8, further comprising a polymer agent and a gelation modulator.

10. The pharmaceutical composition of claim 1, 2, 3, 4, 5, 6, 7 , 8, or 9, wherein the polymer agent comprises an al ky lcellu lose.

11. The pharmaceutical composition of claim 10, wherein the polymer agent is methylcellulose.

12. The pharmaceutical composition of claim 9, 10, or 11, wherein the gelation modulator comprises phosphate, dihydrogen phosphate, hydrogen phosphate, tris

(hydroxymethyl)aminomethane, borate, histidine, carbonate, bicarbonate, citrate, citric acid acetate, tartarate, fumarate, lactate, formate, sulfamate, oxalate, malonate, succinate, maleate, adipate, benzoate, o-toluate, benzene tetracarboxylate, glutamate, e-amino caproate, aspartate, glycinate, arginate, lysinate, taurate, ethanol, dimethyl sulfoxide, glycerin, dimethylformamide, propylene glycol, a polyethylene glycol, a vegetable oil, corn oil, olive oil, castor oil, vitamin E, a phospholipid, a polysorbate 20, a polysorbate 40, a polysorbate 60, a polysorbate 80, a mono-saccharide, a di-saccharide, dextrose, sucrose, a sugar alcohol, mannitol, sorbitol, an antioxidant, ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, sodium bisulfate, sodium sulfite, sodium metabisulfite, EDTA, sodium carboxymethylcellulose, sodium alginate, hydroxypropylmethylcelluloses, carbomers, hyaluronic acid, a hyaluronate salt, or a combination thereof.

13. The pharmaceutical composition of claim 12, wherein the gelation modulator comprises phosphate, dimethyl sulfoxide, citrate, or a combination thereof.

14. A pharmaceutical composition comprising: an active pharmaceutical ingredient, methylcellulose, dimethyl sulfoxide and citrate.

15. The pharmaceutical composition of claim 14 further comprising phosphate.

16. The pharmaceutical composition of claim 11, 14 or 15, wherein the methylcellulose is present at a concentration of about 2% (w/w) to about 10% (w/w).

17. The pharmaceutical composition of claim 16, wherein the citrate is present at a concentration of about 25 mmol/kg to about 200 mmole/kg.

18. The pharmaceutical composition of claim 17, having a pH of about 5.0 to about 9.0.

19. The pharmaceutical composition of claim 17, having a pH of about 6.0 to about 8.0.

20. A pharmaceutical composition comprising: an active pharmaceutical ingredient, methylcellulose, dimethyl sulfoxide and citrate, wherein the pharmaceutical composition has a first storage modulus (G') at about 37 °C and a second G' at about 5 °C, wherein the first G' is higher than the second G'.

21. The pharmaceutical composition of claim 20, wherein the first G' is at least about tenfold higher than the second G'.

22. The pharmaceutical composition of claim 21, having a first complex viscosity at about

37 °C and a second complex viscosity at about 5 °C, wherein the first complex viscosity is higher than the second complex viscosity.

23. The pharmaceutical composition of claim 22, wherein the first complex viscosity is at least twofold higher than the second complex viscosity.

24. The pharmaceutical composition of claim 23, having a first loss modulus (G") at about 37°C and a second G" at about 5 °C, wherein the first G" is higher than the second G".

25. The pharmaceutical composition of claim 24, wherein the % gelation at about 37°C is at least 70%.

26. The pharmaceutical composition of claim 25, wherein the % gelation at about 5°C is no greater than 20%.

27. The pharmaceutical composition of claim 20 or 26, further comprising phosphate.

28. A method of treating a disease, comprising administering the pharmaceutical composition of claim 26 or 27 to a mammal in need thereof.

29. The method of claim 28, wherein the disease is characterized by chronic inflammation, with associated angiogenesis and fibrosis.

30. The method of claim 28, wherein the disease comprises a dermal-related disorder, a benign prostate hyperplasia related disorder, an eye-related disorder, a rosacea-related disorder, a uterine fibroid or a related condition, a neoplastic disease, or an adhesion-related disorder.

31. The method of claim 30, wherein the pharmaceutical composition is administered topically, by intralesional injection, by paralesional injection, by intravitreal injection, by intraprostatic injection, by intramuscular injection, by subcutaneous injection, by intradermal injections, by intra-tissue injection, or by eye drop.

32. The method of claim 28, 29, 30, or 31, wherein the mammal is a human being.

33. A method of delivering an active pharmaceutical ingredient, comprising administering the pharmaceutical composition of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 to a mammal in need of the active pharmaceutical ingredient, wherein the composition provides a therapeutic effect with a reduced active pharmaceutical ingredient dosing frequency.

34. The method of claim 33, wherein the pharmaceutical composition is administered topically, by intralesional injection, by paralesional injection, by intravitreal injection, by intraprostatic injection, by intramuscular injection, by subcutaneous injection, by intradermal injections, by intra-tissue injection, or by eye drop.

35. The method of claim 33 or 34, wherein the mammal is a human being.

36. The method of claim 33, 34, or 35, wherein a single administration of the active pharmaceutical ingredient provides a therapeutically effective concentration of the active pharmaceutical ingredient to the mammal for at least 5 days.

37. The method of claim 36, wherein a single administration of the active pharmaceutical ingredient provides a therapeutically effective concentration of the active pharmaceutical ingredient to the mammal for at least 6 weeks.

38. A method of preparing a pharmaceutical composition having reverse thermal gelation properties, comprising:

mixing a polymer agent into a slurry containing a gelation modulator and an active pharmaceutical ingredient, wherein the mixing occurs at a temperature of about 60 °C to about 80 °C;

wherein the slurry is formed by a method comprising precipitating the active pharmaceutical ingredient into an aqueous liquid, and adding the gelation modulator to the slurry.