.

Pharmaceutical Business Intelligence

  • Anticipate P&T budget requirements
  • Evaluate market entry opportunities
  • Find generic sources and suppliers
  • Predict branded drug patent expiration

► Plans and Pricing

Upgrade to enjoy subscriber-only features like email alerts and data export. See the Plans and Pricing

DrugPatentWatch Database Preview

Claims for Patent: 6,503,537

« Back to Dashboard

Claims for Patent: 6,503,537

Title: Preparation of powder agglomerates
Abstract:The invention relates to a method of producing an agglomerate of drug and solid binder. The process involves producing individual agglomerate particles and then converting the convertible amorphous content of same, following agglomeration, by the application of, for example, moisture. Agglomerates capable of conversion as well as the finished agglomerates and oral and nasal dosing systems including same are also contemplated. The process produces agglomerates which are rugged but which will produce an acceptable fine particle fraction during dosing.
Inventor(s): Yang; Tsong-Toh (Warren, NJ)
Assignee: Schering Corporation (Kenilworth, NJ)
Application Number:09/824,377
Patent Claims: 1. A process of producing agglomerates comprising the steps of: (a) providing particles of at least one first material and particles of at least one solid binder, at least one of said first material and said solid binder having a preselected amount of convertible amorphous content which is capable of being converted to crystalline form upon exposure to a preselected stimulus, said convertible amorphous content being provided in an amount which is sufficient to allow for the formation of agglomerates; (b) agglomerating said particles of said first material and said solid binder while maintaining said preselected amount of convertible amorphous content; and thereafter (c) exposing said convertible amorphous content within said agglomerates to said preselected stimulus so as to convert said convertible amorphous content to a crystalline form, wherein said agglomerates are used in a dosage form of a pharmacologically active agent useful for administration by oral inhalation therapy consisting essentially of: agglometates of particles of a pharmacologically active agent and particles of crystalline solid binder, said particles having an average particle size of 10 .mu.m or less and being provided in a weight ratio of between 100:1 to 1:500, said agglomerates having an average size of between 400 and 700 .mu.m, a bulk density of between about 0.2 and about 0.4 g/cm.sup.3 and a crush strength of between 200 mg and about 1500 mg.

2. The process of claim 1 wherein said first material comprises a pharmacologically active agent.

3. The process of claim 2 wherein said pharmacologically active agent comprises at least one member selected from the group consisting of corticosteroids, .beta.-agonists, anticholinergics, leukotriene antagonists and inhalable proteins or peptides.

4. The process of claim 2, wherein said pharmacologically active agent comprises at least one member selected from the group consisting of: mometasone furoate; beclomethasone dipropionate; budesonide; fluticasone; dexamethasone; flunisolide; triamcinolone; salbutamol; albuterol; terbutaline; salmeterol; bitolterol; ipratropium bromide; oxitropium bromide; sodium cromoglycate; nedocromil sodium; zafirlukast; pranlukast; formoterol; eformoterol; bambuterol; fenoterol; clenbuterol; procaterol; broxaterol; (22R)-6.alpha.,9.alpha.-difluoro-11.beta.,21-dihydroxy-16.alpha.,17.alpha. -propylmethylenedioxy-4-pregnen-3,20-dione; TA-2005; tipredane; insulin; interferons; calcitonins; parathyroid hormones; and granulocyte colony-stimulating factor.

5. The process of claim 2, wherein said pharmacologically active agent comprises mometasone furoate.

6. The process of claim 2, wherein said particles of said pharmacologically active agent have an average particle size of 10 .mu.m or less.

7. The process of claim 1, wherein said solid binder comprises at least one member selected from the group consisting of polyhydroxy aldehydes, polyhydroxy ketones, and amino acids.

8. The process of claim 1, wherein said solid binder comprises a hydrated or anhydrous saccharide.

9. The process of claim 1, wherein said solid binder comprises anhydrous lactose or a hydrated lactose.

10. The process of claim 1 wherein said solid binder comprises anhydrous lactose.

11. The process of claim 2, wherein said particles of said solid binder have an average particle size of 10 .mu.m or less.

12. The process of claim 2, wherein said agglomerate contains between about 1 % and about 50% convertible amorphous content.

13. The process of claim 2, wherein said agglomerate contains between about 3% and about 30% convertible amorphous content.

14. The process of claim 2, wherein said agglomerate contains between about 5% and about 25% convertible amorphous content.

15. The process of claim 2, further comprising the step of mixing said particles of pharmacologically active agent and said solid binder prior to said agglomerating step.

16. The process of claim 14, wherein said particles of pharmacologically active agent and said solid binder are mixed to substantial homogeneity.

17. The process of claim 2, wherein said particles of pharmacologically active agent and said solid binder are agglomerated in a pan rotated with an eccentric motion.

18. The process of claim 2, wherein said agglomerates have an average size of between about 300 and about 1000 .mu.m.

19. The process of claim 2, wherein said agglomerates have a range in size from between about 100 and about 1500 .mu.m.

20. The process of claim 1 wherein said preselected stimulus is atmospheric moisture.

21. The process of claim 1, wherein said solid binder is maintained at a moisture content of less than or equal to that of a relative humidity of 25% when measured at 21.degree. C., prior to crystallization.

22. The process of claim 1, wherein said solid binder is maintained at a moisture content of less than or equal to that of a relative humidity of 20% when measured at 21.degree. C., prior to crystallization.

23. The process of claim 2, further comprising converting said convertible amorphous content of said agglomerate into a crystalline form by exposure of said agglomerates to an atmosphere having a moisture content equal to that of a relative humidity of between about 30% and about 80% when measured at 25.degree. C.

24. The process of claim 23, wherein said convertible amorphous content is converted into a crystalline form by exposure of said agglomerates to an atmosphere having a moisture content equal to that of a relative humidity of between about 40% and about 60% when measured at 25.degree. C.

25. The process of claim 2, wherein said particles of said agglomerate are more strongly bound to one another after conversion of said amorphous content to a crystalline form than before conversion.

26. The process of claim 2, wherein said agglomerates have a crush strength of between about 50 mg and about 5,000 mg after conversion of said convertible amorphous content.

27. The process of claim 2, wherein said agglomerates have a crush strength of between about 200 mg and about 1,500 mg after conversion of said convertible amorphous content.

28. The process of claim 1, further comprising the step of micronizing said solid binder and/or said first material to impart thereto a preselected amount of amorphous content to the resulting particles prior to the step of providing said particles.

29. The process of claim 28, wherein said solid binder is micronized using jet milling with a substantially anhydrous gas.

30. The process of claim 2, wherein said pharmacologically active agent and said solid binder are mixed at a weight ratio of between about 1000:1 to 1:1000.

31. The process of claim 2, wherein said pharmacologically active agent and said solid binder are mixed at a weight ratio of between about 100:1 to 1:500.

32. The process of claim 2, wherein said pharmacologically active agent and said solid binder are mixed at a weight ratio of between about 100:1 to 1:300.

33. The process of claim 2, wherein said pharmacologically active agent and said solid binder are agglomerated at a weight ratio of between about 20:1 to about 1:20.

34. The process of claim 2, wherein said pharmacologically active agent and said solid binder are agglomerated at a weight ratio of between about 1:3 to about 1:10.

35. The product of the process of claim 1.

36. The product of the process of claim 2.

37. The product of the process of claim 3.

38. A process for producing agglomerates containing a pharmacologically active agent, comprising the steps of: (a) providing at least one pharmacologically active agent having an average particle size of below about 10 .mu.m; (b) providing at least one solid binder having an average particle size of about 10 .mu.m or below; at least one of said pharmacologically active agent and said solid binder having a preselected amount of convertible amorphous content which is sufficient to allow for the formation of agglomerates upon conversion; (c) forming a homogeneous mixture of said particles of said pharmacologically active agent and said solid binder while maintaining said preselected amount of convertible amorphous content; (d) agglomerating said mixture of said particles of said pharmacologically active agent and said solid binder while maintaining said preselected amount of convertible amorphous content of said solid binder; and (e) thereafter allowing said convertible amorphous content of said agglomerates to convert to a crystalline form; to form (f) agglomerates which are free-flowing, have bridges and are characterized by having a strength of between 50 mg and 5000 mg, wherein said agglomerates are used in a dosage form of a pharmacologically active agent useful for administration by oral inhalation therapy consisting essentially of: agglomerates of particles of a pharmacologically active agent and particles of crystalline solid binder, said particles having an average particle size of 10 .mu.m or less and being provided in a weight ratio of between 100:1 to 1:500, said agglomerates having an average size of between 400 and 700 .mu.m, a bulk density of between about 0.2 and about 0.4 g/cm.sup.3 and a crush strength of between 200 mg and about 1500 mg.

39. The process of claim 38 wherein said pharmacologically active agent comprises at least one member selected from the group consisting of corticosteroids, .beta.-agonists, anticholinergics, leukotriene antagonists and inhalable proteins or peptides.

40. The process of claim 38, wherein said pharmacologically active agent comprises mometasone furoate.

41. The process of claim 38, wherein said solid binder comprises anhydrous lactose or a hydrated lactose.

42. The process of claim 38, wherein said agglomerate contains between about 1% and about 50% convertible amorphous content prior to conversion.

43. The process of claim 38, wherein said agglomerate contains between about 3% and about 30% convertible amorphous content prior to conversion.

44. The process of claim 38, wherein said agglomerate contains between about 5% and about 25% convertible amorphous content prior to conversion.

45. The process of claim 38, wherein said agglomerates have a strength of between 200 mg and about 1500 mg.

46. A dosage form of a pharmacologically active agent useful for administration by oral inhalation therapy consisting essentially of: agglomerates of particles of a pharmacologically active agent and particles of crystalline solid binder, said particles having an average particle size of 10 .mu.m or less and being provided in a weight ratio of between 100:1 to 1:500, said agglomerates having an average size of between 400 and 700 .mu.m, a bulk density of between about 0.2 and about 0.4 g/cm.sup.3 and a crush strength of between 200 mg and about 1500 mg.

47. The dosage form of claim 46, wherein said crystalline solid binder comprises lactose.

48. The dosage form of claim 47, wherein said crystalline lactose comprises anhydrous lactose.

49. The dosage form of claim 46, wherein said agglomerates have a bulk density of between about 0.29 and about 0.38 g/cm.sup.3.

50. The dosage form of claim 46 wherein said pharmacologically active agent comprises at least one member selected from the group consisting of corticosteroids, .beta.-agonists, anticholinergics, leukotriene antagonists and inhalable proteins or peptides.

51. The dosage form of claim 46, wherein said pharmacologically active agent comprises at least one member selected from the group consisting of: mometasone furoate; beclomethasone dipropionate; budesonide; fluticasone; dexamethasone; flunisolide; triamcinolone; salbutamol; albuterol; terbutaline; salmeterol; bitolterol; ipratropium bromide; oxitropium bromide; sodium cromoglycate; nedocromil sodium; zafirlukast; pranlukast; formoterol; eformoterol; bambuterol; fenoterol; clenbuterol; procaterol; broxaterol; (22R)-6.alpha.,9.alpha.-difluoro-11.beta.,21-dihydroxy-16.alpha.,17.alpha. -propylmethylenedioxy-4-pregnen-3,20-dione; TA-2005; tipredane; insulin; interferons; calcitonins; parathyroid hormones; and granulocyte colony-stimulating factor.

52. The dosage form of claim 46 wherein said agglomerate includes no binder other than said solid binder.

53. An intermediate agglomerate useful for producing a free-flowing crystalline agglomerate dosage form of a pharmacologically active agent useful for administration by oral or nasal inhalation therapy, said intermediate agglomerates comprising: particles of said pharmacologically active agent and particles of solid binder, said pharmacologically active agent or said solid binder having a preselected amount of convertible amorphous content which is sufficient to allow for the formation of crystalline agglomerates upon exposure to moisture, said particles of said pharmacologically active agent and said particles of said solid binder having an average particle size of 10 .mu.m or less, and said particles being provided in a weight ratio of between 1000:1 to 1:1000.

54. The intermediate agglomerate of claim 53 having an average size of between 300 and 1000 .mu.m, and a bulk density of between about 0.2 and about 0.4 g/cm.sup.3.

55. The intermediate agglomerate of claim 53, wherein said lactose comprises anhydrous lactose.

56. The dosage from of claim 53, having a bulk density of between about 0.29 and about 0.38 g/cm.sup.3.

57. The intermediate agglomerate of claim 53, having an average size of between 400 and about 700 .mu.m.

58. The intermediate agglomerate of claim 53 wherein said pharmacologically active agent comprises at least one member selected from the group consisting of corticosteroids, .beta.-agonists, anticholinergics, leukotriene antagonists and inhalable proteins or peptides.

59. The intermediate agglomerate of claim 53, wherein said pharmacologically active agent comprises at least one member selected from the group consisting of: mometasone furoate; beclomethasone dipropionate; budesonide; fluticasone; dexamethasone; flunisolide; triamcinolone; salbutamol; albuterol; terbutaline; salmeterol; bitolterol; ipratropium bromide; oxitropium bromide; sodium cromoglycate; nedocromil sodium; zafirlukast; pranlukast; formoterol; eformoterol; bambuterol; fenoterol; clenbuterol; procaterol; broxaterol; (22R)-6.alpha.,9.alpha.-difluoro-11.beta.,21-dihydroxy-16.alpha.,17.alpha. -propylmethylenedioxy-4-pregnen-3,20-dione; TA-2005; tipredane; insulin; interferons; calcitonins; parathyroid hormones; and granulocyte colony-stimulating factor.

60. The intermediate agglomerate of claim 53, having a convertible amorphous content of between about 1 and about 50% by weight.

61. A dosing system comprising: (a) an inhaler, said inhaler including a storage reservoir for storing an amount of a pharmacologically active agent in the form of a crystalline agglomerate, sufficient to provide a plurality of individual doses thereof, a metering device for measuring and metering a preselected amount of said pharmacologically active agent from said storage reservoir, and a nozzle for conveying said pharmacologically active agent from said metering device to the mouth or nose of a patient; and (b) an amount of a pharmacologically active agent sufficient to provide a plurality of individual doses thereof, said pharmacologically active agent being stored within said storage reservoir, being provided as an agglomerate of particles of said pharmacologically active agent and particles of a crystalline binder, wherein said particles have an average particle size of 10 .mu.m or less and the components thereof are provided in a weight ratio of between 1000:1 to 1:1000, said agglomerates having an average size of between 300 and 1000 .mu.m and a bulk density of between about 0.2 and about 0.4 g/cm.sup.3 ; and said agglomerate and said inhaler, when used in combination, being capable of producing a fine particle fraction of at least 10%, at an inhaled air flow rate about 60 L/min.

62. The dosing system of claim 61, wherein said crystalline agglomerates have a strength of between about 50 mg and about 5000 mg and wherein said inhaler is designed such that it will impart to said agglomerated pharmacologically active agent an amount of force which is sufficient to produce a fine particle fraction of at least 10%, at an inhaled air flow rate about 60 L/min.

63. The dosing system of claim 61, wherein said crystalline agglomerates have a strength of between about 200 mg and about 1,500 mg and wherein said inhaler is designed such that it will impart to said agglomerated pharmacologically active agent an amount of force which is sufficient to produce a fine particle fraction of at least 10%, at an inhaled air flow rate about 60 L/min.

64. A process of producing agglomerates using particles of at least one pharmacologically active agent having an average particle size of 10 .mu.m or less and particles of at least one solid binder, in a weight ratio of pharmacologically active agent to solid binder between about 1000:1 and about 1:1000, at least one of said pharmacologically active agent and said solid binder containing a preselected amount of amorphous content which can be converted to crystalline form upon exposure to a stimulus, said preselected amount being sufficient to allow for the formation of agglomerates, the process comprising agglomerating said particles of pharmacologically active agent and solid binder while maintaining substantially said preselected amount of amorphous content, and thereafter exposing said agglomerates to said stimulus to convert said amorphous content to a crystalline form.

65. The process of claim 64, wherein said agglomerates contain between about 1% and about 50% convertible amorphous content prior to being converted.

66. The process of claim 64, wherein said agglomerates contain between about 3% and about 30% convertible amorphous content prior to being converted.

67. The process of claim 64, wherein said agglomerates contain between about 5% and about 25% convertible amorphous content prior to being converted.

68. The process of claim 64, wherein said agglomerates have an average size between about 100 and about 1500 .mu.m.

69. The process of claim 64, wherein said agglomerates have an average size between about 300 and about 1000 .mu.m.

70. The process of claim 64, wherein said pharmacologically active agent comprises at least one member selected from the group consisting of corticosteroids, .beta.-agonists, anticholinergics, leukotriene antagonists and inhalable proteins or peptides.

71. The process of claim 64, wherein said pharmacologically active agent comprises one or more members selected from the group consisting of: mometasone; beclomethasone; budesonide; fluticasone; dexamethasone; flunisolide; triamcinolone; albuterol; terbutaline; salmeterol; bitolterol; ipratropium; oxitropium; sodium cromoglycate; nedocromil sodium; zafirlukast; pranlukast; eformoterol; bambuterol; fenoterol; clenbuterol; procaterol; broxaterol; (22R)-6.alpha., 9.alpha.-difluoro-11.beta.,21-dihydroxy-16.alpha.,17.alpha.-propylmethylen ediOxy-4-pregnen-3,20-dione; TA-2005; tipredane; insulin; interferons; calcitonins; parathyroid hormones; and granulocyte colony-stimulating factor; salts and esters thereof.

72. The process of claim 64, wherein said pharmacologically active agent comprises mometasone furoate.

73. The process of claim 64, wherein said solid binder comprises at least one member selected from the group consisting of polyhydroxy aldehydes, polyhydroxy ketones and amino acids.

74. The process of claim 64, wherein said solid binder comprises a hydrated or anhydrous saccharide.

75. The process of claim 64, wherein said solid binder comprises anhydrous lactose or a hydrated lactose.

76. The process of claim 64, wherein said solid binder comprises anhydrous lactose.
« Back to Dashboard

For more information try a trial or see the database preview and plans and pricing

How are People Using DrugPatentWatch?

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.

`abc