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Last Updated: March 28, 2024

Claims for Patent: 5,952,008


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Summary for Patent: 5,952,008
Title: Processes for preparing compositions for inhalation
Abstract:A pharmaceutical composition including a mixture of active compounds (A) a pharmaceutically active polypeptide, and (B) an enhancer compound which enhances the systemic absorption of the polypeptide in the lower respiratory tract of a patient, the mixture being in the form of a dry powder for inhalation in which at least 50% of the total mass of the active compounds consists of primary particles having a diameter less than or equal to about 10 microns, the primary particles optionally being formed into agglomerates.
Inventor(s): Backstrom; Kjell Goran Erik (Lund, SE), Dahlback; Carl Magnus Olof (Lund, SE), Edman; Peter (Bjarred, SE), Johansson; Ann Charlotte Birgit (Lund, SE)
Assignee: AB Astra (Sodertalje, SE)
Application Number:08/858,122
Patent Claims:1. A process for the manufacture of a pharmaceutical composition suitable for administration by oral inhalation from a dry powder inhaler device, comprising

providing a solution in which are dissolved (a) a pharmaceutically active polypeptide, and (b) an enhancer compound which enhances the systemic absorption of the polypeptide in the lower respiratory tract of a patient;

removing the solvent from said solution to yield a dry solid comprising said polypeptide and said enhancer compound;

pulverizing said dry solid to produce a powder, wherein at least 50% of the total mass of said powder is in the form of primary particles having a diameter less than about 10 microns, said primary particles being optionally agglomerated; and

loading the powder into a dry powder inhaler device adapted for inhalation through the mouth.

2. A process as claimed in claim 1, comprising the step of forming the primary particles into agglomerates.

3. A process as claimed in claim 1, wherein said polypeptide is selected from the group consisting of vasopressin, vasopressin analogues, desmopressin, glucagon, corticotropin, gonadotropin, calcitonin, C-peptide of insulin, parathyroid hormone, human growth hormone, growth hormone, growth hormone releasing hormone, oxytocin, corticotropin releasing hormone, a somatostatin analogue, a gonadotropin agonist analogue, atrial natriuretic peptide, thyroxine releasing hormone, follicle stimulating hormone, prolactin; an interleukin, a growth factor, a polypeptide vaccine, an enzyme, an endorphin, a glycoprotein, a lipoprotein, and a polypeptide involved in the blood coagulation cascade, that exerts its pharmacological effect systemically.

4. A process as claimed in claim 1, wherein said polypeptide has a molecular weight of up to 20 kD.

5. A process as claimed in claim 1, wherein said enhancer compound is selected from the group consisting of an anionic surfactant, a cationic surfactant, a phospholipid, an alkyl glycoside, a cyclodextrin, a salt of capric acid, and a sodium, potassium or organic amine salt of a fatty acid.

6. A process as claimed in claim 1, wherein said enhancer compound is selected from the group consisting of dimethyl-.beta.-cyclodextrin, dioctanoylphosphatidylcholine, lysophosphatidylcholine, and a salt of caprate, laurate, oleate, or myristate.

7. A process as claimed in claim 1, wherein the enhancer compound constitutes between 20% and 50% by weight of said dry solid.

8. A process as claimed in claim 1, wherein at least 90% of the total mass of said powder is in the form of said primary particles having a diameter less than about 10 microns.

9. A process as claimed in claim 1, wherein the solution further comprises a dissolved pharmaceutically acceptable carrier.

10. A process as claimed in claim 1, comprising the additional step of mixing particles of a pharmaceutically acceptable carrier with said powder.

11. A process as claimed in claim 10, wherein the carrier particles have a diameter less than about 10 microns.

12. A process as claimed in claim 10, wherein the carrier particles have a diameter between 60 and 800 microns.

13. A process as claimed in claim 1, wherein said enhancer compound is a bile salt.

14. A process as claimed in claim 1, wherein said enhancer compound is a salt of ursodeoxycholate, taurocholate, glycocholate, or taurodihydrofusidate.

15. A process as claimed in claim 1, wherein the solvent is removed by spray drying.

16. A process as claimed in claim 1, wherein the solvent is removed by vacuum concentration.

17. A process as claimed in claim 1, wherein the solvent is removed by open drying.

18. A process for the preparation of a pharmaceutical composition suitable for administration by oral inhalation from a dry powder inhaler device, comprising

dry mixing (a) a pharmaceutically active polypeptide, and (b) an enhancer compound which enhances the absorption of the polypeptide in the lower respiratory tract of a patient,

micronizing the obtained mixture to produce a micronized mixture, wherein at least 50% of the total mass of said micronized mixture is in the form of primary particles having a diameter less than about 10 microns, said primary particles being optionally agglomerated; and

loading the micronized mixture into a dry powder inhaler device adapted for inhalation through the mouth.

19. A process as claimed in claim 18, comprising the step of forming the primary particles into agglomerates.

20. A process as claimed in claim 18, wherein said polypeptide is selected from the group consisting of vasopressin, a vasopressin analogue, desmopressin, glucagon, corticotropin, gonadotropin, calcitonin, C-peptide of insulin, parathyroid hormone, human growth hormone, growth hormone, growth hormone releasing hormone, oxytocin, corticotropin releasing hormone, a somatostatin analogue, a gonadotropin agonist analogue, atrial natriuretic peptide, thyroxine releasing hormone, follicle stimulating hormone, prolactin, an interleukin, a growth factor, a polypeptide vaccine, an enzyme, an endorphin, a glycoprotein, a lipoprotein, and a polypeptide involved in the blood coagulation cascade, that exerts its pharmacological effect systemically.

21. A process as claimed in claim 18, wherein said polypeptide has a molecular weight of up to 20 Kd.

22. A process as claimed in claim 18, wherein said enhancer compound is selected from the group consisting of an anionic surfactant, a cationic surfactant, a phospholipid, an alkyl glycoside, a cyclodextrin, a salt of capric acid, and a sodium, potassium or organic amine salt of a fatty acid.

23. A process as claimed in claim 18, wherein said enhancer compound is selected from the group consisting of dimethyl-.beta.-cyclodextrin, dioctanoylphosphatidylcholine, lysophosphatidylcholine, and a salt of caprate, laurate, oleate, or myristate.

24. A process as claimed in claim 18, wherein said enhancer compound constitutes between 20% and 50% by weight of said mixture.

25. A process as claimed in claim 18, wherein at least 90% of the total mass of said micronized mixture is in the form of said primary particles having a diameter less than about 10 microns.

26. A process as claimed in claim 18, wherein a pharmaceutically acceptable carrier is mixed with the polypeptide and enhancer compound in the dry mixing step.

27. A process as claimed in claim 18, comprising the additional step of mixing particles of a pharmaceutically acceptable carrier with the micronized mixture.

28. A process as claimed in claim 27, wherein the carrier particles have a diameter less than about 10 microns.

29. A process as claimed in claim 27, wherein the carrier particles have a diameter between 60 and 800 microns.

30. A process as claimed in claim 18, wherein said enhancer compound is a bile salt.

31. A process as claimed in claim 18, wherein said enhancer compound is a salt of ursodeoxycholate, taurocholate, glycocholate, or taurodihydrofusidate.

32. A process as claimed in claim 18, wherein the solvent is removed by spray drying.

33. A process as claimed in claim 18, wherein the solvent is removed by vacuum concentration.

34. A process as claimed in claim 18, wherein the solvent is removed by open drying.

35. A process for the manufacture of a pharmaceutical composition suitable for administration by oral inhalation from a dry powder inhaler device, comprising

providing a first micronized preparation comprising a polypeptide and a second micronized preparation comprising an enhancer compound which enhances the absorption of the polypeptide in the lung of a patient;

mixing said first and second micronized preparations to form a powder mixture, wherein at least 50% of the total mass of said polypeptide and enhancer in said powder mixture is in the form of primary particles having a diameter less than about 10 microns, said primary particles being optionally agglomerated; and

loading the powder mixture into a dry powder inhaler device adapted for inhalation through the mouth.

36. A process as claimed in claim 35, comprising the step of forming the primary particles into agglomerates.

37. A process as claimed in claim 35, wherein said polypeptide is selected from the group consisting of vasopressin, a vasopressin analogue, desmopressin, glucagon, corticotropin, gonadotropin, calcitonin, C-peptide of insulin, parathyroid hormone, growth hormone, growth hormone releasing hormone, oxytocin, corticotropin releasing hormone, a somatostatin analogue, a gonadotropin agonist analogue, atrial natriuretic peptide, thyroxine releasing hormone, follicle stimulating hormone, prolactin, an interleukin, a growth factor, a polypeptide vaccine, an enzyme, an endorphin, a glycoprotein, a lipoprotein, and a polypeptide involved in the blood coagulation cascade, that exerts its pharmacological effect systemically.

38. A process as claimed in claim 35, wherein said polypeptide has a molecular weight of up to 20 kD.

39. A process as claimed in claim 35, wherein said enhancer compound is selected from the group consisting of an anionic surfactant, a cationic surfactant, a phospholipid, an alkyl glycoside, a cyclodextrin, a salt of capric acid, and a sodium, potassium or organic amine salt of a fatty acid.

40. A process as claimed in claim 35, wherein said enhancer compound is selected from the group consisting of dimethyl-.beta.-cyclodextrin, dioctanoylphosphatidylcholine, lysophosphatidylcholine, and a salt of caprate, laurate, oleate, or myristate.

41. A process as claimed in claim 35, wherein said enhancer compound constitutes between 20% and 50% by weight of said mixture.

42. A process as claimed in claim 35, further comprising the step of combining said powder mixture with coarse particles of a pharmaceutically acceptable carrier to form an ordered mixture, said coarse particles having a diameter between 60 and 800 microns.

43. A process as claimed in claim 35, wherein at least 90% of the total mass of said polypeptide and enhancer is in the form of said primary particles having a diameter less than about 10 microns.

44. A process as claimed in claim 35, wherein the powder mixture additionally comprises micronized particles of a pharmaceutically acceptable carrier.

45. A process as claimed in claim 35, wherein said enhancer compound is a bile salt.

46. A process as claimed in claim 35, wherein said enhancer compound is a salt of ursodeoxycholate, taurocholate, glycocholate, or taurodihydrofusidate.

47. A process as claimed in claim 35, wherein the solvent is removed by spray drying.

48. A process as claimed in claim 35, wherein the solvent is removed by vacuum concentration.

49. A process as claimed in claim 35, wherein the solvent is removed by open drying.

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