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Details for Patent: 6,495,167

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Details for Patent: 6,495,167

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)
Filing Date:Jul 09, 2001
Application Number:09/901,205
Claims:1. A process of producing agglomerates comprising the steps of: (a) providing particles of a first material selected from the group consisting of formoterol, mometasone furoate, and a combination thereof, 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 sufficient to allow for the formation of bridges between particles; (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: 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.

2. The process of claim 1, wherein said first material comprises mornetasone furoate.

3. The process of claim 1, wherein said at least one first material comprises formoterol.

4. The process of claim 1, wherein said particles of said at least one first material have an average particle size of 10 .mu.m or less.

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

6. The process of claim 5, wherein said solid binder comprises anhydrous lactose.

7. The process of claim 1, wherein said particles of said solid binder have an average particle size of 10 .mu.m or less.

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

9. The process of claim 8, wherein said agglomerate contains between about 3% and about 30% convertible amorphous content.

10. The process of claim 9, wherein said agglomerate contains between about 5% and about 25% convertible amorphous content.

11. The process of claim 1, further comprising the step of mixing said particles of said at least one first material and said solid binder prior to said agglomerating step.

12. The process of claim 1, wherein said particles of said at least one first material and said solid binder are mixed to substantial homogeneity.

13. The process of claim 1, wherein said particles of said at least one first material and said solid binder are agglomerated in a pan rotated with an eccentric motion.

14. The process of claim 1, wherein said agglomerates have an average size of between about 300 and about 100 .mu.m.

15. The process of claim 1, wherein said agglomerates have a range in size from between about 100 and about 1500 .mu.m.

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

17. 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.

18. 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.

19. The process of claim 1, 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.

20. The process of claim 19, 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.

21. The process of claim 1, 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.

22. The process of claim 1, wherein said agglomerates have a crush strength of between about 50 mg and about 5,000 mg after conversion of said convertible amorphous content.

23. The process of claim 22, wherein said agglomerates have a crush strength of between about 200 mg and about 1,500 mg after conversion of said convertible amorphous content.

24. 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.

25. The process of claim 24, wherein said solid binder is micronized using jet milling with a substantially anhydrous gas.

26. The process of claim 1, wherein said first material and said solid binder are mixed at a weight ratio of between about 1000:1 to 1:1000.

27. The process of claim 26, wherein said first material and said solid binder are mixed at a weight ratio of between about 100:1 to 1:500.

28. The process of claim 27, wherein said at least one first material and said solid binder are mixed at a weight ratio of between about 100:1 to 1:300.

29. The process of claim 28, wherein said at least one first material and said solid binder are agglomerated at a weight ratio of between about 20:1 to about 1:20.

30. The process of claim 29, wherein said first at least one material and said solid binder are agglomerated at a weight ratio of between about 1:3 to about 1:10.

31. The product of the process of claim 1.

32. A process for producing agglomerates which are free-flowing, have bridges and are characterized by having a crush strength of between 50 mg and 5000 mg, comprising the steps of: (a) providing at least one pharmacologically active agent selected from the group consisting of formoterol, mometasone furoate and a combination thereof, and 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 for the formation of bridges between particles; (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 converting said convertible amorphous content of said agglomerates 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: 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.

33. The process of claim 32, wherein said solid binder comprises anhydrous lactose or a hydrated lactose.

34. The process of claim 32, wherein said agglomerate contains between about 1% and about 50% convertible amorphous content prior to conversion.

35. The process of claim 34, wherein said agglomerate contains between about 3% and about 30% convertible amorphous content prior to conversion.

36. The process of claim 35, wherein said agglomerate contains between about 5% and about 25% convertible amorphous content prior to conversion.

37. The process of claim 32, wherein said agglomerates have a strength of between 200 mg and about 1500 mg.

38. A pharmaceutical dosage form comprising agglomerates of particles of a pharmacologically active agent selected from the group consisting of formoterol, mometasone furoate and a combination thereof, and particles of a 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 of said pharmacologically active agent to said crystalline solid binder, 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 dosage form of claim 38, wherein said crystalline solid binder comprises lactose.

40. The dosage form of claim 39, wherein said crystalline lactose comprises anhydrous lactose.

41. The dosage form of claim 38, wherein said agglomerates have a bulk density of between about 0.29 and about 0.38 g/cm.sup.3.

42. The dosage form of claim 38, wherein said agglomerate includes no binder other than said solid binder.

43. Agglomerates comprising: particles of a pharmacologically active agent that is selected from the group consisting of formoterol, mometasone furoate and a combination thereof, and particles of a solid binder, at least one of said pharmacologically active agent and said solid binder having a preselected amount of convertible amorphous content which is sufficient for the formation of crystalline agglomerates having bridges between particles 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 of said pharmacologically active agent to said solid binder.

44. The agglomerate of claim 43 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.

45. The agglomerate of claim 43, wherein said lactose comprises anhydrous lactose.

46. The agglomerate of claim 43, having a bulk density of between about 0.29 and about 0.38 g/cm.sup.3.

47. The agglomerate of claim 43, having an average size of between 400 and about 700 .mu.m.

48. The agglomerate of claim 43, having a convertible amorphous content of between about 1 and about 50% by weight.

49. A dosing system comprising: (a) an inhaler including a storage reservoir for storing an amount of a medicament 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 medicament from said storage reservoir, and a nozzle for conveying said medicament from said metering device to the mouth or nose of a patient; and (b) an amount of said medicament sufficient to provide a plurality of individual doses thereof, said medicament being stored within said storage reservoir, and being provided as agglomerates of particles of formoterol, mometasone furoate and a combination thereof, 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 of said particles of formoterol, mometasone furoate and combinations thereof, to said crystalline binder, 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, producing a fine particle fraction of at least 10% of said preselected amount of medicament having particle sizes less than 6.8 .mu.m at an inhaled air flow rate about 60 L/min.

50. The dosing system of claim 49, 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.

51. The dosing system of claim 49, 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 airflow rate about 60 L/min.

52. A process of producing agglomerates comprising the steps of: (a) providing particles of a first material selected from the group consisting of formoterol, budesonide and a combination thereof, 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 which is sufficient to allow for the formation of bridges between particles; (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 whorein 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.

53. The process of claim 52, wherein said particles of said pharmacological agent have an average particle size of 10 .mu.m or less.

54. The process of claim 52, wherein said solid binder comprises at least one member selected from the group comprising polyhydroxy aldehydes, polyhydroxy ketones, and amino acids.

55. The process of claim 54, wherein said solid binder comprises a hydrated or anhydrous saccharide.

56. The process of claim 54, wherein said solid binder comprises anhydrous lactose or a hydrated lactose.

57. The process of claim 56, wherein said solid binder comprises anhydrous lactose.

58. The process of claim 59, wherein said particles of said solid binder have an average particle size of 10 .mu.m or less.

59. The process of claim 56, wherein said agglomerate contains between about 1% and about 50% convertible amorphous content.

60. The process of claim 59, wherein said agglomerate contains between about 3% and about 30% convertible amorphous content.

61. The process of claim 60, wherein said agglomerate contains between about 5% and about 25% convertible amorphous content.

62. The process of claim 1, further comprising the step of mixing said particles said pharmacological agent and said solid binder prior to said agglomerating step.

63. The process of claim 62, wherein said particles of pharmacologically active agent and said solid binder are mixed to substantial homogeneity.

64. The process of claim 52, wherein said particles of pharmacologically active agent and said solid binder are agglomerated in a pan rotated with an eccentric motion.

65. The process of claim 52, wherein said agglomerates have an average size of between about 300 and about 1000 .mu.m.

66. The process of claim 65, wherein said agglomerates have a range in size from between about 100 and about 1500 .mu.m.

67. The process of claim 52, wherein said preselected stimulus is atmospheric moisture.

68. The process of claim 52, 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.

69. The process of claim 68, 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.

70. The process of claim 69, 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.

71. The process of claim 70, 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.

72. The process of claim 52, 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.

73. The process of claim 52, wherein said agglomerates have a crush strength of between about 50 mg and about 5,000 mg after conversion of said convertible amorphous content.

74. The process of claim 73, wherein said agglomerates have a crush strength of between about 200 mg and about 1,500 mg after conversion of said convertible amorphous content.

75. The process of claim 52, 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.

76. The process of claim 75, wherein said solid binder is micronized using jet milling with a substantially anhydrous gas.

77. The process of claim 52, wherein said pharmacologically active agent and said solid binder are mixed at a weight ratio of between about 1000:1 to 1:1000.

78. The process of claim 77, wherein said pharmacologically active agent and said solid binder are mixed at a weight ratio of between about 100:1 to 1:500.

79. The process of claim 78, wherein said pharmacologically active agent and said solid binder are mixed at a weight ratio of between about 100:1 to 1:300.

80. The process of claim 79, wherein said pharmacologically active agent and said solid binder are agglomerated at a weight ratio of between about 20:1 to about 1:20.

81. The process of claim 80, wherein said pharmacologically active agent and said solid binder are agglomerated at a weight ratio of between about 1:3 to about 1:10.

82. The product of the process of claim 52.

83. A process for producing agglomerates which are free-flowing, have bridges and are characterized by having a crush strength of between 50 mg and 5000 mg, comprising the steps of: (a) providing at least one pharmacologically active agent selected from the group consisting of formoterol. budesonide and a combination thereof, and 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; said pharmacologically active agent and said solid binder having a preselected amount of convertible amorphous content which is sufficient for the formation of bridges between particles; (c) forming a homogeneous mixture of said particles of pharmacologically active agent and said solid binder while maintaining said preselected amount of convertible amorphous content; (d) agglomerating said mixture of said particles of pharmacologically active agent and said solid binder while maintaining said preselected amount of convertible amorphous content of said solid binder; and (e) thereafter converting said convertible amorphous content of said agglomerates 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: 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.

84. The process of claim 83, wherein said solid binder comprises anhydrous lactose or a hydrated lactose.

85. The process of claim 83, wherein said agglomerate contains between about 1% and about 50% convertible amorphous content prior to conversion.

86. The process of claim 85, wherein said agglomerate contains between about 3% and about 30% convertible amorphous content prior to conversion.

87. The process of claim 86, wherein said agglomerate contains between about 5% and about 25% convertible amorphous content prior to conversion.

88. The process of claim 83, wherein said agglomerates have a strength of between 200 mg and about 1500 mg.

89. A pharmaceutical dosage form comprising agglomerates of particles of a pharmacologically active agent selected from the group consisting of formoterol, budesonide or combinations thereof, and particles of a 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 of said pharmacologically active agent to said crystalline solid binder, 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 290 mg and about 1500 mg.

90. The dosage form of claim 89, wherein said crystalline solid binder comprises lactose.

91. The dosage form of claim 89, wherein said crystalline lactose comprises anhydrous lactose.

92. The dosage form of claim 89, wherein said agglomerates have a bulk density of between about 0.29 and about 0.38 g/cm.sup.3.

93. The dosage form of claim 89, wherein said agglomerate includes no binder other than said solid binder.

94. Agglomerates comprising: particles of a pharmacologically active agent that is selected from the group consisting of formoterol, budesonide or a combination thereof, and particles of a solid binder, at laeast one of said pharmacologically active agent and said solid binder having a preselected amount of convertible amorphous content which is sufficient for the formation of crystalline agglomerates having bridges between particles 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 of said pharmacologically active agent to said solid binder.

95. The agglomerate of claim 94, 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.

96. The agglomerate of claim 94, wherein said lactose comprises anhydrous lactose.

97. The dosage from of claim 94, having a bulk density of between about 0.29 and about 0.38 g/cm.sup.3.

98. The agglomerate of claim 94, having an average size of between 400 and about 700 .mu.m.

99. The agglomerate of claim 94, having a convertible amorphous content of between about 1 and about 50% by weight.

100. A dosing system comprising: (a) an inhaler including a storage reservoir for storing an amount of a medicament 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 medicament from said storage reservoir, and a nozzle for conveying said medicament from said metering device to the mouth or nose of a patient; and (b) an amount of said medicament sufficient to provide a plurality of individual doses thereof, the medicament being stored within said storage reservoir, and being provided as agglomerates of particles of formoterol, budesonide or combinations thereof, 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 of said particles of formoterol, budesonide or combinations thereof, to said particles of crystalline binder, 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, producing a fine particle fraction of at least 10% of said preselected amount of medicament having particle sizes less than 6.8 .mu.m at an inhaled air flow rate about 60 L/min.

101. The dosing system of claim 100, 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 formoterol and budesonide 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.

102. The dosing system of claim 100, 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 formoterol and budesonide 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.
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