Sulfoalkyl ether cyclodextrin based controlled release solid pharmaceutical formulations

• US 6,046,177 A
• Filed: 01/13/1999
• Issued: 04/04/2000
• Est. Priority Date: 05/05/1997
• Status: Expired due to Term

• Current Assignee: CyDex Pharmaceuticals, Inc. (Ligand Pharmaceuticals, Inc.)
• Original Assignee: CyDex Inc (Ligand Pharmaceuticals, Inc.)
• Inventors: Mosher, Gerold L., Rao, Venkatramana M., Rajewski, Roger A., McGinity, James W., Stella, Valentino J.
• Primary Examiner(s): Kunz, Gary L.
• Application Number:
  US09/229,513
• Time in Patent Office: 447 Days
• Field of Search: 514/58, 514/778, 514/964, 514/965, 536/103
• US Class Current: 514/58
• CPC Class Codes: A61K 47/40 Cyclodextrins; Derivatives thereof
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• CPC Class Codes: A61K 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/2826 Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/2853 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61P 5/40 Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

Sulfoalkyl ether cyclodextrin (SAE-CD) based controlled release pharmaceutical formulations are provided by the present invention. The present solid pharmaceutical formulations consist of a core comprising a physical mixture of one or more SAE-CD derivatives, an optional release rate modifier, a therapeutic agent, a major portion of which is not complexed to the SAE-CD, and an optional release rate modifying coating surrounding the core. The present formulations are advantageously easier to prepare than other SAE-CD based formulations in the art yet provide similar or improved effectiveness. The SAE-CD derivative is used to modify the bioavailability and/or rate of bioabsorption of therapeutic agents. Multi-layered, osmotic pump, coated, and uncoated tablet, minitablet, pellet, micropellet, particle, powder, and granule dosage forms are disclosed herein.

Claims

1. A controlled release solid pharmaceutical formulation consisting of a core comprising a first composition comprising a physical mixture of:

a therapeutic agent;

at least one sulfoalkyl ether cyclodextrin; and

at least one release rate modifier;

wherein,

a major portion of the therapeutic agent is not complexed with the sulfoalkyl ether cyclodextrin; and

the therapeutic agent of the first composition is released from the core at a controlled rate in the absence of a release rate modifying coat surrounding the core.

2. The controlled release solid pharmaceutical formulation of claim 1 wherein decreasing the viscosity of said release rate modifier decreases a rate of release of said therapeutic agent and increases a rate of release of said sulfoalkyl ether cyclodextrin from said formulation.

3. The controlled release solid pharmaceutical formulation of claim 1 wherein said release rate modifier is present in an amount sufficient to render a first rate of release of said therapeutic agent and a second rate of release of said sulfoalkyl ether cyclodextrin independent of a viscosity of said release rate modifier.

4. The controlled release solid pharmaceutical formulation of claim 3 wherein said release rate modifier is present in excess of said therapeutic agent and said sulfoalkyl ether cyclodextrin on a weight basis.

5. The controlled release solid pharmaceutical formulation of claim 3 wherein a ratio of said release rate modifier to said sulfoalkyl ether cyclodextrin is about 1:

1 to about 20;

1 on a weight basis.

6. The controlled release solid pharmaceutical formulation of claim 1 wherein said release rate modifier is present in an amount sufficient to render a first rate of release of said therapeutic agent and a second rate of release of said sulfoalkyl ether cyclodextrin is dependent upon a viscosity of said release rate modifier.

7. The controlled release solid pharmaceutical formulation of claim 6 wherein said sulfoalkyl ether cyclodextrin is present in excess of said therapeutic agent and said release rate modifier on a weight basis.

8. The controlled release solid pharmaceutical formulation of claim 6 wherein a ratio of said release rate modifier to said sulfoalkyl ether cyclodextrin is about 1:

1 to about 1;

20 on a weight basis.

9. The controlled release solid pharmaceutical formulation of claim 6 wherein said release rate modifier is swellable in an environment of use.

10. The controlled release solid pharmaceutical formulation of claim 1 wherein release of said sulfoalkyl ether cyclodextrin from said formulation is independent of a ratio of an amount of said therapeutic agent to an amount of said sulfoalkyl ether cyclodextrin.

11. The controlled release solid pharmaceutical formulation of claim 1 wherein release of said therapeutic agent from said formulation approximates release of said therapeutic agent from a second formulation similar to said pharmaceutical formulation except that in said second formulation all of said therapeutic agent is complexed with said sulfoalkyl ether cyclodextrin.

12. The controlled release solid pharmaceutical formulation of claim 1 wherein increasing an amount of said release rate modifier with respect to an amount of said therapeutic agent will effect a decrease in a rate of release of said therapeutic agent and a decrease in a rate of release of said sulfoalkyl ether cyclodextrin.

13. The controlled release solid pharmaceutical formulation of claim 1 wherein increasing an amount of said therapeutic agent with respect to an amount of said sulfoalkyl ether cyclodextrin will effect a decrease in a rate of release of said therapeutic agent.

14. The controlled release solid pharmaceutical formulation of claim 1, wherein said core further comprises a different second composition comprising a preformed therapeutic agent/sulfoalkyl ether cyclodextrin inclusion complex, wherein said therapeutic agent of said second composition is released from the core at a rapid rate.

15. The controlled release solid pharmaceutical formulation of claim 1, wherein a molar ratio of said therapeutic agent to said sulfoalkyl ether cyclodextrin is in the range of about 2:

1 to about 1;

10.

16. The controlled release solid pharmaceutical formulation of claim 1 wherein said sulfoalkyl ether is a compound or mixture of compounds of the formula (I):

##STR2## wherein;

n is 4, 5 or 6;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are each, independently, --O-- or --O--(C2-C6 alkylene)

--SO₃ --, wherein at least one of R₁ and R₂ is independently --O--(C2-C6 alkylene)--SO₃ --; and

S₁, S₂, S₃, S₄, S₅, S₆, S₇, S₈ and S₉ are each, independently, a pharmaceutically acceptable cation.

48. The controlled release solid pharmaceutical formulation of claim 1, wherein about 5%-75% of said therapeutic agent is released within about 6 hours.

49. The controlled release solid pharmaceutical formulation of claim 1, wherein more than 75% of said therapeutic agent is not complexed with said sulfoalkyl ether cyclodextrin.

94. The controlled release solid pharmaceutical formulation of claim 1 wherein release of said sulfoalkyl ether cyclodextrin from said formulation is dependent on a ratio of an amount of said therapeutic agent to an amount of said sulfoalkyl ether cyclodextrin.

17. A controlled release solid pharmaceutical formulation comprising:

a core comprising a first composition comprising a physical mixture of a therapeutic agent and at least one sulfoalkyl ether cyclodextrin, wherein a major portion of the therapeutic agent is not complexed with the sulfoalkyl ether cyclodextrin; and

a coating surrounding said core and consisting of a film forming agent;

wherein, said therapeutic agent of the first composition is released from the core at a controlled rate in the absence of a pore forming agent in the coating.

18. The controlled release solid pharmaceutical formulation of claim 17 wherein said coating is a semipermeable membrane having a passageway therethrough.

19. The controlled release solid pharmaceutical formulation of claim 17 wherein said core further comprises a release rate modifier.

20. The controlled release solid pharmaceutical formulation of claim 17 wherein release of said therapeutic agent from said formulation approximates release of said therapeutic agent from a second formulation substantially similar to said pharmaceutical formulation except that in said second formulation of said therapeutic agent is complexed with said sulfoalkyl ether cyclodextrin.

21. The controlled release solid pharmaceutical formulation of claim 17, wherein said core further comprises a different second composition comprising a preformed therapeutic agent/sulfoalkyl ether cyclodextrin inclusion complex, wherein said therapeutic agent of said second composition is released from the core at a rapid rate.

22. The controlled release solid pharmaceutical formulation of claim 17 wherein said sulfoalkyl ether is a compound or mixture of compounds of the formula (I):

##STR3## wherein;

n is 4, 5 or 6;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are each, independently, --O-- or --O--(C2-C6 alkylene)

--SO₃ --, wherein at least one of R₁ and R₂ is independently --O--(C2-C6 alkylene)--SO₃ --; and

S₁, S₂, S₃, S₄, S₅, S₆, S₇, S₈ and S₉ are each, independently, a pharmaceutically acceptable cation.

50. The controlled release solid pharmaceutical formulation of claim 17, wherein about 5%-75% of said therapeutic agent is released within about 6 hours.

51. The controlled release solid pharmaceutical formulation of claim 17, wherein more than 75% of said therapeutic agent is not complexed with said sulfoalkyl ether cyclodextrin.

78. The controlled release solid pharmaceutical formulation of claim 21, wherein said physical mixture is present in excess of said inclusion complex on a weight basis.

79. The controlled release solid pharmaceutical formulation of claim 21, wherein said inclusion complex is present in excess of said physical mixture on a weight basis.

80. The controlled release solid pharmaceutical formulation of claim 21, wherein said therapeutic agent in said inclusion complex is the same as said therapeutic agent in said physical mixture.

81. The controlled release solid pharmaceutical formulation of claim 21, wherein said therapeutic agent in said inclusion complex is different than said therapeutic agent in said physical mixture.

23. A multi-layered controlled release solid pharmaceutical formulation comprising:

at least one first layer comprising a physical mixture of a therapeutic agent and a sulfoalkyl ether cyclodextrin; and

at least one second layer comprising a release rate modifier;

wherein,

said first and second layers are juxtaposed;

said therapeutic agent is released from said core at a controlled rate; and

a major portion of said therapeutic agent is not complexed with said sulfoalkyl ether cyclodextrin.

24. The multi-layered controlled release solid pharmaceutical formulation of claim 23 wherein said sulfoalkyl ether is a compound or mixture of compounds of the formula (I):

##STR4## wherein;

n is 4, 5 or 6;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are each, independently, --O-- or --O--(C2-C6 alkylene)

--SO₃ --, wherein at least one of R₁ and R₂ is independently --O--(C2-C6 alkylene)--SO₃ --; and

S₁, S₂, S₃, S₄, S₅, S₆, S₇, S₈ and S₉ are each, independently, a pharmaceutically acceptable cation.

25. The multi-layered controlled release solid pharmaceutical formulation of claim 23 wherein said pharmaceutical composition is surrounded by a coating comprising a film forming agent.

26. The multi-layered controlled release solid pharmaceutical formulation of claim 23 wherein said first layer surrounds said second layer.

27. The multi-layered controlled release solid pharmaceutical formulation of claim 23 wherein said first layer independently further comprises a release rate modifier.

28. The multi-layered controlled release solid pharmaceutical formulation of claim 23 wherein said formulation is a tablet, minitablet, granule, pellet or micropellet.

52. The multi-layered controlled release solid pharmaceutical formulation of claim 23, wherein about 5%-75% of said therapeutic agent is released within about 6 hours.

53. The multi-layered controlled release solid pharmaceutical formulation of claim 23, wherein more than 75% of said therapeutic agent is not complexed with said sulfoalkyl ether cyclodextrin.

29. A multi-layered combined rapid and controlled release solid pharmaceutical formulation comprising:

at least one controlled release first layer comprising a physical mixture of a first therapeutic agent, a release rate modifier and a sulfoalkyl ether cyclodextrin for releasing said first therapeutic agent at a controlled rate into a first environment of use; and

at least one rapid release second layer comprising a preformed complex of a second therapeutic agent and a sulfoalkyl ether cyclodextrin for releasing said second therapeutic agent rapidly into a second environment of use;

wherein,

said first and second layers are juxtaposed;

a major portion of said first therapeutic agent is not complexed with said sulfoalkyl ether cyclodextrin.

30. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 29 wherein said sulfoalkyl ether is a compound or mixture of compounds of the formula (I). ##STR5## wherein:

n is 4, 5 or 6;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are each, independently --O -- or --O--(C2-C6 alkylene)

--SO₃ --, wherein at least one of R₁ and R₂ is independently --O--(C2-C6 alkylene)--SO₃ --; and

S₁, S₂, S₃, S₄, S₅, S₆, S₇, S₈ and Sg are each, independently, a pharmaceutically acceptable cation.

31. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 29 wherein said pharmaceutical composition is surrounded by a coating comprising a film forming agent.

32. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 29 wherein said at least one rapid release second layer surrounds said at least one controlled release first layer.

33. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 29 wherein said formulation is a tablet, minitablet, granule, pellet or micropellet.

54. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 29, wherein about 5%-75% of said therapeutic agent is released within about 6 hours.

55. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 29, wherein more than 75% of said therapeutic agent is not complexed with said sulfoalkyl ether cyclodextrin.

82. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 29, wherein said physical mixture in said first layer is present in excess of said inclusion complex in said second layer on a weight basis.

83. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 29, wherein said inclusion complex in said second layer is present in excess of said physical mixture in said first layer on a weight basis.

84. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 29, wherein said first and second environments of use are the same.

85. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 29, wherein said first and second environments of use are different.

86. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 29, wherein said first and second therapeutic agents are the same.

87. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 29, wherein said first and second therapeutic agents are different.

34. A multi-layered combined rapid and controlled release solid pharmaceutical formulation comprising:

at least one controlled release first layer comprising a physical mixture of a first therapeutic agent, a release rate modifier and a sulfoalkyl ether cyclodextrin for releasing said first therapeutic agent at a controlled rate into a first environment of use; and

at least one rapid release second layer comprising a physical mixture of a second therapeutic agent and a sulfoalkyl ether cyclodextrin for releasing said second therapeutic agent rapidly into a second environment of use;

wherein,

said first and second layers are juxtaposed; and

major portions of each of said first and second therapeutic agents are not complexed with said sulfoalkyl ether cyclodextrin.

35. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 34 wherein said sulfoalkyl ether is a compound or mixture of compounds of the formula (I). ##STR6## wherein:

n is 4, 5 or 6;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are each, independently, --O-- or --O--(C2-C6 alkylene)

--SO₃ --, wherein at least one of R₁ and R₂ is independently --O--(C2-C6 alkylene)--SO₃ --; and

S₁, S₂, S₃, S₄, S₅, S₆, S₇, S₈ and S₉ are each, independently, a pharmaceutically acceptable cation.

36. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 34 wherein said pharmaceutical composition is surrounded by a coating comprising a film forming agent.

37. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 34 wherein said at least one rapid release second layer surrounds said at least one controlled release first layer.

38. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 34 wherein said formulation is a tablet, minitablet, granule, pellet or micropellet.

39. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 34 comprising:

one controlled release first layer comprising a physical mixture of a first therapeutic agent, a release rate modifier and a sulfoalkyl ether cyclodextrin for releasing said first therapeutic agent at a controlled rate into a first environment of use; and

two rapid release second layers each comprising a physical mixture of a second therapeutic agent and a sulfoalkyl ether cyclodextrin for releasing said second therapeutic agent rapidly into a second environment of use;

wherein,

said controlled release first layer is disposed between said two rapid release second layers.

56. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 34, wherein about 5%-75% of said therapeutic agent is released within about 6 hours.

57. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 34, wherein more than 75% of said therapeutic agent is not complexed with said sulfoalkyl ether cyclodextrin.

88. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 34, wherein said physical mixture in said first layer is present in excess of said physical mixture in said second layer on a weight basis.

89. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 34, wherein said physical mixture in said second layer is present in excess of said physical mixture in said first layer on a weight basis.

90. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 34, wherein said first and second environments of use are the same.

91. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 34, wherein said first and second environments of use are different.

92. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 34, wherein said first and second therapeutic agents are substantially the same.

93. The multi-layered combined rapid and controlled release solid pharmaceutical formulation of claim 34, wherein said first and second therapeutic agents are different.

40. An osmotic solid pharmaceutical formulation for the controlled diffusional and osmotic delivery of a therapeutic agent to an environment of use comprising:

a core comprising a physical mixture of a sulfoalkyl ether cyclodextrin, a therapeutic agent and a pharmaceutically acceptable carrier; and

a membrane surrounding said core and comprising a film forming agent and a pore forming agent, said membrane having a passageway therethrough for communicating said core to an environment of use;

wherein,

a first portion of said therapeuic agent diffuses through said membrane and a second portion of said therapeutic agent passes through said passageway; and

a major portion of said therapeutic agent is not complexed with said sulfoalkyl ether cyclodextrin.

41. The osmotic solid pharmaceutical formulation of claim 40, wherein said membrane is at least one of semipermeable and microporous.

42. The osmotic solid pharmaceutical formulation of claim 40, wherein said membrane has a thickness and composition such that said therapeutic agent is primarily delivered through said passageway.

43. The osmotic solid pharmaceutical formulation a of claim 40, wherein said membrane has a thickness and composition such that said therapeutic agent is primarily delivered through said membrane by diffusion.

44. The osmotic solid pharmaceutical formulation of claim 40, wherein said core further comprises an osmagent.

45. The osmotic solid pharmaceutical formulation of claim 40, wherein said core further comprises a separate composition comprising an inclusion complex of said therapeutic agent and said sulfoalkyl ether cyclodextrin.

46. The osmotic solid pharmaceutical formulation of claim 40, wherein about 5%-75% of said therapeutic agent is released within about 6 hours.

47. The osmotic solid pharmaceutical formulation of claim 40, wherein more than 75% of said therapeutic agent is not complexed with said sulfoalkyl ether cyclodextrin.

58. A combination rapid and controlled release solid pharmaceutical formulation comprising a physical mixture of:

a first group of particles comprising a physical mixture of a first therapeutic agent, a release rate modifier and a sulfoalkyl ether cyclodextrin for releasing said first therapeutic agent at a controlled rate into a first environment of use; and

a second group of particles comprising an inclusion complex of a second therapeutic agent and a sulfoalkyl ether cyclodextrin for releasing said second therapeutic agent rapidly into a second environment of use.

59. The combination rapid and controlled release solid pharmaceutical formulation of claim 58, wherein said sulfoalkyl ether is a compound or mixture of compounds of the formula (I):

##STR7## wherein;

n is 4, 5 or 6;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are each, independently, --O-- or --O--(C2-C6 alkylene)

--SO₃ --, wherein at least one of R₁ and R₂ is independently --O--(C2-C6 alkylene)--SO₃ --; and

S₁, S₂, S₃, S₄, S₅, S₆, S₇, S₈ and S₉ are each, independently, a pharmaceutically acceptable cation.

60. The combination rapid and controlled release solid pharmaceutical formulation of claim 58, wherein said formulation is a tablet, capsule, microcapsule, or minitablet.

61. The combination rapid and controlled release solid pharmaceutical formulation of claim 58, wherein in said first group of particles said release rate modifier is present in excess of said therapeutic agent and said sulfoalkyl ether cyclodextrin on a weight basis.

62. The combination rapid and controlled release solid pharmaceutical formulation of claim 58, wherein in said first group of particles said release rate modifier is present in an amount sufficient to render a first rate of release of said therapeutic agent and a second rate of release of said sulfoalkyl ether cyclodextrin is independent of a viscosity of said release rate modifier.

63. The combination rapid and controlled release solid pharmaceutical formulation of claim 58, wherein in said first group of particles decreasing a viscosity of said release rate modifier decreases a rate of release of said therapeutic agent and increases a rate of release of said sulfoalkyl ether cyclodextrin from said formulation.

64. The combination rapid and controlled release solid pharmaceutical formulation of claim 58, wherein in said first group of particles said release rate modifier is present in an amount sufficient to render a first rate of release of said therapeutic agent and a second rate of release of said sulfoalkyl ether cyclodextrin is dependent upon a viscosity of said release rate modifier.

65. The combination rapid and controlled release solid pharmaceutical formulation of claim 64, wherein in said first group of particles said sulfoalkyl ether cyclodextrin is present in excess of said therapeutic agent and said release rate modifier on a weight basis.

66. The combination rapid and controlled release solid pharmaceutical formulation of claim 58, wherein in said first group of particles release of said sulfoalkyl ether cyclodextrin from said formulation is independent of a ratio of an amount of said therapeutic agent to an amount of said sulfoalkyl ether cyclodextrin.

67. The combination rapid and controlled release solid pharmaceutical formulation of claim 58, wherein in said first group of particles release of said therapeutic agent from said formulation approximates release of said therapeutic agent from a second formulation similar to said pharmaceutical formulation except that in said second formulation of said therapeutic agent is complexed with said sulfoalkyl ether cyclodextrin.

68. The combination rapid and controlled release solid pharmaceutical formulation of claim 58, wherein in said first group of particles increasing an amount of said release rate modifier with respect to an amount of said therapeutic agent will effect a decrease in a rate of release of said therapeutic agent and a decrease in a rate of release of said sulfoalkyl ether cyclodextrin.

69. The combination rapid and controlled release solid pharmaceutical formulation of claim 58, wherein in said first group of particles increasing an amount of said therapeutic agent with respect to an amount of said sulfoalkyl ether cyclodextrin will effect a decrease in a rate of release of said therapeutic agent.

70. The combination rapid and controlled release solid pharmaceutical formulation of claim 58, wherein said physical mixture in said first group of particles is present in excess of said inclusion complex in said second group of particles on a weight basis.

71. The combination rapid and controlled release solid pharmaceutical formulation of claim 58, wherein said inclusion complex in said second group of particles is present in excess of said physical mixture in said first group of particles on a weight basis.

72. The combination rapid and controlled release solid pharmaceutical formulation of claim 58, wherein said first and second environments of use are about the same.

73. The combination rapid and controlled release solid pharmaceutical formulation of claim 58, wherein said first and second therapeutic agents are the same.

74. The combination rapid and controlled release solid pharmaceutical formulation of claim 58, wherein said first and second therapeutic agents are different.

75. The combination rapid and controlled release solid pharmaceutical formulation of claim 58, wherein said first and second environments of use are different.

76. The combination rapid and controlled release solid pharmaceutical formulation of claim 58, wherein particles in one or more of said first and second groups of particles are coated with a membrane comprising a film-forming agent.

77. The combination rapid and controlled release solid pharmaceutical formulation of claim 76, wherein said membrane further comprises a pore forming agent.

95. The combination rapid and controlled release solid pharmaceutical formulation of claim 58, wherein in said first group of particles release of said sulfoalkyl ether cyclodextrin from said formulation is dependent on a ratio of an amount of said therapeutic agent to an amount of said sulfoalkyl ether cyclodextrin.