FORMULATIONS

Abstract

Provided herein are high-dose formulations of acamprosate in a pharmaceutically acceptable salt form, as well as methods of preparing the same, and methods of using the same.

Claims

1. In a method of manufacturing an oval uncoated tablet composition comprising acamprosate in a pharmaceutically acceptable salt form and a carbomer homopolymer, wherein the acamprosate is present in a dose of at least 400 mg and the composition is prepared by blending: (1) a preparation of granules with (2) extra-granular materials, the improvement that comprises including a cellulose derivative in each of (1) the preparation of granules, and (2) the extra-granular materials, so that the composition comprises: the acamprosate in a dose of about 66 wt % to about 72 wt %; the carbomer homopolymer in an amount of about 2 wt % to about 15 wt %; and the cellulose derivative in an amount of about 5 wt % to about 9 wt %.

2. The improvement of claim 1, wherein the tablet composition is characterized in that, when it is placed in either acetate solution (pH 4.5) or HCl solution (pH 1.0) in vitro, it releases the acamprosate at a rate that is approximately linear with the square root of time, and with comparable rate constants in each solution.

3. The improvement of claim 1 or 2, wherein the tablet composition is characterized by a % swelling in the length of the tablet composition in a range of about 100% to about 180% when placed in 0.1 N HCl (pH 1.0), acetate solution (pH 4.5) or phosphate solution (pH 6.8).

4. The improvement of any one of claims 1-3, wherein the tablet composition is characterized by a % swelling in the thickness of the tablet composition in a range of about 100% to about 175% when placed in 0.1 N HCl (pH 1.0), acetate solution (pH 4.5) or phosphate solution (pH 6.8).

5. The improvement of any one of claims 1-4, wherein the total weight of the tablet composition is about 1000 mg to about 1280 mg.

6. The improvement of any one of claims 1-5, wherein the total weight of the tablet composition is about 1120 mg to about 1200 mg.

7. The improvement of any one of claims 1-6, wherein the total weight of the tablet composition is about 1140 mg to about 1180 mg.

8. The improvement of any one of claims 1-7, wherein the dose of the acamprosate is about 660 mg to about 921 mg.

9. The improvement of any one of claims 1-8, wherein the dose of the acamprosate is about 740 mg to about 864 mg.

10. The improvement of any one of claims 1-9, wherein the dose of the acamprosate is about 752 mg to about 849 mg.

11. The improvement of any one of claims 1-10, wherein the dose of the acamprosate is about 800 mg.

12. The improvement of any one of claims 1-11, wherein the carbomer homopolymer is carbomer homopolymer type B.

13. The improvement of any one of claims 1-12, wherein the carbomer homopolymer type B is in an amount of about 3 wt % to about 7 wt %.

14. The improvement of any one of claims 1-13, wherein the carbomer homopolymer type B is in an amount of about 60 mg.

15. The improvement of any one of claims 1-14, wherein the cellulose derivate is carboxymethyl cellulose (CMC 7HF).

16. The improvement of any one of claims 1-15, wherein the cellulose derivative is in an amount of about 6 wt % to about 8 wt %.

17. The improvement of any one of claims 1-16, wherein the cellulose derivative is in an amount of about 60 mg to about 100 mg.

18. The improvement of any one of claims 1-17, wherein the cellulose derivative is in an amount of about 80 mg.

19. The improvement of any one of claims 1-18, wherein the tablet composition comprises any one of Formulations 5-12 from Tables 10, 11, and 16.

20. The improvement of any one of claims 1-19, wherein the tablet composition comprises Formulation 5 from Table 10.

21. An uncoated tablet composition comprising: acamprosate in a pharmaceutically acceptable salt form in a dose of about 66 wt % to about 72 wt %; carbomer homopolymer type B in an amount of about 3 wt % to about 7 wt %; a cellulose derivative in an amount of about 5 wt % to about 9 wt %; and optionally one or more pharmaceutically acceptable excipients.

22. The tablet composition of claim 21, wherein the tablet composition is oval.

23. The tablet composition of claim 21 or 22, wherein the tablet composition is characterized in that, when it is placed in either acetate solution (pH 4.5) or HCl solution (pH 1.0) in vitro, it releases the acamprosate at a rate that is approximately linear with the square root of time, and remains comparable.

24. The tablet composition of any one of claims 21-23, wherein the tablet composition is characterized by a % swelling in the length of the tablet composition in a range of about 100% to about 130% when placed in 0.1 N HCl (pH 1.0), acetate solution (pH 4.5) or phosphate solution (pH 6.8).

25. The tablet composition of any one of claims 21-24, wherein the tablet composition is characterized by a % swelling in the thickness of the tablet composition in a range of about 100% to about 180% when placed in 0.1 N HCl (pH 1.0), acetate solution (pH 4.5) or phosphate solution (pH 6.8).

26. The tablet composition of any one of claims 21-25, wherein the total weight of the tablet composition is about 1000 mg to about 1280 mg.

27. The tablet composition of any one of claims 21-26, wherein the total weight of the tablet composition is about 1120 mg to about 1200 mg.

28. The tablet composition of any one of claims 21-27, wherein the total weight of the tablet composition is about 1140 mg to about 1180 mg.

29. The tablet composition of any one of claims 21-28, wherein the dose of the acamprosate is about 660 mg to about 921 mg.

30. The tablet composition of any one of claims 21-29, wherein the dose of the acamprosate is about 740 mg to about 864 mg.

31. The tablet composition of any one of claims 21-30, wherein the dose of the acamprosate is about 752 mg to about 849 mg.

32. The tablet composition of any one of claims 21-31, wherein the dose of the acamprosate is about 800 mg.

33. The tablet composition of any one of claims 21-32, wherein the carbomer homopolymer type B is in an amount of about 50 mg to about 70 mg.

34. The tablet composition of any one of claims 21-33, wherein the carbomer homopolymer type B is in an amount of about 60 mg.

35. The tablet composition of any one of claims 21-34, wherein the cellulose derivate is carboxymethyl cellulose (CMC 7HF).

36. The tablet composition of any one of claims 21-35, wherein the cellulose derivative is in an amount of about 6 wt % to about 8 wt %.

37. The tablet composition of any one of claims 21-36, wherein the cellulose derivative is in an amount of about 60 mg to about 100 mg.

38. The tablet composition of any one of claims 21-37, wherein the cellulose derivative is in an amount of about 80 mg.

39. The tablet composition of any one of claims 21-38, wherein the tablet composition comprises Formulation 5 from Table 10.

40. An uncoated tablet composition comprising: acamprosate in a pharmaceutically acceptable salt form, in a dose of about 66 wt % to about 72 wt %; carbomer homopolymer type B in an amount of about 6 wt % to about 10 wt %; gelatin type B in an amount of about 2 wt % to about 5 wt %; and optionally one or more pharmaceutically acceptable excipients.

41. The tablet composition of claim 40, wherein the tablet composition is oval.

42. The tablet composition of claim 40 or 41, wherein the tablet composition is characterized in that, when it is placed in either acetate solution (pH 4.5) or HCl solution (pH 1.0) in vitro, it releases the acamprosate at a rate that is approximately linear with the square root of time, and remains comparable.

43. The tablet composition of any one of claims 40-42, wherein the tablet composition is characterized by a % swelling in the length of the tablet composition in a range of about 100% to about 130% when placed in 0.1 N HCl (pH 1.0), acetate solution (pH 4.5), or phosphate solution (pH 6.8).

44. The tablet composition of any one of claims 40-43, wherein the tablet composition is characterized by a % swelling in the thickness of the tablet composition in a range of about 100% to about 180% when placed in 0.1 N HCl (pH 1.0), acetate solution (pH 4.5), or phosphate solution (pH 6.8).

45. The tablet composition of any one of claims 40-44, wherein the total weight of the tablet composition is about 1000 mg to about 1280 mg.

46. The tablet composition of any one of claims 40-45, wherein the total weight of the tablet composition is about 1080 mg to about 1160 mg.

47. The tablet composition of any one of claims 40-46, wherein the total weight of the tablet composition is about 1100 mg to about 1140 mg.

48. The tablet composition of any one of claims 40-47, wherein the dose of the acamprosate is about 660 mg to about 921 mg.

49. The tablet composition of any one of claims 40-48, wherein the dose of the acamprosate is about 713 mg to about 835 mg.

50. The tablet composition of any one of claims 40-49, wherein the dose of the acamprosate is about 726 mg to about 821 mg.

51. The tablet composition of any one of claims 40-50, wherein the dose of the acamprosate is about 800 mg.

52. The tablet composition of any one of claims 40-51, wherein the gelatin type B is in an amount of about 3 wt % to about 4 wt %.

53. The tablet composition of any one of claims 40-52, wherein the gelatin type B is in an amount of about 40 mg.

54. The tablet composition of any one of claims 40-53, wherein the tablet composition comprises Formulation 6 from Table 11.

55. The tablet composition of any one of claims 40-53, wherein the tablet composition comprises Formulation 7 from Table 11.

56. The tablet composition of any one of claims 40-53, wherein the tablet composition comprises Formulation 8 from Table 11.

57. An uncoated tablet composition comprising: acamprosate in a pharmaceutically acceptable salt form, in a dose of about 66 wt % to about 72 wt %; carbomer homopolymer type C, in an amount of about 2 wt % to about 15 wt %; and optionally one or more pharmaceutically acceptable excipients.

58. The tablet composition of claim 57, wherein the tablet composition is oval.

59. The tablet composition of claim 57 or 58, wherein the tablet composition is characterized in that, when it is placed in either acetate solution (pH 4.5) or HCl solution (pH 1.0) in vitro, it releases the acamprosate at a rate that is approximately linear with the square root of time, and remains comparable.

60. The tablet composition of any one of claims 57-59, wherein the tablet composition is characterized by a % swelling in the length of the tablet composition in a range of about 100% to about 130% when placed in 0.1 N HCl (pH 1.0), acetate solution (pH 4.5) or phosphate solution (pH 6.8).

61. The tablet composition of any one of claims 57-60, wherein the tablet composition is characterized by a % swelling in the thickness of the tablet composition in a range of about 100% to about 180% when placed in 0.1 N HCl (pH 1.0), acetate solution (pH 4.5) or phosphate solution (pH 6.8).

62. The tablet composition of any one of claims 57-61, wherein the total weight of the tablet composition is about 1000 mg to about 1280 mg.

63. The tablet composition of any one of claims 57-62, wherein the total weight of the tablet composition is about 1080 mg to about 1160 mg.

64. The tablet composition of any one of claims 57-63, wherein the total weight of the tablet composition is about 1100 mg to about 1140 mg.

65. The tablet composition of any one of claims 57-64, wherein the dose of the acamprosate is about 660 mg to about 921 mg.

66. The tablet composition of any one of claims 57-65, wherein the dose of the acamprosate is about 713 mg to about 835 mg.

67. The tablet composition of any one of claims 57-66, wherein the dose of the acamprosate is about 726 mg to about 821 mg.

68. The tablet composition of any one of claims 57-67, wherein the dose of the acamprosate is about 800 mg.

69. The tablet composition of any one of claims 57-68, wherein the carbomer homopolymer type C is in an amount of about 4 wt % to about 12 wt %.

70. The tablet composition of any one of claims 57-69, wherein the carbomer homopolymer type C is in an amount of about 30 mg to about 140 mg.

71. The tablet composition of any one of claims 57-70, wherein the carbomer homopolymer type C is in an amount of about 60 mg.

72. The tablet composition of any one of claims 57-71, wherein the carbomer homopolymer type C is in an amount of about 90 mg.

73. The tablet composition of any one of claims 57-72, wherein the tablet composition comprises Formulation 9 from Table 16.

74. The tablet composition of any one of claims 57-72, wherein the tablet composition comprises Formulation 10 from Table 16.

75. The tablet composition of any one of claims 57-72, wherein the tablet composition comprises Formulation 11 from Table 16.

76. The tablet composition of any one of claims 57-72, wherein the tablet composition comprises Formulation 12 from Table 16.

77. An oral dosage form comprising one or more tablet compositions of any one of claims 21-76.

78. The oral dosage form of claim 77, comprising one tablet composition.

79. The oral dosage form of claim 78, wherein the one tablet composition is less than or equal to 22 mm in the largest dimension.

80. The oral dosage form of claim 78 or 79, wherein the one tablet composition is less than or equal to 20 mm in the largest dimension.

81. The oral dosage form of any one of claims 78-80, wherein the one tablet composition is less than or equal to 13 mm in the largest dimension.

82. The oral dosage form of any one of claims 78-81, wherein the one tablet composition is less than or equal to 8 mm in the largest dimension.

83. The oral dosage form of claim 77, comprising a plurality of tablet compositions.

84. The oral dosage form of claim 83, wherein each tablet composition is less than or equal to 6 mm in the largest dimension.

85. The oral dosage form of claim 83 or 84, wherein each tablet composition is less than or equal to 4 mm in the largest dimension.

86. The oral dosage form of any one of claims 83-85, wherein each tablet composition is less than or equal to 2 mm in the largest dimension.

87. The oral dosage form of any one of claims 83-86, wherein each tablet composition is less than or equal to 1 mm in the largest dimension.

88. The oral dosage form of any one of claims 83-87, wherein the dose of acamprosate is at least 400 mg.

89. The oral dosage form of any one of claims 83-88, wherein the dose of acamprosate is at least 800 mg.

90. The oral dosage form of any one of claims 83-89, wherein the dose of acamprosate is about 800 mg.

91. The oral dosage form of any one of claims 83-90, wherein the dose of acamprosate is about 1000 mg.

92. A method of preparing an uncoated tablet composition comprising acamprosate in a pharmaceutically acceptable salt form, comprising: (i) blending a preparation of granules that comprises the acamprosate with extra-granular materials that comprise a carbomer homopolymer to form a blended material, wherein each of the granules and the extra-granular materials comprises a cellulose derivative material; and (ii) compressing the blended material to form the uncoated tablet composition.

93. The method of claim 92, wherein the method further comprises a step of first providing the preparation of granules.

94. The method of claim 92 or 93, wherein the step of providing the preparation of granules comprises (a) forming wet granules and (b) drying the wet granules to form the preparation of granules.

95. The method of any one of claims 92-94, wherein the method further comprises a step of coating the uncoated tablet composition.

96. The method of any one of claims 92-95, wherein the preparation of granules comprises about 2 wt % to about 6 wt % of carboxymethyl cellulose

97. The method of any one of claims 92-96, wherein the preparation of granules comprises about 2 wt % to about 6 wt % of carboxymethyl cellulose and the extragranular materials comprise about 20 wt % to about 30 wt % of carboxymethyl cellulose, so that the tablet composition comprises a total of about 6 wt % to about 8 wt % of carboxymethyl cellulose.

98. The method of any one of claims 92-97, wherein the preparation of granules comprises the acamprosate in an amount of about 70 wt % to about 90 wt %.

99. The method of any one of claims 92-98, wherein the preparation of granules comprises the acamprosate in an amount of about 80 wt %.

100. The method of any one of claims 92-99, wherein the extra-granular materials comprise a carbomer homopolymer in an amount of about 15 wt % to about 90 wt %.

101. The method of any one of claims 92-100, wherein the extra-granular materials comprise carbomer homopolymer type B in an amount of about 35 wt % to about 60 wt %.

102. The method of any one of claims 92-101, wherein the extra-granular materials comprise carbomer homopolymer type B in an amount of about 37.5 wt %.

103. The method of any one of claims 92-101, wherein the extra-granular materials comprise carbomer homopolymer type C in an amount of about 15 wt % to about 90 wt %.

104. The method of any one of claims 92-103, wherein the tablet composition comprises any one of Formulations 5-12 from Tables 9, 10, and 15.

105. The method of any one of claims 92-104, wherein the wet granules are dried until % loss on drying (LOD) is no more than 2%.

106. The method of any one of claims 92-105, wherein the tablet composition is oval.

107. The method of any one of claims 92-106, wherein the tablet composition is characterized in that, when it is placed in either acetate solution (pH 4.5) or HCl solution (pH 1.0) in vitro, it releases the acamprosate at a rate that is approximately linear with the square root of time, and remains comparable.

108. The method of any one of claims 92-107, wherein the tablet composition has a release profile that is comparable to that of Formulation 2.

109. The method of any one of claims 92-108, wherein the tablet composition is characterized by a % swelling in the length of the tablet composition in a range of about 100% to about 130% when placed in 0.1 N HCl (pH 1.0), acetate solution (pH 4.5) or phosphate solution (pH 6.8).

110. The method of any one of claims 92-109, wherein the tablet composition is characterized by a % swelling in the thickness of the tablet composition in a range of about 100% to about 180% when placed in 0.1 N HCl (pH 1.0), acetate solution (pH 4.5) or phosphate solution (pH 6.8).

111. An uncoated tablet composition, wherein the tablet composition is obtained by a method of any one of claims 92-110.

112. An oral dosage form comprising one or more tablet compositions obtained by a method of any one of claims 92-110.

113. A method of administering a therapeutically effective dose of acamprosate to a patient, the method comprising a step of: administering to the patient a tablet composition of any one of claim 21-76 or 111 or an oral dosage form of any one of claim 77-91 or 112.

114. The method of claim 113, wherein the step of administering comprises administering 1 to 4 tablet compositions or oral dosage forms per day.

115. The method of claim 113 or 114, wherein the step of administering comprises administering 1 to 4 tablet compositions or oral dosage forms once per day.

116. The method of any one of claims 113-115, wherein the step of administering comprises administering 1 or 2 tablet compositions or oral dosage forms once per day.

117. The method of claim 113 or 114, wherein the step of administering comprises administering 1 or 2 tablet compositions twice per day.

118. The method of any one of claims 113-117, wherein the patient is in the fed mode.

119. The method of any one of claims 113-117, wherein the patient is in the fasted mode.

120. The method of any one of claims 113-119, wherein the step of administering comprises administering to a patient with a neuropsychiatric disorder selected from the group consisting of psychogenic nonepileptic seizures (PNES), tardive dyskinesia (TD), tardive akathisia, dystonia, blepharospasm, levodopa-induced dyskinesia (LID) in patients with Parkinson's disease, dyskinetic movements in Rett's Syndrome, dyskinetic movements in DiGeorge Syndrome, dyskinetic movements and dystonia in Wilson's disease, post-hypoxic myoclonus, simple tics, Tourette Syndrome (TS), obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), symptoms of schizophrenia, depression, bipolar disorder, autism spectrum disorders, autistic symptoms in Fragile X syndrome, alcoholism, tinnitus, generalized anxiety disorder, and repetitive and stereotypic self-injurious behaviors (SIB) in persons with developmental disabilities such as biting, skin-picking, hitting oneself, and head-banging.

121. The method of any one of claims 113-120, wherein the tablet composition or oral dosage form comprises any one of Formulations 5-12 from Tables 10, 11, and 16.

122. The method of any one of claims 113-121, wherein the tablet composition or oral dosage form comprises Formulation 5 from Table 10.

Description

BRIEF DESCRIPTION OF THE DRAWING

[0056] FIG. 1A depicts the dissolution profile of round 800 mg tablets of Example 1 (Formulation 2) in 0.1N HCl versus oval 800 mg tablets of Example 1 prepared with by (i) extrusion or (ii) milling without a screen (see Example 4).

[0057] FIG. 1B depicts the dissolution profile of round 800 mg tablets of Example 1 in pH 4.5 acetate buffer versus oval 800 mg tablets of Example 1 prepared with by (i) extrusion or (ii) milling without a screen (see Example 4).

[0058] FIG. 2A depicts the dissolution profile of round 800 mg tablets of Example 1 in 0.1N HCl versus oval 800 mg tablets of Example 1, prepared according to modification (d) of Example 4.

[0059] FIG. 2B depicts the dissolution profile of round 800 mg tablets of Example 1 in pH 4.5 acetate buffer versus oval 800 mg tablets of Example 1 prepared according to modification (d) of Example 4.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0060] In general, the present disclosure provides new pharmaceutical compositions that comprise one or more active agents in a high dose (e.g., tablet formulations in which a significant percentage of the weight of the tablet is comprised of active agent). The present disclosure also provides technologies for preparing such compositions, and furthermore defines and describes certain performance and physical characteristics of particularly useful compositions.

[0061] In some embodiments, teachings of the present disclosure are particularly applicable to tablet compositions, which may be coated or uncoated.

[0062] In some embodiments, teachings of the present disclosure are particularly applicable to tablet compositions containing acidic active agents. In some embodiments, the acidic active agent is present as a pharmaceutically acceptable salt form.

[0063] In some embodiments, an active agent is administered in a high dose. In some embodiments, an active agent is administered in a dosage form containing a dose of about 400 mg or higher. In some embodiments, an active agent is administered in a dosage form containing a dose of about 800 mg or higher. In some embodiments, such a dosage form is a tablet containing a dose of about 800 mg or higher.

[0064] In some embodiments, an active agent is administered in a fed mode. In some embodiments, an active agent is administered is a fasted mode. In some embodiments, an active agent can be administered with or without food with no adverse effect on bioavailability or efficacy. In some embodiments, the release profile is substantially the same in either fed or fasted mode.

[0065] In some embodiments, an active agent is administered as multiple dosage forms in a single administration. In some embodiments, an active agent is administered once a day. In some embodiments, an active agent is administered twice a day. In some embodiments, an active agent is administered three times a day. In some embodiments, an active agent is administered multiple times a day.

[0066] The teachings of the present disclosure may be particularly useful for compositions that contain high doses of active agent. For example, in some embodiments, provided dosage forms include an active agent in a dose of at least 400 mg. In some embodiments, provided dosage forms include an active agent in a dose of at least 500 mg. In some embodiments, provided dosage forms include an active agent in a dose of at least 600 mg. In some embodiments, provided dosage forms include an active agent in a dose of at least 700 mg. In some embodiments, provided dosage forms include an active agent in a dose of at least 800 mg. In some embodiments, provided dosage forms include an active agent in a dose of at least 900 mg. In some embodiments, provided dosage forms include an active agent in a dose of at least 1000 mg.

[0067] In some embodiments, provided compositions include an active agent at a dose that is at least 30% w/w of total weight of the dosage form. In some embodiments, provided compositions include an active agent at a dose that is at least 40% w/w of total weight of the dosage form. In some embodiments, provided compositions include an active agent at a dose that is at least 50% w/w of total weight of the dosage form. In some embodiments, provided compositions include an active agent at a dose that is at least 60% w/w of total weight of the dosage form. In some embodiments, provided compositions include an active agent at a dose that is at least 70% w/w of total weight of the dosage form. In some embodiments, provided compositions include an active agent at a dose that is at least 80% w/w of total weight of the dosage form. In some embodiments, provided compositions include an active agent at a dose that is at least 90% w/w of total weight of the dosage form. In some embodiments, provided compositions include an active agent at a dose that is at least 95% w/w of total weight of the dosage form.

[0068] In some embodiments, an active agent is acamprosate. In some embodiments, an active agent may be or comprise an active metabolite thereof. In some embodiments, an active agent is an acamprosate agent. In some embodiments, an acamprosate agent is or comprises a prodrug of acamprosate. In some embodiments, an acamprosate agent is provided and/or utilized in a salt form. In some embodiments, an active agent is acamprosate calcium. In some embodiments, an active agent is acamprosate magnesium. In some embodiments, an active agent is acamprosate lithium. In some embodiments, an active agent is acamprosate sodium. In some embodiments, an acamprosate agent is provided and/or utilized in a formulation. In some embodiments, an acamprosate agent is provided and/or utilized in a tablet composition.

[0069] Among other things, the present disclosure demonstrates that carbomers are particularly well suited for the preparation of high dose, extended release tablets. In some embodiments, the provided formulations result in improved tolerability as demonstrated by a lack of apparent GI side effects. In some embodiments, sustained release of active agent can result in a lower frequency of dosing. In some embodiments, provided formulations can show improved pharmacokinetics versus immediate release versions of the same active agent. In some embodiments, provided formulations afford diffusion-controlled release kinetics over an approximate 10-hour period. In some embodiments, an active agent release profile approximates diffusion-controlled release kinetics.

[0070] In some embodiments, provided compositions include active agent in an amount that is at least 3-fold greater than that of carbomer homopolymer. In some embodiments, provided compositions include active agent in an amount that is at least 6-fold greater than that of carbomer homopolymer. In some embodiments, provided compositions include active agent in an amount that is at least 10-fold greater than that of carbomer homopolymer. In some embodiments, provided compositions include active agent in an amount that is at least 20-fold greater than that of carbomer homopolymer. In some embodiments, provided compositions include active agent in an amount that is at least 40-fold greater than that of carbomer homopolymer.

Problems with Acamprosate Compositions

[0071] As disclosed above and in the Prior Fogel Filings, acamprosate is useful for the treatment of neuropsychiatric disorders, including tardive dyskinesia and other movement disorders induced by chronic exposure of patients to neuroleptic (antipsychotic) drugs, Tourette syndrome, and mental disorders such as posttraumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD), due to its actions on glutamate and GABA transmission. In addition, acamprosate may be useful in the treatment of Psychogenic Nonepileptic Seizures (PNES). Among other things, the Prior Fogel Filings specifically demonstrated that homopolymer type B carbomers and homopolymer type A carbomers can be particularly useful when preparing high dose formulations, and particularly when preparing tablet formulations containing a high dose of active agent (e.g., tablet formulations in which a significant percentage of the weight of the tablet is comprised of active agent).

[0072] As disclosed above, high dose compositions pose particular challenges for formulation. Active agents typically do not have appropriate characteristics to form a viable tablet, and there is limited physical space to include other components, if the final composition is to be small enough in size (e.g., to be easily swallowed or to be a mini-tablet). Furthermore, high dose compositions are often accompanied by unwanted side effects (e.g., due to dose dumping and/or negative food effects). Providing an extended-release high dose composition can overcome some of these side effects but also poses its own challenges, including identification of components that can be added in suitable quantities (e.g., in order for the tablet to be a suitable size) and that impart acceptable tablet characteristics (e.g., friability, hardness, etc.). The Prior Fogel Filings demonstrated that acamprosate calcium could be formulated as an extended release high dose tablet with the addition of low weight percentages of homopolymer type B carbomers or homopolymer type A carbomers.

[0073] The present disclosure identifies the source of a problem with existing acamprosate tablet compositions and/or with technologies used to prepare them, wherein the tablet compositions fail to achieve one or more desirable characteristics. Desirable tablet characteristics can include any of the following characteristics alone or in combination: [0074] (i) extended release dissolution profile; [0075] (ii) dissolution profile that is substantially the same at pH 1.0 and at pH 4.5; [0076] (iii) dissolution profile that is substantially the same as a reference tablet (e.g., Formulation 2); [0077] (iv) suitable friability; [0078] (v) suitable hardness; [0079] (vi) suitable firmness according to the scale of Example 2; [0080] (vii) suitable % swelling by length; [0081] (viii) suitable % swelling by width; [0082] (ix) suitable % erosion; [0083] (x) suitable shape; and [0084] (xi) suitable size.
The present disclosure also provides novel compositions and technologies that achieve tablet compositions with desirable characteristics and presents solutions to the above-identified problem.

[0085] Without wishing to be bound by any particular theory, the present disclosure proposes that dissolution rates achieved with the provided formulations are unique and well-suited to the administration of high dose active agents. In some embodiments, greater than 90% of active agent is released over 12 hours at pH 1.0. In some embodiments, greater than 90% of active agent is released over 12 hours at pH 4.5. In some embodiments, the release rate of active agent is linear with the square root of time. In some embodiments, greater than 70% of active agent is released over 6 hours at pH 1.0. In some embodiments, greater than 70% of active agent is released over 6 hours at pH 4.5. In some embodiments, the release of active agent is accomplished without degradation of the tablet composition.

[0086] Alternatively or additionally, without wishing to be bound by any particular theory, the present disclosure proposes that the release characteristics of the formulations of the present disclosure may be a relevant feature. In some embodiments, release characteristics of tablet compositions of provided formulations are comparable at pH values that are representative of the fed and fasted state in a subject. In some embodiments, provided formulations have comparable release characteristics in both 0.1 N HCl solution (pH 1.0, a pH value representative of a fasted subject) and in acetate buffer (pH 4.5, a pH value representative of a fed subject). In some embodiments, provided formulations have comparable release profiles of an active agent at pH 1.0 and pH 4.5.

[0087] Without wishing to be bound by theory, comparable release profiles at pH 1.0 and pH 4.5 is a relevant feature, because such compositions may be taken on an empty stomach (fasted) or with a meal (fed) and achieve similar release of active agent, which may lead to better patient compliance. Accordingly, in some embodiments, compositions with comparable release profiles in both fed and fasted states can be administered without regard to the fed or fasted status of the patient.

[0088] Alternatively or additionally, without wishing to be bound by any particular theory, the present disclosure proposes that the release characteristics of the Prior Fogel Formulations may be desirable. A similarity factor (f2) of the release profile of a provided tablet composition relative to the release profile of a reference tablet composition (e.g., a tablet composition of the Prior Fogel Formulations) is calculated as described in Example 5. A desirable similarity factor (f2) can be >40%, >50%, >60%, >70%, >80%, or >90%. A desirable similarity factor (f2) can be in a range of about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, or about 90% to about 100%.

[0089] Alternatively or additionally, without wishing to be bound by any particular theory, the present disclosure proposes that friability achieved with provided tablet compositions is unique and well suited to administration of high dose active agents. Friability refers to the property of a composition to maintain (or lose) structural integrity. Those of ordinary skill in the art are aware that satisfactory tablet compositions are characterized by friability within a desirable range. Friability testing is typically performed to assess likelihood of a tablet breaking into smaller pieces under relevant conditions (e.g., during manufacturing, storage, transit, etc.). Friability values are typically expressed as a % of the tablet remaining after application of relevant conditions or stresses. Tablets which have a poor friability value crumble easily and are typically understood to not be viable as a commercial product (e.g., due to poor stability). Typical friability tests evaluate ability of a tablet to withstand abrasion in packaging, handling and shipping. For example, a weight (w1) may be determined for tablets at an initial time, prior to application of a relevant condition or stress. Subsequently, a tablet is exposed to the condition or stress, typically by being placed in a friabilator, where they are exposed to rotation at a selected speed and for a selected amount of time. A second weight (w2) in then determined, and is compared with the initial weight. Friability, which is expressed as a percent, is then calculated according to the formula: Friability=(w1−w2)×100/w1. In some embodiments, desirable tablets are typically characterized by a friability of <3%, <2%, <1%, or <0.5%. In some embodiments, desirable tablets are typically characterized by a friability in the range of 0% to about 3%, 0% to about 2%, 0% to about 1%, or 0% to about 0.5%. In some embodiments, a tablet composition has a friability value of <3%. In some embodiments, a tablet composition has a friability value of <2%. In some embodiments, a tablet composition has a friability value of <1%. In some embodiments, a tablet composition has a friability value of <0.5%.

[0090] Alternatively or additionally, without wishing to be bound by any particular theory, the present disclosure proposes that tablet compositions described herein achieve a tablet hardness that renders them superior to certain other comparable tablet compositions. Acceptable hardness values can be >3 kp, >5 kp, >10 kp, >15 kp, or >18 kp. Acceptable hardness values can be in the range of about 3 kp to about 20 kp, about 5 kp to about 20 kp, about 10 kp to about 20 kp, about 15 kp to about 20 kp, or about 18 kp to about 20 kp.

[0091] Alternatively or additionally, without wishing to be bound by any particular theory, the present disclosure proposes that tablet compositions described herein achieve a tablet firmness that renders them superior to certain other comparable tablet compositions. Tablet firmness can be assessed on a 1-5 scale, as described in Example 2. In some embodiments, acceptable firmness values are in the range of about 3.0 to about 5.0, about 4.0 to about 5.0, or about 4.5 to about 5.0. In some embodiments, acceptable firmness values are >3.0, >4.0, or >4.5.

[0092] Alternatively or additionally, without wishing to be bound by any particular theory, the present disclosure proposes that tablet compositions described herein achieve a % swelling by length at pH 1.0, pH 4.5, and/or pH 6.8 that renders them superior to certain other comparable tablet compositions. In some embodiments, acceptable % swelling (length) values are >100%, >110%, >120%, >130%, >140%, >150%, >160%, >170%, >180%, or >190%. In some embodiments, acceptable % swelling (length) values are in the range of about 100% to about 110%, about 100% to about 120%, about 100% to about 130%, about 100% to about 140%, about 100% to about 150%, about 100% to about 160%, about 100% to about 170%, about 100% to about 180%, about 130% to about 140%, about 130% to about 160%, or about 130% to about 180%.

[0093] In some embodiments, a tablet composition has a % swelling (length) in the range of about 100% to about 110% in 0.1 N HCl (pH 1.0). In some embodiments, a tablet composition has a % swelling (length) in the range of about 110% to about 120% in 0.1 N HCl (pH 1.0). In some embodiments, a tablet composition has a % swelling (length) in the range of about 110% to about 130% in 0.1 N HCl (pH 1.0). In some embodiments, a tablet composition has a swelling (length) in the range of about 130% to about 180% in 0.1 N HCl (pH 1.0).

[0094] In some embodiments, a tablet composition has a % swelling (length) in the range of about 100% to about 110% in acetate buffer (pH 4.5). In some embodiments, a tablet composition has a % swelling (length) in the range of about 110% to about 120% in acetate buffer (pH 4.5). In some embodiments, a tablet composition has a % swelling (length) in the range of about 110% to about 130% in acetate buffer (pH 4.5). In some embodiments, a tablet composition has a % swelling (length) in the range of about 130% to about 180% in acetate buffer (pH 4.5).

[0095] In some embodiments, a tablet composition has a % swelling (length) in the range of about 100% to about 110% in phosphate buffer (pH 6.8). In some embodiments, a tablet composition has a % swelling (length) in the range of about 110% to about 120% in phosphate buffer (pH 6.8). In some embodiments, a tablet composition has a % swelling (length) in the range of about 110% to about 130% in phosphate buffer (pH 6.8). In some embodiments, a tablet composition has a % swelling (length) in the range of about 130% to about 180% in phosphate buffer (pH 6.8).

[0096] Alternatively or additionally, without wishing to be bound by any particular theory, the present disclosure proposes that tablet compositions described herein achieve a % swelling by width at pH 1.0, pH 4.5, and/or pH 6.8 that renders them superior to certain other comparable tablet compositions. In some embodiments, acceptable % swelling (width) values are >100%, >110%, >120%, >130%, >140%, >150%, >160%, >170%, >180%, or >190%. In some embodiments, acceptable % swelling (width) values are in the range of about 100% to about 110%, about 100% to about 120%, about 100% to about 130%, about 100% to about 140%, about 100% to about 150%, about 100% to about 160%, about 100% to about 170%, about 100% to about 180%, about 130% to about 140%, about 130% to about 160%, or about 130% to about 180%.

[0097] In some embodiments, a tablet composition has a % swelling (width) in the range of about 130% to about 140% in 0.1 N HCl (pH 1.0). In some embodiments, a tablet composition has a % swelling (width) in the range of about 130% to about 160% in 0.1 N HCl (pH 1.0). In some embodiments, a tablet composition has a % swelling (width) in the range of about 130% to about 180% in 0.1 N HCl (pH 1.0).

[0098] In some embodiments, a tablet composition has a % swelling (width) in the range of about 130% to about 140% in acetate buffer (pH 4.5). In some embodiments, a tablet composition has a % swelling (width) in the range of about 130% to about 160% in acetate buffer (pH 4.5). In some embodiments, a tablet composition has a % swelling (width) in the range of about 130% to about 180% in acetate buffer (pH 4.5).

[0099] In some embodiments, a tablet composition has a % swelling (width) in the range of about 130% to about 140% in phosphate buffer (pH 6.8). In some embodiments, a tablet composition has a % swelling (width) in the range of about 130% to about 160% in phosphate buffer (pH 6.8). In some embodiments, a tablet composition has a % swelling (width) in the range of about 130% to about 180% in phosphate buffer (pH 6.8).

[0100] Alternatively or additionally, without wishing to be bound by any particular theory, the present disclosure proposes that tablet compositions described herein achieve a erosion at pH 1.0, pH 4.5, and/or pH 6.8 after 2 and/or 6 hours that renders them superior to certain other comparable tablet compositions. % Erosion can be measured as described in Example 5. In some embodiments, desirable % erosion values are ≤30%, ≤40%, ≤50%, ≤60%, ≤70%, or ≤80%. In some embodiments, desirable % erosion values are in the range of about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 30% to about 50%, or about 30% to about 60%. In some embodiments, a tablet composition has a % erosion value after 2 h in the range of about 20% to about 50%. In some embodiments, a tablet composition has a % erosion value after 6 h in the range of about 20% to about 80%.

[0101] In some embodiments, a tablet composition has a % erosion value at pH 1.0 in the range of about 30% to about 40%. In some embodiments, a tablet composition has a erosion value at pH 1.0 in the range of about 40% to about 50%. In some embodiments, a tablet composition has a % erosion value at pH 1.0 in the range of about 50% to about 60%.

[0102] In some embodiments, a tablet composition has a % erosion value at pH 4.5 in the range of about 30% to about 40%. In some embodiments, a tablet composition has a % erosion value at pH 4.5 in the range of about 40% to about 50%. In some embodiments, a tablet composition has a % erosion value at pH 4.5 in the range of about 50% to about 60%.

[0103] In some embodiments, a tablet composition has a % erosion value at pH 6.8 in the range of about 30% to about 40%. In some embodiments, a tablet composition has a % erosion value at pH 6.8 in the range of about 40% to about 50%. In some embodiments, a tablet composition has a % erosion value at pH 6.8 in the range of about 50% to about 60%.

[0104] Alternatively or additionally, without wishing to be bound by any particular theory, the present disclosure proposes that tablet compositions described herein with a particular size and/or shape render them superior to certain other comparable tablet compositions. Difficulty swallowing tablets can be a problem for many individuals. In some cases, this can lead to adverse events and patient noncompliance with treatment regimens. Surveys have shown that problems with swallowing tablets and capsules goes beyond the patient population with clinically recognized dysphagia and may affect as much as 40% of the American population. Of those who reported difficulty swallowing tablets and capsules, less than a quarter discussed the problem with their health care professional, 8% admitted to skipping a dose of prescribed medication, and 4% have discontinued therapy because the tablets and/or capsules were difficult to swallow (Harris Interactive Inc. for Schwarz Pharma, 2003, Pill-Swallowing Problems in America: A National Survey of Adults. 1-39). Those who report difficulty swallowing tablets frequently mention the size of the tablet being a major factor (Bhosle M, Benner J, DeKoven M, Shelton J., 2009, Difficult to Swallow: Patient Preferences for Alternative Valproate Pharmaceutical Formulations. Patient Prefer Adherence 3, 161-171; Agency for Health Care Policy and Research, March 1999, Diagnosis and Treatment of Swallowing Disorders (Dysphagia) in Acute-Care Stroke Patients. Summary, Evidence Report/Technology Assessment: Number 8). Accordingly, compliance with a medication regimen may be influenced by tablet size.

[0105] Studies have been performed in a cohort of frail elderly persons to examine the effect of the size of tablets on the status of swallowing during taking medicine. The group determined a desirable size of tablet using subjective evaluation. The most desired size based upon ease of swallowing and handling is in the range of about 7 mm to about 8 mm as the largest dimension, though tablets and capsules of up to 22 mm in the largest dimension are considered acceptable by the FDA. Other studies have shown that increases in size are associated with increases in patient complaints about swallowing, and in particular when tablets are of a size greater than approximately 8 mm in diameter. In another study measuring time of esophageal transit, significantly more patients were aware of the tablets sticking in the esophagus when the tablet was >8 mm in the largest dimension. Prolonged esophageal transit time can lead to pain and localized esophagitis due to disintegration of the tablet in the esophagus. This can further lead to serious medical conditions such as ulceration, stricture, and perforation.

[0106] Shape also plays a role in the ease of a patient swallowing medication. Additionally, the shape of a tablet may have an impact on the esophageal transit time. For any given size of a tablet, certain shapes may be easier to swallow than others. In vitro studies have shown that flat tablets have a greater adherence to the esophagus than capsule-shaped tablets (e.g., oval-shaped) (Marvola M., Rajaniemi M., Marttila E., Vahervuo K., Sothmann A., 1983, Effect of Dosage Form and Formulation Factors on the Adherence of Drugs to the Esophagus. Journal of Pharmaceutical Sciences 72(9), 1034-1036). Human studies have suggested that oval tablets may be easier to swallow and have faster esophageal transit times than the corresponding round tablets of the same weight (Channer, K, Virjee, J P. 1986, The Effect of Size and Shape of Tablets on their Esophageal Transit. Journal of Clinical Pharmacology, 26, 141-146; Hey H., Jorgensen F., Sorensen K., Hasselbelch H., Wamberg T., 1982, Esophageal Transit of Six Commonly used Tablets and Capsules. British Medical Journal 285, 1717-1719). Accordingly, compliance with a medication regimen may be influenced by the tablet shape.

[0107] The present disclosure provides tablet compositions of a size and shape so as to facilitate swallowing and/or to facilitate patient compliance with a medication regimen. In some embodiments, acceptable sizes of tablet compositions are ≤22 mm, ≤20 mm, ≤18 mm, ≤15 mm, ≤13 mm, ≤10 mm, ≤8 mm, ≤6 mm, ≤4 mm, or ≤2 mm in the largest dimension. In some embodiments, acceptable lengths for the largest dimension of a tablet composition are in the range of about 1 mm to about 22 mm, about 2 mm to about 22 mm, about 4 mm to about 22 mm, about 8 mm to about 22 mm, about 18 mm to about 22 mm, about 4 mm to about 20 mm, about 8 mm to about 20 mm, about 15 mm to about 20 mm, about 1 mm to about 8 mm, about 2 mm to about 8 mm, about 4 mm to about 8 mm, about 1 mm to about 4 mm, or about 2 mm to about 4 mm.

[0108] In some embodiments, acceptable shapes of tablet compositions are oval or round. In some embodiments, a tablet composition is oval. In some embodiments, a tablet composition is round.

Dosage Forms of Provided Compositions

Tablet Compositions

[0109] In some embodiments, provided compositions are in an oral dosage form, such as a pill, tablet, capsule, or other composition that can be swallowed by a patient. In some embodiments, provided compositions are in the form of beads, pellets, spheroids, sprinkles, microspheres, microparticles, mini-tablets, etc. In some embodiments, provided compositions are tablet compositions. In some embodiments, tablet compositions comprise a formulation described herein. In some embodiments, an oral dosage form comprises a single tablet composition (e.g., a tablet). In some embodiments, an oral dosage form comprises a plurality of tablet compositions (e.g., mini-tablets or sprinkles).

[0110] In some embodiments, provided compositions are in the form of a coated or uncoated tablet composition. Many coatings for tablets are generally known in the art, and any suitable coating can be utilized. In some embodiments, a coated composition is an oval-shaped tablet. In some embodiments, a coated composition is a round or circular tablet. In some embodiments, a coating is Opadry® II White or Opadry® II Blue. In some embodiments, the total weight of the coating is between about 2% and about 4% of the weight of the uncoated tablet composition. In some embodiments, the coating does not affect release characteristics (e.g., rate and/or kinetics of release) of a provided composition.

[0111] In some embodiments, acceptable sizes of tablet compositions comprising a single tablet are ≤22 mm, ≤20 mm, ≤18 mm, ≤15 mm, ≤13 mm, ≤10 mm, ≤8 mm, ≤6 mm, ≤4 mm, or ≤2 mm in the largest dimension. In some embodiments, acceptable lengths for the largest dimension of a tablet composition are in the range of about 1 mm to about 22 mm, about 2 mm to about 22 mm, about 4 mm to about 22 mm, about 8 mm to about 22 mm, about 18 mm to about 22 mm, about 4 mm to about 20 mm, about 8 mm to about 20 mm, about 15 mm to about 20 mm, about 1 mm to about 8 mm, about 2 mm to about 8 mm, about 4 mm to about 8 mm, about 1 mm to about 4 mm, or about 2 mm to about 4 mm.

Mini-Tablets

[0112] The present disclosure includes the recognition that it may be desirable to provide formulations that are small in size but provide a high dose of an active agent. In some patient populations, there can be a lesser ability to swallow tablets. For example, children and adolescents, in addition to the elderly, are more likely to have difficulties swallowing tablets. In such patient populations, a composition comprising a multitude of small tablets (i.e., mini-tablets) with a high dose of active agent may be effective in increasing patient compliance.

[0113] The present disclosure thus provides insight that oral dosage forms comprising small tablets (i.e., mini-tablets) that comprise and/or deliver acamprosate (e.g., in a pharmaceutically acceptable salt form) are particularly desirable and/or useful (for example, with populations that may struggle to swallow large tablets and/or where particularly high doses are desirable). The present disclosure provides such mini-tablet compositions that comprise and/or deliver acamprosate. In some embodiments, mini-tablet compositions are mini-tablets comprising formulations described herein. However, provided insights relating to mini-tablet dosage forms, and uses thereof may, in some embodiments, be applicable to other acamprosate compositions (e.g., Prior Fogel Formulations, and/or one or more other formulations, e.g., as described in one or more of WO 2012/050922, U.S. Pat. No. 6,426,087, or “CAMPRAL® (acamprosate calcium) Delayed-Release Tablets, Highlights of Prescribing Information,” 2004.

[0114] In some embodiments, mini-tablets can be dispersed in suitable food, such as applesauce or pudding, so that patients who have trouble swallowing can take the medication in a different way. By formulating the active agent in a smaller format, swallowing is facilitated, which may benefit certain populations, including children, adolescents, and the elderly, that have difficulty swallowing tablets to comply with a medication regimen.

[0115] In some embodiments, oral dosage forms comprising mini-tablets as described herein are provided as beads (e.g., mini-tablets) in a capsule. In some embodiments, a capsule comprising mini-tablets of provided formulations can be broken and the internal mini-tablets can be sprinkled onto soft foods to allow for swallowing without chewing.

[0116] In some embodiments, the largest dimension of a provided mini-tablet is ≤4 mm, ≤3 mm, ≤2 mm, or ≤1 mm. In some embodiments, the largest dimension of a provided mini-tablet is in the range of from about 4 mm to about 0.5 mm, from about 4 mm to about 1 mm, from about 4 mm to about 2 mm, from about 3 mm to about 0.5 mm, from about 3 mm to about 1 mm, from about 3 mm to about 2 mm, from about 2 mm to about 0.5 mm, or from about 2 mm to about 1 mm.

[0117] In some embodiments, each mini-tablet may be individually and independently coated or uncoated. In some embodiments, a capsule comprising multiple mini-tablets may be coated or uncoated. Many coatings for tablets are generally known in the art, and any suitable coating can be utilized.

[0118] In some embodiments, oral dosage forms comprising a plurality of mini-tablets as described herein are formulated (e.g., in a capsule) so that the total dose of acamprosate in the dosage form is about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. In some such embodiments, acamprosate is in a dose of about 800 mg. In some embodiments, acamprosate is in a dose of about 400 mg.

[0119] In some embodiments, oral dosage forms comprising a plurality of mini-tablets as described herein are formulated (e.g., in a capsule) so that the total dose of acamprosate (i.e., the dose per unit dosage form) is at least 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg. In some such embodiments, the dose of acamprosate is at least 400 mg. In some embodiments, the dose of acamprosate is at least 800 mg.

Components of Provided Tablet Compositions

[0120] As noted above, the formulation of drug products containing a large dose of active pharmaceutical ingredient (“API”), is challenging, particularly when preparing an oral formulation. The Prior Fogel Filings specifically demonstrated that homopolymer type B carbomers and homopolymer type A carbomers can be particularly useful when preparing high dose formulations, and particularly when preparing tablet formulations containing a high dose of active agent. Furthermore, the Prior Fogel Formulations demonstrated certain desirable characteristics, including an extended release profile and fed/fasted equivalence.

[0121] The present disclosure provides different compositions for high dose formulations of acamprosate, which also demonstrate certain desirable characteristics (see above). In some embodiments, the provided compositions utilize different amounts of carbomer homopolymers and/or alternative carbomer homopolymers (e.g., carbomer homopolymer C). In some embodiments, the provided compositions outperform the Prior Fogel Formulations with respect to one or more desirable characteristics.

[0122] In some embodiments, the total weight of a provided composition is in the range of about 900 mg to about 1300 mg, about 1000 mg to about 1280 mg, about 1120 mg to about 1200 mg, or about 1140 mg to about 1180 mg. In some embodiments, the total weight of an uncoated tablet composition is in the range of about 900 mg to about 1300 mg, about 1000 mg to about 1280 mg, about 1120 mg to about 1200 mg, about 1140 mg to about 1180 mg, about 1080 mg to about 1160 mg, or about 1100 mg to about 1140 mg. In some embodiments, the total weight of an uncoated tablet composition is in the range of about 1140 mg to about 1180 mg. In some embodiments, the total weight of an uncoated tablet composition is in the range of about 1100 mg to about 1140 mg.

[0123] In some embodiments, the total weight of a provided composition is about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg, about 1190 mg, about 1200 mg, about 1250 mg, or about 1300 mg. In some embodiments, the total weight of an uncoated tablet composition is about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg, about 1190 mg, about 1200 mg, about 1250 mg, or about 1300 mg. In some embodiments, the total weight of an uncoated tablet composition is about 1120 mg. In some embodiments, the total weight of an uncoated tablet composition is about 1160 mg.

[0124] In some embodiments, provided compositions comprise acamprosate as the active agent. In some embodiments, in a provided composition, acamprosate is in a pharmaceutically acceptable salt form, such as acamprosate calcium. In some embodiments, a provided uncoated tablet composition comprises acamprosate in a pharmaceutically acceptable salt form. In some embodiments, a provided uncoated tablet composition comprises acamprosate calcium.

[0125] In some embodiments, a provided tablet composition comprises a dose of acamprosate in the range of about 30 wt % to about 80 wt %, about 40 wt % to about 80 wt %, about 50 wt % to about 80 wt %, about 60 wt % to about 80 wt %, about 30 wt % to about 50 wt %, about 40 wt % to about 60 wt %, about 50 wt % to about 70 wt %, or about 60 wt % to about 80 wt %. In some embodiments, acamprosate is in a dose in a range of about 60 wt % to about 80 wt %. In some embodiments, acamprosate is in a dose in a range of about 30 wt % to about 50 wt %. In some embodiments, acamprosate is in a dose in a range of about 66 wt % to about 72 wt %. In some embodiments, acamprosate is in a dose in a range of about 36 wt % to about 44 wt %.

[0126] In some embodiments, a provided tablet composition comprises a dose of acamprosate of about 30 wt %, about 40 wt %, about 50 wt %, about 60 wt %, about 70 wt %, or about 80 wt %. In some embodiments, acamprosate is in a dose of about 70 wt %. In some embodiments, acamprosate is in a dose of about 60 wt %. In some embodiments, acamprosate is in a dose of about 40 wt %. In some embodiments, acamprosate is in a dose of about 71 wt %. In some embodiments, acamprosate is in a dose of about 67 wt %.

[0127] In some embodiments, a provided tablet composition comprises a dose of acamprosate of about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. In some embodiments, acamprosate is in a dose of about 800 mg. In some embodiments, acamprosate is in a dose of about 400 mg.

[0128] In some embodiments, provided tablet compositions comprise a dose of acamprosate that is at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, or at least 1000 mg. In some embodiments, the dose of acamprosate is at least 400 mg. In some embodiments, the dose of acamprosate is at least 800 mg.

[0129] In some embodiments, provided compositions comprise one or more carbomer homopolymers. Carbomer homopolymers are high molecular weight polymers of acrylic acid that are chemically cross-linked with polyalkenyl alcohols or divinyl glycol. Carbomer homopolymers are divided into three types: A, B, and C. Carbomer homopolymers are polymers of acrylic acid chemically cross-linked with allyl ethers of pentaerythritol. All three carbomer homopolymer types are flocculated powders averaging about 2 to 7 microns in diameter. The three types of carbomer homopolymer are differentiated by their viscosity characteristics. The aqueous viscosity for a 0.5% aqueous solution of carbomer homopolymer type A is 4,000-11,000 mPa.Math.s, for type B, 25,000-45,000 mPa.Math.s and for type C, 40,000-60,000 mPa.Math.s.

[0130] The molecular weights of carbomer homopolymers are extremely high due to extensive cross-linking. Each particle can be viewed as a network structure of polymer chains that are interconnected by crosslinks. Because of their large molecular weights and high degree of cross-linking, carbomer homopolymers do not dissolve in water but instead swell in water up to 1,000 times their original volume and ten times their original diameter. Common analytical techniques used to characterize the molecular weight of linear (i.e., not cross linked) polymers such as gel permeation chromatography, light scattering, ultracentrifugation and osmometry all require that the polymer be soluble and are therefore not useful for determining the molecular weight of a carbomer homopolymer. The calculated molecular weight for a crosslinked carbomer homopolymer with a primary particle size of 0.2 micron could be as high as 4.5 billion due to the cross linking of many polymer chains.

[0131] Typical usage levels of carbomer homopolymers in extended-release tablets are 3-30% w/w depending on the properties of the active agent, co-excipients and processing parameters. The appropriate amount of carbomer required for extended release is a function of the properties of the active agent, other additives in the formulation and the processing parameters. Generally, increasing the amount of carbomer in a formulation leads to slower and more linear release of the active agent. Commonly, higher doses of active agent, especially active agents with good water solubility, require larger amounts of polymer. For water-soluble active agents, 10% w/w carbomer homopolymer is recommended when used in a wet granulation process. For a direct compression process, 25% w/w carbomer homopolymer is recommended. For active agents that have low water solubility, less carbomer is required.

[0132] The present disclosure details the surprising finding that certain anionic and higher solubility active agents (e.g., acamprosate) can be successfully formulated for extended release using lower than typical amounts of carbomer homopolymer (e.g., 2 wt % to 12 wt %). Such insight leads to the ability to utilize carbomer homopolymers in tablet compositions even when active agent is present at such a high dose that it comprises a material percentage of the tablet weight (e.g., at least 40 wt %, at least 50 wt %, at least 60 wt %, at least 70 wt %, at least 80 wt %, or more of the tablet weight). Furthermore, utilization of smaller amounts of carbomer homopolymer than are typically recommended allows for extended release tablet compositions of suitable size (e.g., tablet compositions that are easy to swallow).

[0133] Without wishing to be bound by theory, carbomer homopolymers are anionic in nature, and therefore, the release of active agent may be pH-dependent. Accordingly, carbomer homopolymers have typically been paired with cationic active agents (e.g., basic active agents in a salt form). The present disclosure details the surprising result that carbomer homopolymers can be particularly useful with an anionic active agent, notwithstanding their own anionic characteristics.

[0134] In some embodiments, provided tablet compositions comprise a carbomer homopolymer, such as carbomer homopolymer type A, carbomer homopolymer type B, or carbomer homopolymer type C. In some embodiments, a tablet composition comprises carbomer homopolymer type A. In some embodiments, a tablet composition comprises carbomer homopolymer type B. In some embodiments, a tablet composition comprises carbomer homopolymer type C.

[0135] In some embodiments, tablet compositions provided by the present disclosure include a polymer matrix that comprises or consists of a carbomer homopolymer. In some such embodiments, a carbomer homopolymer is a carbomer homopolymer type A. In some embodiments, a carbomer homopolymer is a carbomer homopolymer type B. In some embodiments, a carbomer homopolymer is a carbomer homopolymer type C.

[0136] In some embodiments, a provided tablet composition comprises a carbomer homopolymer in the range of about 2 wt % to about 15 wt %, about 4 wt % to about 12 wt %, about 6 wt % to about 10 wt %, about 3 wt % to about 7 wt %, or about 4 wt % to about 6 wt %. In some embodiments, a carbomer homopolymer is present in an amount of about 2 wt % to about 15 wt %. In some embodiments, a carbomer homopolymer is present in an amount of about 3 wt % to about 7 wt %. In some embodiments, a carbomer homopolymer is present in an amount of about 4 wt % to about 6 wt %.

[0137] In some embodiments, a carbomer homopolymer is present in an amount of about 2 wt %, about 3 wt %, about 4 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %, about 10 wt %, about 11 wt %, or about 12 wt %. In some embodiments, a carbomer homopolymer is present in an amount of about 3 wt %. In some embodiments, a carbomer homopolymer is present in an amount of about 5 wt %. In some embodiments, a carbomer homopolymer is present in an amount of about 8 wt %. In some embodiments, a carbomer homopolymer is present in an amount of about 13 wt %.

[0138] In some embodiments, a provided tablet composition comprises a carbomer homopolymer in a range of about 30 mg to about 140 mg, about 50 mg to about 120 mg, about 70 mg to about 100 mg, about 30 mg to about 70 mg, about 50 mg to about 100 mg, about 50 mg to about 70 mg, or about 70 mg to about 100 mg. In some embodiments, a carbomer homopolymer is in an amount of about 50 mg to about 70 mg. In some embodiments, a carbomer homopolymer is in an amount of about 70 mg to about 100 mg.

[0139] In some embodiments, a carbomer homopolymer is in an amount of about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, or about 140 mg. In some embodiments, a carbomer homopolymer is present in an amount of about 30 mg. In some embodiments, a carbomer homopolymer is present in an amount of about 60 mg. In some embodiments, a carbomer homopolymer is present in an amount of about 90 mg. In some embodiments, a carbomer homopolymer is present in an amount of about 140 mg.

[0140] In some embodiments, a provided composition comprises a carbomer homopolymer type A in a range of about 2 wt % to about 15 wt %, about 4 wt % to about 12 wt %, about 6 wt % to about 10 wt %, about 3 wt % to about 7 wt %, or about 4 wt % to about 6 wt %. In some embodiments, a carbomer homopolymer type A is present in about 2 wt % to about 15 wt %. In some embodiments, a carbomer homopolymer type A is in an amount of about 3 wt % to about 7 wt %. In some embodiments, a carbomer homopolymer type A is in an amount of about 4 wt % to about 6 wt %. In some embodiments, a carbomer homopolymer type A is in an amount of about 4 wt % to about 6 wt %.

[0141] In some embodiments, a carbomer homopolymer type A is in an amount of about 2 wt %, about 3 wt %, about 4 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %, about 10 wt %, about 11 wt %, or about 12 wt %. In some embodiments, a carbomer homopolymer type A is in an amount of about 3 wt %. In some embodiments, a carbomer homopolymer type A is in an amount of about 5 wt %. In some embodiments, a carbomer homopolymer type A is in an amount of about 8 wt %. In some embodiments, a carbomer homopolymer type A is in an amount of about 13 wt %.

[0142] In some embodiments, a provided composition comprises a carbomer homopolymer type A in a range of about 30 mg to about 140 mg, about 50 mg to about 120 mg, about 70 mg to about 100 mg, about 30 mg to about 70 mg, about 50 mg to about 100 mg, about 50 mg to about 70 mg, or about 70 mg to about 100 mg. In some embodiments, a carbomer homopolymer type A is in an amount of about 50 mg to about 70 mg. In some embodiments, a carbomer homopolymer type A is in an amount of about 70 mg to about 100 mg.

[0143] In some embodiments, a carbomer homopolymer type A is in an amount of about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, or about 140 mg. In some embodiments, a carbomer homopolymer type A is in an amount of about 60 mg. In some embodiments, a carbomer homopolymer type A is in an amount of about 80 mg.

[0144] In some embodiments, a provided composition comprises a carbomer homopolymer type B in a range of about 2 wt % to about 15 wt %, about 4 wt % to about 12 wt %, about 6 wt % to about 10 wt %, about 3 wt % to about 7 wt %, or about 4 wt % to about 6 wt %. In some embodiments, a carbomer homopolymer type B is in an amount of about 2 wt % to about 15 wt %. In some embodiments, a carbomer homopolymer type B is in an amount of about 3 wt % to about 7 wt %. In some embodiments, a carbomer homopolymer type B is in an amount of about 4 wt % to about 6 wt %.

[0145] In some embodiments, a carbomer homopolymer type B is in an amount of about 2 wt %, about 3 wt %, about 4 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %, about 10 wt %, about 11 wt %, or about 12 wt %. In some embodiments, a carbomer homopolymer type B is in an amount of about 5 wt %. In some embodiments, a carbomer homopolymer type B is in an amount of about 8 wt %.

[0146] In some embodiments, a provided composition comprises a carbomer homopolymer type B in a range of about 30 mg to about 140 mg, about 50 mg to about 120 mg, about 70 mg to about 100 mg, about 30 mg to about 70 mg, about 50 mg to about 100 mg, about 50 mg to about 70 mg, or about 70 mg to about 100 mg. In some embodiments, a carbomer homopolymer type B is in an amount of about 50 mg to about 70 mg. In some embodiments, a carbomer homopolymer type B is in an amount of about 70 mg to about 100 mg.

[0147] In some embodiments, a carbomer homopolymer type B is in an amount of about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, or about 140 mg. In some embodiments, a carbomer homopolymer type B is in an amount of about 60 mg. In some embodiments, a carbomer homopolymer type B is in an amount of about 90 mg.

[0148] In some embodiments, a provided composition comprises a carbomer homopolymer type C in the range of about 2 wt % to about 15 wt %, about 4 wt % to about 12 wt %, about 6 wt % to about 10 wt %, about 3 wt % to about 7 wt %, or about 4 wt % to about 6 wt %. In some embodiments, a carbomer homopolymer type C is in an amount of about 2 wt % to about 15 wt %. In some embodiments, a carbomer homopolymer type C is in an amount of about 4 wt % to about 12 wt %.

[0149] In some embodiments, a carbomer homopolymer type C is in an amount of about 2 wt %, about 3 wt %, about 4 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %, about 10 wt %, about 11 wt %, or about 12 wt %. In some embodiments, a carbomer homopolymer type C is in an amount of about 3 wt %. In some embodiments, a carbomer homopolymer type C is in an amount of about 5 wt %. In some embodiments, a carbomer homopolymer type C is in an amount of about 8 wt %. In some embodiments, a carbomer homopolymer type C is in an amount of about 13 wt %.

[0150] In some embodiments, a provided composition comprises a carbomer homopolymer type C in a range of about 30 mg to about 140 mg, about 50 mg to about 120 mg, about 70 mg to about 100 mg, about 30 mg to about 70 mg, about 50 mg to about 100 mg, about 50 mg to about 70 mg, or about 70 mg to about 100 mg. In some embodiments, a carbomer homopolymer type C is in an amount of about 50 mg to about 70 mg. In some embodiments, a carbomer homopolymer type C is in an amount of about 70 mg to about 100 mg.

[0151] In some embodiments, a carbomer homopolymer type C is in an amount of about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, or about 140 mg. In some embodiments, a carbomer homopolymer type C is in an amount of about 60 mg. In some embodiments, a carbomer homopolymer type C is in an amount of about 80 mg.

[0152] Alternatively or additionally, in some embodiments, tablet compositions provided by the present disclosure comprise a polymer selected from the group consisting of carboxymethyl cellulose (e.g., Aqualon® CMC-7HF), an acrylates copolymer (e.g., a poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid 7:3:1, such as EUDRAGIT® FS 30 D), and gelatin type B. In some embodiments, a polymer selected from the group consisting of carboxymethyl cellulose (e.g., Aqualon® CMC-7HF), an acrylates copolymer (e.g., a poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid 7:3:1, such as EUDRAGIT® FS 30 D), and gelatin type B is present in a provided tablet composition in addition to a carbomer homopolymer.

[0153] In some embodiments, a provided composition comprises carboxymethyl cellulose (e.g., Aqualon® CMC-7HF). In some embodiments, carboxymethyl cellulose is part of a polymer matrix. In some embodiments, carboxymethyl cellulose is in an amount of about 0.5 wt % to about 9 wt %, about 3 wt % to about 9 wt %, about 5 wt % to about 9 wt %, or about 6 wt % to about 8 wt %. In some embodiments, carboxymethyl cellulose is in an amount of about 5 wt % to about 9 wt %.

[0154] In some embodiments, carboxymethyl cellulose is in an amount of about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, or about 9 wt %. In some embodiments, carboxymethyl cellulose is in an amount of about 1 wt %. In some embodiments, carboxymethyl cellulose is in an amount of about 3 wt % (e.g., 3.5 wt %). In some embodiments, carboxymethyl cellulose is in an amount of about 7 wt % (e.g., 6.8 wt %).

[0155] In some embodiments, a provided composition comprises carboxymethyl cellulose (e.g., Aqualon® CMC-7HF) in an amount of about 10 mg to about 100 mg, about 10 mg to about 40 mg, about 40 mg to about 80 mg, or about 60 mg to about 100 mg.

[0156] In some embodiments, carboxymethyl cellulose is in an amount of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg. In some embodiments, carboxymethyl cellulose is in an amount of about 10 mg. In some embodiments, carboxymethyl cellulose is in an amount of about 40 mg. In some embodiments, carboxymethyl cellulose is in an amount of about 80 mg.

[0157] In some embodiments, a provided composition comprises an acrylates copolymer (e.g., a poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid 7:3:1, such as EUDRAGIT® FS 30 D). In some embodiments, an acrylates copolymer is part of a polymer matrix. In some embodiments, an acrylates copolymer is in an amount of about 0.5 wt % to about 9 wt %, about 0.5 wt % to about 5 wt %, or about 0.5 wt % to about 1.5 wt %. In some embodiments, an acrylates copolymer is in an amount of about 0.5 wt % to about 1.5 wt %.

[0158] In some embodiments, an acrylates copolymer is in an amount of about 0.5 wt %, about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt %, or about 5 wt %. In some embodiments, an acrylates copolymer is in an amount of about 0.5 wt %.

[0159] In some embodiments, a provided composition comprises an acrylates copolymer (e.g., a poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid 7:3:1, such as EUDRAGIT® FS 30 D) in an amount of about 5 mg to about 50 mg, about 5 mg to about 20 mg, or about 5 mg to about 15 mg. In some embodiments, an acrylates copolymer is in an amount of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg. In some embodiments, an acrylates copolymer is in an amount of about 10 mg.

[0160] In some embodiments, a provided composition comprises gelatin type B. In some embodiments, gelatin type B is part of a polymer matrix. In some embodiments, gelatin type B is in an amount of about 0.5 wt % to about 5 wt %, about 2 wt % to about 5 wt %, or about 3 wt % to about 4 wt %. In some embodiments, gelatin type B is in an amount of about 2 wt % to about 5 wt %.

[0161] In some embodiments, gelatin type B is in an amount of about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt %, or about 5 wt %. In some embodiments, gelatin type B is in an amount of about 4 wt % (e.g., 3.6 wt %).

[0162] Those skilled in the art of pharmaceutical formulation appreciate that formulations typically include one or more components other than active agent. Formulations provided by the present disclosure may include one or more such components other than the active agent(s). Any acceptable other components for therapeutic use can be used, including those described, for example, in the incorporated material of Remington: The Science and Practice of Pharmacy (2003), which is incorporated herein by reference in its entirety. Other components can refer to any substance, not itself a therapeutic agent, used as a carrier and/or diluent and/or adjuvant, or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition into a discrete article such as a capsule or tablet suitable for oral administration. In some embodiments, such other components are not polymers. In some embodiments, such other components are not part of a polymer matrix (e.g., throughout which one or more active agents may be distributed), even if they may be polymers (or polymeric) themselves. In some embodiments, other components may be selected from, for example, binders, carriers, color additives, diluents, disintegrants, fillers, glidants, lubricants, and combinations thereof. In some embodiments, other components may be or comprise a coating.

[0163] In some embodiments, certain provided formulations include one or more fillers, diluents or carriers. In some embodiments, a filler, diluent, or carrier is or comprises calcium carbonate DC, calcium phosphate dibasic, calcium phosphate tribasic, calcium silicate, compressible sugars, lactose, maltodextrin, mannitol, microcrystalline cellulose (e.g., Avicel® Ph 102), pregelatinized starch, sorbitol, sugar spheres, talc, talc powder, xylitol, and combinations of one or more of the same, or the like. In some embodiments, a filler, diluent, or carrier is or comprises microcrystalline cellulose. In some embodiments, a filler, diluent, or carrier is microcrystalline cellulose in combination with one or more other agents such as, for example, calcium carbonate DC, calcium phosphate dibasic, calcium phosphate tribasic, compressible sugars, lactose, maltodextrin, mannitol, pregelatinized starch, sorbitol, xylitol, and combinations of one or more of the same, or the like. In some embodiments, a filler, diluent, or carrier is or comprises talc (e.g., talc powder). In some embodiments, a filler, diluent, or carrier is or comprises a combination of microcrystalline cellulose and talc. In some embodiments, a filler, diluent, or carrier is or comprises sugar spheres.

[0164] In some embodiments, certain provided formulations include one or more glidants. Suitable glidants are known in the art and can include CarboSil®, calcium silicate, calcium stearate, colloidal silicon dioxide, corn starch, fumed silicon dioxide, magnesium carbonate, magnesium laurel sulfate, magnesium oxide, magnesium stearate (MGST), metallic stearates, silicon dioxide, starch, starch 1500, stearowet C®, zinc stearate, and combinations thereof. In some embodiments, a provided composition comprises colloidal silicon dioxide. In some embodiments, colloidal silicon dioxide is in an amount of about 0.5 wt % to about 2 wt %.

[0165] In some embodiments, certain provided formulations include one or more lubricants, for example, to improve powder flow, prevent the blend from adhering to tableting equipment and punch surfaces and provide lubrication to allow tablets to be cleanly ejected from tablet dies. Suitable lubricants are known in the art and can include calcium stearate, glyceryl behenate, hydrogenated vegetable oil, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, stearic acid, and mixtures thereof. In some embodiments, a provided composition comprises magnesium stearate. In some embodiments, magnesium stearate is in an amount of about 0.5 wt % to about 2 wt %.

[0166] In some embodiments, certain provided formulations include one or more binders, for example, to impart cohesive qualities to a formulation, and thus ensure that the resulting dosage form remains intact after compaction. Suitable binder materials include, but are not limited to, microcrystalline cellulose, gelatin, sugars (including, for example, sucrose, glucose, dextrose and maltodextrin), polyethylene glycol, waxes, natural and synthetic gums, polyvinylpyrrolidone (e.g, Povidone K90), cellulosic polymers (including, for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, hydroxyethyl cellulose, and the like). In some embodiments, the binder is a povidone. In some embodiments, the povidone is Povidone K90 (CAS number 9003-39-8).

[0167] In some embodiments, certain provided formulations include one or more disintegrants, for example, to facilitate tablet disintegration after administration, and are generally starches, clays, celluloses, algins, gums or crosslinked polymers. Suitable disintegrants include, but are not limited to, alginic acid, cornstarch, croscarmellose sodium, crospovidone, crosslinked polyvinylpyrrolidone (PVP-XL), microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, Starcap 500®, and Starcap 1500 ®. In some embodiments, a provided composition comprises Starcap 500®. In some embodiments, a provided composition comprises Starcap 1500®.

[0168] In some embodiments, provided formulations include a coating, for example, a film coating. Where film coatings are involved, coating preparations can include, for example, a film-forming polymer, a plasticizer, or the like. In some embodiments, the coatings include pigments and/or opacifiers. Non-limiting examples of film-forming polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl pyrrolidine, and starches. Non-limiting examples of plasticizers include polyethylene glycol, tributyl citrate, dibutyl sebecate, castor oil, and acetylated monoglyceride. Furthermore, non-limiting examples of pigments and opacifiers include iron oxides of various colors, lake dyes of many colors, titanium dioxide, and the like.

[0169] In some embodiments, a provided composition includes one or more color additives or colorants. The colorants can be used in amounts sufficient to distinguish dosage form strengths. Preferably, color additives approved for use in drugs are added to the commercial formulations to differentiate tablet strengths. The use of other pharmaceutically acceptable colorants and combinations thereof are encompassed by the current invention.

Provided Technologies for Preparing Tablet Compositions

[0170] Another aspect of the present disclosure is the preparation of tablet compositions with provided technologies. The Prior Fogel Filings disclose round or circular tablet compositions prepared by providing a preparation of granules comprising acamprosate and blending the preparation of granules with extra-granular materials comprising a carbomer homopolymer. The Prior Fogel Filings do not describe a tablet composition prepared from a preparation of granules and extra-granular materials that both comprise a cellulose derivative. The Prior Fogel Filings do not describe the preparation of an oval tablet composition by providing a preparation of granules comprising acamprosate and blending the preparation of granules with extra-granular materials comprising a carbomer homopolymer. As described above, the Prior Fogel Formulations demonstrated unexpected effects of certain polymers (e.g., carbomer homopolymer type B or carbomer homopolymer type A) for preparing extended release formulations of acamprosate or a pharmaceutically acceptable salt thereof.

[0171] While the formulations prepared in the Prior Fogel Filings can provide round tablet compositions with desirable characteristics, the present disclosure identifies a source of variability with the process when the process is used to prepare oval tablet compositions (Example 4). As disclosed above, oval tablet compositions are desirable for a number of reasons, including ease of swallowing to encourage patient compliance. The present disclosure also provides a solution to the problem of variability in the process used to prepare oval tablet compositions.

[0172] A method of preparing an uncoated tablet composition comprising acamprosate in a pharmaceutically acceptable salt form, can comprise: [0173] (i) blending a preparation of granules that comprise the acamprosate with extra-granular materials that comprise a carbomer homopolymer to form a blended material, wherein each of the granules and the extra-granular materials comprises a cellulose derivative material; and [0174] (ii) compressing the blended material to form the uncoated tablet composition.

[0175] In some embodiments, the method further comprises first providing a preparation of granules. In some embodiments, the providing a preparation of granules comprises (a) forming wet granules and (b) drying the wet granules to form the preparation of granules. In some embodiments, forming wet granules comprises a wet granulation step (e.g., with purified water). In some embodiments, drying the wet granules comprises drying until loss on drying (LOD) is <10%, <5%, or <2%. In some embodiments, drying the wet granules comprises drying until loss on drying (LOD) is <2%. In some embodiments, the method further comprises coating the uncoated tablet composition.

[0176] Another aspect of the present disclosure is an improvement to a method of manufacturing an oval uncoated tablet composition comprising acamprosate in a pharmaceutically acceptable salt form, and a carbomer homopolymer, wherein the acamprosate is present in a dose of at least 400 mg and the composition is prepared by blending: [0177] (1) a preparation of granules with [0178] (2) extra-granular materials,
the improvement that comprises including a cellulose derivative in each of (1) the preparation of granules; and (2) the extra-granular material, so that the composition comprises: [0179] the acamprosate in a dose of about 66 wt % to about 72 wt %; [0180] the carbomer homopolymer in an amount of about 3 wt % to about 7 wt %; and [0181] the cellulose derivative in an amount of about 5 wt % to about 9 wt %.

[0182] In some embodiments, a preparation of granules weighs from about 900 mg to about 1100 mg. In some embodiments, a preparation of granules weighs about 1000 mg. In some embodiments, a preparation of granules makes up about 80 wt % to about 90 wt % of the uncoated tablet composition. In some embodiments, a preparation of granules makes up about 85 wt % of the uncoated tablet composition. In some embodiments, a preparation of granules makes up about 86 wt % of the uncoated tablet composition.

[0183] Alternatively or additionally, in some embodiments, extra-granular materials weigh from about 150 mg to about 170 mg. In some embodiments, extra-granular materials weigh about 160 mg. In some embodiments, extra-granular materials make up about 10 wt % to about 20 wt % of the uncoated tablet composition. In some embodiments, extra-granular materials make up about 13 wt % of the uncoated tablet composition. In some embodiments, extra-granular materials make up about 14 wt % of the uncoated tablet composition.

[0184] Alternatively or additionally, in some embodiments, a preparation of granules comprises acamprosate in an amount of about 70 wt % to about 90 wt %. In some embodiments, a preparation of granules comprises acamprosate in an amount of about 80 wt %. In some embodiments, a preparation of granules comprises acamprosate in an amount of about 70 wt % to about 90 wt %, so that an uncoated tablet composition comprises acamprosate in an amount of about 66 wt % to about 72 wt %. In some embodiments, a preparation of granules comprises acamprosate in an amount of about 80 wt %, so that an uncoated tablet composition comprises acamprosate in an amount of about 69 wt %. In some embodiments, a preparation of granules comprises acamprosate in an amount of at least 400 mg. In some embodiments, a preparation of granules comprises acamprosate in an amount of about 400 mg to about 1000 mg. In some embodiments, a preparation of granules comprises acamprosate in an amount of about 800 mg.

[0185] Alternatively or additionally, in some embodiments, a preparation of granules comprises a cellulose derivative in an amount of about 2 wt % to about 6 wt %. In some embodiments, a preparation of granules comprises a cellulose derivative in an amount of about 4 wt %. In some embodiments, a preparation of granules comprises carboxymethyl cellulose (e.g., CMC 7HF) in an amount of about 2 wt % to about 6 wt %. In some embodiments, a preparation of granules comprises carboxymethyl cellulose (e.g., CMC 7HF) in an amount of about 4 wt % (e.g., about 40 mg).

[0186] Alternatively or additionally, in some embodiments, extra-granular materials comprise a cellulose derivative in an amount of about 20 wt % to about 30 wt %. In some embodiments, extra-granular materials comprise a cellulose derivative in an amount of about 25 wt %. In some embodiments, extra-granular materials comprise carboxymethyl cellulose (e.g., CMC 7HF) in an amount of about 20 wt % to about 30 wt %. In some embodiments, extra-granular materials comprise carboxymethyl cellulose (e.g., CMC 7HF) in an amount of about 25 wt % (e.g., 40 mg).

[0187] Alternatively or additionally, in some embodiments, both a preparation of granules and extra-granular materials comprise a cellulose derivative. In some embodiments, a preparation of granules comprises about 2 wt % to about 6 wt % of carboxymethyl cellulose (e.g., CMC 7HF), and extra-granular materials comprise about 20 wt % to about 30 wt % of carboxymethyl cellulose (e.g., CMC 7HF), so that an uncoated tablet composition comprises a total of about 5 wt % to about 9 wt % of carboxymethyl cellulose (e.g., about 80 mg).

[0188] Alternatively or additionally, in some embodiments, extra-granular materials comprise a carbomer homopolymer (e.g., carbomer homopolymer type A, carbomer homopolymer type B, or carbomer homopolymer typer C). In some embodiments, extra-granular materials comprise a carbomer homopolymer in an amount of about 15 wt % to about 90 wt %. In some embodiments, extra-granular materials comprise a carbomer homopolymer in an amount of about 35 wt % to about 60 wt %. In some embodiments, extra-granular materials comprise a carbomer homopolymer in an amount of about 37.5 wt % (e.g., 60 mg).

[0189] In some embodiments, extra-granular materials comprise carbomer homopolymer type B in an amount of about 35 wt % to about 60 wt %. In some embodiments, extra-granular materials comprise carbomer homopolymer type B in an amount of about 37.5 wt %. In some embodiments, extra-granular materials comprise carbomer homopolymer type B in an amount of about 60 mg. In some embodiments, extra-granular materials comprise carbomer homopolymer type B, in an amount so that an uncoated tablet composition comprises about 3 wt % to about 7 wt % carbomer homopolymer type B.

[0190] Alternatively or additionally, in some embodiments, extra-granular materials comprise both carbomer homopolymer type B and carboxymethyl cellulose. In some embodiments, extra-granular materials comprise carbomer homopolymer type B and carboxymethyl cellulose in a ratio of 3:2. In some embodiments, extra-granular materials comprise about 60 mg carbomer homopolymer type B and about 40 mg carboxymethyl cellulose. In some embodiments, extra-granular materials comprise carbomer homopolymer type B and carboxymethyl cellulose, in amounts so that an uncoated tablet composition comprises about 3 wt % to about 7 wt % carbomer homopolymer type B and about 5 wt % to about 9 wt % carboxymethyl cellullose.

[0191] Alternatively or additionally, in some embodiments, a preparation of granules comprises an acrylates copolymer (e.g., EUDRAGIT® FS 30 D). In some embodiments, a preparation of granules comprises about 10 mg of an acrylates copolymer. In some embodiments, a preparation of granules comprises an amount of acrylates copolymer so that the acrylates copolymer is present in an uncoated tablet composition within the range of about 0.5 wt % to about 1.5 wt %. In some embodiments, a preparation of granules comprises an amount of acrylates copolymer so that the acrylates copolymer is present in an uncoated tablet composition in about 0.9 wt %.

[0192] Alternatively or additionally, in some embodiments, extra-granular materials comprise carbomer homopolymer type B and gelatin type B. In some embodiments, extra-granular materials comprise carbomer homopolymer type B and gelatin type B in a ratio of 9:4. In some embodiments, extra-granular materials comprise about 90 mg carbomer homopolymer type B and about 40 mg gelatin type B. In some embodiments, extra-granular materials comprise carbomer homopolymer type B and gelatin type B in an amount so that an uncoated tablet composition comprises carbomer homopolymer type B in an amount of about 3 wt % to about 7 wt % and gelatin type B in an amount of about 2 wt % to about 5 wt %.

[0193] Alternatively or additionally, in some embodiments, extra-granular materials comprise carbomer homopolymer type C and carboxymethyl cellulose. In some embodiments, extra-granular materials comprise carbomer homopolymer type C and carboxymethyl cellulose in a ratio of 3:2. In some embodiments, extra-granular materials comprise carbomer homopolymer type C and carboxymethyl cellulose in a ratio of 9:4. In some embodiments, extra-granular materials comprise carbomer homopolymer type C and carboxymethyl cellulose in a ratio of 3:4. In some embodiments, extra-granular materials comprise about 60 mg carbomer homopolymer type C and about 40 mg carboxymethyl cellulose. In some embodiments, extra-granular materials comprise about 90 mg carbomer homopolymer type C and about 40 mg carboxymethyl cellulose. In some embodiments, extra-granular materials comprise about 30 mg carbomer homopolymer type C and about 40 mg carboxymethyl cellulose. In some embodiments, extra-granular materials comprise about 140 mg carbomer homopolymer type C. In some embodiments, extra-granular materials comprise carbomer homopolymer type C and optionally carboxymethyl cellulose in an amount so that an uncoated tablet composition comprises carbomer homopolymer type C in an amount of about 2 wt % to about 15 wt % and carboxymethyl cellulose in an amount of 0 wt % to about 5 wt %.

[0194] In some embodiments, provided technologies (e.g., a method of preparing an uncoated tablet composition comprising acamprosate) can be used to prepare a tablet composition comprising any one of the Formulations disclosed herein (e.g., Formulations 3-6 or 9-12). The provided technologies can also be used to improve certain characteristics of a Formulation disclosed herein (e.g., by adding an amount of cellulose derivative to both a preparation of granules and extra-granular materials).

Combinations

[0195] Compositions described herein may also include one or more additional therapeutic agents. In some embodiments, additional therapeutic agents are selected from first-generation neuroleptics (antipsychotics), second-generation neuroleptics, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and the anti-nausea drug metoclopramide. Without wishing to be bound by theory, extended-release properties of provided formulations make it feasible to formulate fixed-dose combinations of acamprosate and other agents, such as those described herein. Additional benefits of a fixed dose combination of acamprosate with another therapeutic agent include increased patient compliance, increased therapeutic effects, and reduced side effects. Fixed dose combinations with first-generation neuroleptics, for example, can provide effective treatment of psychosis with a lesser risk of metabolic side effects (e.g., weight gain, glucose intolerance, and/or increased risk of atherosclerotic cardiovascular disease) than seen with second-generation neuroleptic drugs, with a lesser risk of tardive dyskinesia than seen with first-generation neuroleptic drugs given alone, and with, unexpectedly, increased relief of mental symptoms compared with first-generation neuroleptic drugs given alone.

[0196] In some embodiments, a provided composition further comprises one or more additional therapeutic agents, such as a first generation neuroleptic, a second generation neuroleptic, a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). In some embodiments, a provided composition is a unit dosage form that includes, consists of, or consists essentially of both acamprosate and at least one additional therapeutic agent. In some embodiments, a composition is a multilayer (e.g., bilayer) composition wherein each layer comprises one active agent. In some embodiments, a composition is not a bilayer composition, wherein active agents are dispersed in a polymer matrix.

[0197] In some embodiments, a composition is administered to a patient who is receiving or has received one or more other medications, such as a first generation neuroleptic, a second generation neuroleptic, a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor (SNRI), an anti-nausea drug, an NMDA modulator, and/or an α.sub.2A adrenergic receptor agonist, or any combination thereof.

[0198] In some embodiments, a composition as described herein further comprises or is administered to a patient who is receiving or has received a second medication selected from one or more of a neuroleptic (antipsychotic) medication, a SSRI, a SNRI, an antidepressant other than an SSRI or SNRI, an anti-anxiety medication other than an SSRI or SNRI or the like, an anti-nausea drug, an NMDA modulator, and an α.sub.2A adrenergic receptor agonist.

[0199] In some embodiments, a provided composition further comprises a neuroleptic medication. In some embodiments, a provided composition further comprises a first generation neuroleptic. In some embodiments, a first generation neuroleptic is selected from chlorpromazine, fluphenazine, haloperidol, loxapine, molindone, perphenazine, pimozide, thioridazine, thiothixene, and trifluoperazine, or the like.

[0200] In some embodiments, a provided composition further comprises a second generation neuroleptic. In some embodiments, a second generation neuroleptic is selected from aripiprazole, asenapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone, or the like.

[0201] In some embodiments, a provided composition further comprises a SSRI or SNRI. In some such embodiments, a SSRI or SNRI is selected from one or more of citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, and venlafaxine, or the like.

[0202] In some embodiments, a provided composition further comprises an anti-depressant other than an SSRI or SNRI.

[0203] In some embodiments, a provided composition further comprises an anti-anxiety medication other than an SSRI or SNRI.

[0204] In some embodiments, a provided composition further comprises an anti-nausea drug. In some embodiments, an anti-nausea drug is metoclopramide.

[0205] In some embodiments, a provided composition further comprises an NMDA modulator. In some embodiments, a NMDA modulator is memantine. In some embodiments, a NMDA modulator is amantadine.

[0206] In some embodiments, a provided composition further comprises an α.sub.2A adrenergic receptor agonist. In some embodiments, the α.sub.2A adrenergic receptor agonist is guanfacine.

[0207] In some embodiments, a provided composition further comprises one or more additional therapeutic agents selected from the group consisting of amantadine, aripiprazole, asenapine, chlorpromazine, citalopram, clonidine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, fluphenazine, guanfacine, haloperidol, iloperidone, loxapine, lurasidone, memantine, metoclopramide, milnacipran, molindone, olanzapine, paliperidone, paroxetine, perphenazine, pimozide, prazosin, quetiapine, risperidone, sertraline, thioridazine, thiothixene, trifluoperazine, venlafaxine, and ziprasidone, and any combination thereof.

[0208] In some embodiments, a provided composition is administered to a patient who is receiving or has received one or more additional therapeutic agents selected from the group consisting of amantadine, aripiprazole, asenapine, chlorpromazine, citalopram, clonidine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, fluphenazine, guanfacine, haloperidol, iloperidone, loxapine, lurasidone, metoclopramide, memantine, milnacipran, molindone, olanzapine, paliperidone, paroxetine, perphenazine, pimozide, prazosin, quetiapine, risperidone, sertraline, thioridazine, thiothixene, trifluoperazine, venlafaxine, and ziprasidone, and any combination thereof.

[0209] In some embodiments, a provided composition further comprises amantadine. Amantadine (trade names Gocovri®, Symadine®, or Symmetrel®) is used to treat symptoms of Parkinson's disease, such as levodopa-induced dyskinesia (LID). Without wishing to be bound by any theory, an extended-release combination of acamprosate and amantadine may be particularly useful for treating symptoms of Parkinson's disease, such as levodopa-induced dyskinesia (LID).

[0210] In some embodiments, amantadine is in a dose of from about 50 mg to about 300 mg, such as about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg, or any ranges between any two values. In some embodiments, a total daily dosage of amantadine is from about 100 mg to about 400 mg, such as about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg, or any ranges between any two values.

[0211] In some embodiments of a composition further comprising amantadine, acamprosate is in a dose of from about 400 mg to about 1500 mg, such as about 400 mg, about 500 mg, about 800 mg, about 1000 mg, about 1300 mg, or about 1500 mg, or any ranges between any two values. In some such embodiments, a composition comprises about 800 mg acamprosate and about 50 mg or about 100 mg amantadine or about 1000 mg acamprosate and about 50 mg or about 100 mg amantadine.

[0212] In some embodiments, a composition comprising acamprosate and amantadine is for use in treating levodopa-induced dyskinesia in patients with Parkinson's disease. In some embodiments, a method of treating levodopa-induced dyskinesia in patients with Parkinson's disease comprises administering a therapeutically effective dose of a composition comprising acamprosate and amantadine to a patient in need thereof.

[0213] In some embodiments, a provided composition further comprises clonidine. Clonidine is used to treat high blood pressure, anxiety disorders, and attention disorders, among others. Without wishing to be bound by any theory, an extended-release combination of acamprosate and clonidine may be particularly useful for treating Tourette syndrome.

[0214] In some embodiments, clonidine is in a dose of from about 0.025 mg to about 0.25 mg, such as about 0.025 mg, about 0.05 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, or about 0.25 mg, or any ranges between any two values. In some embodiments, a total daily dosage of clonidine is from about 0.05 mg to about 0.5 mg, such as about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, or about 0.5 mg, or any ranges between any two values.

[0215] In some embodiments of a composition further comprising clonidine, acamprosate is in a dose of from about 400 mg to about 1500 mg, such as about 400 mg, about 500 mg, about 800 mg, about 1000 mg, about 1300 mg, or about 1500 mg, or any ranges between any two values. In some such embodiments, a composition comprises about 800 mg acamprosate and about 0.1 mg clonidine or about 800 mg acamprosate and about 0.05 mg clonidine.

[0216] In some embodiments, a composition comprising acamprosate and clonidine is for use in treating Tourette syndrome. In some embodiments, a method of treating Tourette syndrome comprises administering a therapeutically effective dose of a composition comprising acamprosate and clonidine to a patient in need thereof.

[0217] In some embodiments, a provided composition further comprises fluvoxamine. Fluvoxamine (trade name Luvox®, among others) is used to treat obsessive-compulsive disorder (OCD), major depression disorder, and anxiety disorders, among others. Fluvoxamine is the only SSRI with sigma-1 agonist effects, and one that may be uniquely useful for treating OCD. Without wishing to be bound by any theory, an extended-release combination of acamprosate and fluvoxamine may be particularly useful for treating OCD.

[0218] In some embodiments, fluvoxamine is in a dose of from about 25 mg to about 100 mg, such as about 25 mg, about 50 mg, about 75 mg, or about 100 mg, or any ranges between any two values. In some embodiments, a total daily dosage of fluvoxamine is from about 50 mg to about 300 mg, such as about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg, or any ranges between any two values.

[0219] In some embodiments of a composition further comprising fluvoxamine, acamprosate is in a dose of from about 400 mg to about 1500 mg, such as about 400 mg, about 500 mg, about 800 mg, about 1000 mg, about 1300 mg, or about 1500 mg, or any ranges between any two values. In some such embodiments, a composition comprises about 800 mg acamprosate and about 25 mg fluvoxamine or about 800 mg acamprosate and about 75 mg fluvoxamine.

[0220] In some embodiments, a composition comprising acamprosate and fluvoxamine is for use in treating OCD. In some embodiments, a method of treating OCD comprises administering a therapeutically effective dose of a composition comprising acamprosate and fluvoxamine to a patient in need thereof.

[0221] In some embodiments, a provided composition further comprises guanfacine. Guanfacine is used to treat high blood pressure and attention disorders. Without wishing to be bound by any theory, an extended-release combination of acamprosate and guanfacine may be particularly useful for treating Tourette syndrome.

[0222] In some embodiments, guanfacine is in a dose of from about 0.25 mg to about 8 mg, such as about 0.25 mg, about 0.5 mg, about 1 mg, about 2 mg, about 4 mg, or about 8 mg, or any ranges between any two values. In some embodiments, a total daily dosage of guanfacine is from about 0.5 mg to about 10 mg, such as about 0.5 mg, about 1 mg, about 2 mg, about 4 mg, about 7 mg, or about 8 mg, or any ranges between any two values.

[0223] In some embodiments of a composition further comprising guanfacine, acamprosate is in a dose of from about 400 mg to about 1500 mg, such as about 400 mg, about 500 mg, about 800 mg, about 1000 mg, about 1300 mg, or about 1500 mg, or any ranges between any two values. In some such embodiments, a composition comprises about 800 mg acamprosate and about 1 mg or about 4 mg guanfacine or about 1000 mg acamprosate and about 1 mg or about 4 mg guanfacine.

[0224] In some embodiments, a composition comprising acamprosate and guanfacine is for use in treating Tourette syndrome. In some embodiments, a method of treating Tourette syndrome comprises administering a therapeutically effective dose of a composition comprising acamprosate and guanfacine to a patient in need thereof.

[0225] In some embodiments, a provided composition further comprises memantine. Memantine is used to treat moderate to severe Alzheimer's disease, as well as symptoms of Parkinson's disease. In some embodiments, the present disclosure encompasses the recognition that memantine is useful to treat symptoms of Parkinson's disease, such as levodopa-induced dyskinesia (LID). Without wishing to be bound by any theory, an extended-release combination of acamprosate and memantine may be particularly useful for treating symptoms of Parkinson's disease, such as levodopa-induced dyskinesia (LID).

[0226] In some embodiments, memantine is in a dose of from about 5 mg to about 40 mg, such as about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg, or any ranges between any two values. In some embodiments, the total daily dosage of memantine is from about 5 mg to about 40 mg, such as about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg, or any ranges between any two values.

[0227] In some embodiments of a composition further comprising memantine, acamprosate is in a dose of from about 400 mg to about 1500 mg, such as about 400 mg, about 500 mg, about 800 mg, about 1000 mg, about 1300 mg, or about 1500 mg, or any ranges between any two values. In some such embodiments, a composition comprises about 800 mg acamprosate and about 10 mg or about 15 mg memantine or about 1000 mg acamprosate and about 10 mg or about 15 mg memantine.

[0228] In some embodiments, a composition comprising acamprosate and memantine is for use in treating levodopa-induced dyskinesia in patients with Parkinson's disease. In some embodiments, a method of treating levodopa-induced dyskinesia in patients with Parkinson's disease comprises administering a therapeutically effective dose of a composition comprising acamprosate and memantine to a patient in need thereof.

[0229] In some embodiments, a provided composition further comprises molindone. Molindone (trade name Moban®) is an antipsychotic drug used to treat schizophrenia and psychosis. It is the only neuroleptic associated with weight loss rather than weight gain. Without wishing to be bound by any theory, an extended-release combination of acamprosate and molindone may be particularly useful for treating psychosis and obesity or metabolic syndrome, because acamprosate may reduce the risk that molindone will induce tardive dyskinesia (TD).

[0230] In some embodiments, molindone is in a dose of from about 5 mg to about 50 mg, such as about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, or about 50 mg, or any ranges between any two values. In some embodiments, a total daily dosage of molindone is from about 10 mg to about 200 mg, such as about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, or any ranges between any two values.

[0231] In some embodiments of a composition further comprising molindone, acamprosate is in a dose of from about 400 mg to about 1500 mg, such as about 400 mg, about 500 mg, about 800 mg, about 1000 mg, about 1300 mg, or about 1500 mg, or any ranges between any two values. In some such embodiments, a composition comprises about 800 mg acamprosate and about 5 mg molindone, about 800 mg acamprosate and about 50 mg molindone, or about 1000 mg acamprosate and about 10 mg molindone.

[0232] In some embodiments, a composition comprising acamprosate and molindone is for use in treating psychosis and obesity or metabolic syndrome. In some embodiments, a method of treating psychosis and obesity or metabolic syndrome comprises administering a therapeutically effective dose of a composition comprising acamprosate and molindone to a patient in need thereof.

[0233] In some embodiments, a provided composition further comprises prazosin. Prazosin (trade names Minipress®, Vasoflex®, Pressin® or Hypovase®) is a sympatholytic drug used to treat high blood pressure and anxiety, PTSD, and panic disorder. It is an alpha-adrenergic blocker that is specific for the alpha-1 receptors. Without wishing to be bound by any theory, combining prazosin with an extended release formulation of acamprosate provided herein may enhance its central nervous system (CNS) levels relative to its systemic levels, as prazosin is both a substrate of and an inhibitor of the ABCG2 efflux pump, which determines the level of prazosin in the CNS. The enhanced CNS levels may reduce the hypotension seen early on in treatment with prazosin, mitigate prazosin food effect, and/or improve the efficacy of prazosin.

[0234] In some embodiments, prazosin is in a dose of from about 0.5 mg to about 15 mg, such as about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, or about 15 mg, or any ranges between any two values. In some embodiments, a total daily dosage of prazosin is from about 1 mg to about 40 mg, such as about about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, or about 40 mg, or any ranges between any two values.

[0235] In some embodiments of a composition further comprising prazosin, acamprosate is in a dose of from about 400 mg to about 1500 mg, such as about 400 mg, about 500 mg, about 800 mg, about 1000 mg, about 1300 mg, or about 1500 mg, or any ranges between any two values. In some such embodiments, a composition comprises about 800 mg acamprosate and about 1 mg prazosin or about 1000 mg acamprosate and about 10 mg prazosin.

[0236] In some embodiments, a composition comprising acamprosate and prazosin is for use in treating PTSD (e.g., PTSD with nightmares). In some embodiments, a method of treating PTSD (e.g., PTSD with nightmares) comprises administering a therapeutically effective dose of a composition comprising acamprosate and prazosin to a patient in need thereof.

Uses of Provided Compositions

Methods of Treatment

[0237] The present disclosure also provides methods of treating a disease, disorder, or condition, such as a neuropsychiatric disorder, in a patient in need thereof, such treatment comprising administering to said patient a composition or a unit dosage form of a composition described herein.

[0238] In some embodiments, a disease, disorder, or condition is selected from psychogenic nonepileptic seizures (PNES), tardive dyskinesia (TD), tardive akathisia, dystonia, blepharospasm, levodopa-induced dyskinesia (LID) in patients with Parkinson's disease, dyskinetic movements in Rett's Syndrome, dyskinetic movements in DiGeorge Syndrome, dyskinetic movements and dystonia in Wilson's disease, post-hypoxic myoclonus, simple tics, Tourette Syndrome (TS), obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), symptoms of schizophrenia, depression, bipolar disorder, autism spectrum disorders, autistic symptoms in Fragile X syndrome, alcoholism, tinnitus, generalized anxiety disorder, and repetitive and stereotypic self-injurious behaviors (SIB) in persons with developmental disabilities such as biting, skin-picking, hitting oneself, and head-banging.

[0239] In some embodiments, provided methods comprise reducing anxiety and/or agitation in a patient receiving a neuroleptic, anti-anxiety, or antidepressant medication.

[0240] In some embodiments, provided methods comprise reducing severity of or reducing or delaying the onset of a disease, disorder, syndrome condition. In some embodiments, provided methods comprise treating or selecting a particular patient, group or population of patients to receive treatment.

[0241] In some embodiments, provided methods comprise treating or selecting a patient in need of taking acamprosate or another medication described herein with food, without food, in a fed or in a fasted stated. In some embodiments, a patient is in a fed state. In some embodiments, a patient is in a fasted state. In some embodiments, a patient, group or population is susceptible to GI side effects of acamprosate and/or another medication, and needs to take the acamprosate and/or the another medication with or without food, and therefore desires to take the acamprosate and the another medication in the same manner.

[0242] In some embodiments, a patient, group or population is one that needs to take about 1000 mg, about 1500 mg, about 2000 mg, about 2500 mg, about 3000 mg, about 3500 mg or about 4000 mg of acamprosate daily.

[0243] In some cases, a patient, group or population is one susceptible to non-compliance with a treatment regimen comprising acamprosate and/or another medication, or one that needs a treatment regimen with fewer side effects in order to encourage or facilitate compliance. In some embodiments, a patient, group or population is one that needs to avoid or delay the onset of side effects of a neuroleptic treatment, such as the onset of TD. In some embodiments, a patient, group, or population is one that experiences anxiety or depression, and/or is taking a medication for anxiety or depression and needs to treat a condition.

[0244] In some embodiments, a patient, group, or population comprises pediatric patients. In some embodiments, a patient, group, or population comprises adolescent patients. In some embodiments, a patient, group, or population comprises elderly patients. In some embodiments, a patient, group, or population comprises patients that experience difficulty swallowing a pill (e.g., pediatric, adolescent, or elderly populations in need of treatment with acamprosate).

[0245] In some embodiments, a provided composition is administered once, twice or three times daily. In some embodiments, provided methods comprise, for example, administering to a patient in need thereof a total daily dosage of acamprosate of from about 500 mg to about 4000 mg per day. In some embodiments, a method comprises, for example, administering to a patient acamprosate at a daily dosage of about 1000 mg to about 2000 mg, about 2000 mg to about 3000 mg, or about 3000 mg to about 4000 mg, on a once-a-day schedule with or without food (i.e., in a fed or a fasted state). In some embodiments, a method comprises administering to a patient acamprosate at a daily dosage of 1000 mg to 4000 mg once a day with or without food (i.e., in a fed or a fasted state).

[0246] In some embodiments, a method comprises administering to a patient acamprosate at a daily dosage of about 1000 mg to about 2000 mg, about 2000 mg to about 3000 mg, or about 3000 mg to about 4000 mg, on a twice-a-day schedule with or without food (i.e., in a fed or a fasted state). In some embodiments, a method comprises administering to a patient acamprosate at a daily dosage of about 1000 mg to about 2000 mg, about 2000 mg to about 3000 mg, or about 3000 mg to about 4000 mg, on a thrice-a-day schedule with or without food (i.e., in a fed or a fasted state).

[0247] In some embodiments, provided methods comprise administering to a patient about 4000 mg of acamprosate per day. In some embodiments, provided method comprise administering to a patient about 3200 mg of acamprosate per day.

[0248] In some embodiments, provided methods comprise administering to a patient acamprosate in two tablet compositions twice a day wherein each tablet composition comprises about 800 mg to about 1000 mg of acamprosate (e.g., so that the patient is administered about 3200 mg to about 4000 mg of acamprosate per day). In some embodiments, once or twice daily acamprosate administration is at a dosage of about 1000 mg, less than or equal to 4000 mg, more than 1000 mg, or equal to or less than 3000 mg, (e.g., in a dosage of about 1000 mg to about 2000 mg, or about 2000 mg to about 3000 mg, or about 3000 mg to about 4000 mg).

[0249] Without being limited thereto, in some embodiments, acamprosate can be administered as one, two, three, or four units of a dosage form, for example, as one, two, three, or four tablet compositions. In some embodiments, a unit dosage form has a total weight of up to 1500 mg, (e.g., from about 1000 mg to about 1500 mg, from about 1100 mg to about 1300 mg, or from about 1100 mg to about 1200 mg). In some embodiments, a unit dosage form weight can be between about 400 mg and about 1500 mg, between about 800 mg and about 1200 mg, between about 1000 mg and about 1200 mg, between about 1100 mg and about 1200 mg, or any value or sub range within those ranges.

[0250] In some embodiments, provided methods comprises administering a composition comprising acamprosate to a patient in need thereof, wherein the patient is in a fed or fasted state, and the patient may choose to take each individual dose on each individual occasion in either the fed state or the fasting state. In some embodiments, a patient is administered a composition or a unit dose of a composition described herein in a fasted state. In some embodiments, a patient is administered a composition or a unit dose of a composition described herein in a fed state. In some embodiments, provided methods specifically exclude administration in the fasted or the fed state.

[0251] In some embodiments, a patient is administered a composition or a unit dose of a composition described herein immediately prior to food intake (e.g., within 30 minutes or within 60 minutes prior to taking food), with food, or soon after food intake (e.g., within 30 minutes, within 60 minutes or within 2 hours after food intake). In some embodiments, a patient is administered a composition or a unit dose of a composition described herein without food, for example, after an overnight fast, or not less than 30-60 minutes prior to a meal or not less than 1 hour, 2 hours, 3 hours after a meal, or more. In some embodiments, a patient is administered a composition or a unit dose of a composition described herein at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours or more after food intake, or any time there between. In some embodiments, a patient is administered a composition or a unit dose of a composition described herein at least 30 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours or more before food intake, or any time there between.

[0252] Without wishing to be bound by theory, due to fed/fasted equivalence of provided compositions, provided compositions provide flexibility to a patient with respect to when and/or how a provided composition is taken, which favors patient compliance. For example, in some embodiments, when a composition is given TID (e.g, three times a day), it can be taken, for example, with food for one or two doses and without food for one or two doses. In some embodiments, when a patient is already taking other medications, doses of the acamprosate compositions provided herein can be taken at the same time as the other medications. Most patients with neuropsychiatric disorders will be on other medications and may tolerate the other medication better if taken with or without food. Accordingly, in some embodiments, provided compositions are administered to a patient in need thereof in any suitable manner (e.g., with or without food).

[0253] In some embodiments, acamprosate is administered once or twice daily in order to achieve a particular total daily dosage, and a composition comprising acamprosate is formulated to release at least 50% of the acamprosate over a 2-8 hour period or any sub value or sub range there between. In some embodiments, at least 50% of the acamprosate is released within the first 4 hours. In some embodiments, at least 90% of the acamprosate is released from the composition within 8 hours.

Combination Therapy

[0254] The present disclosure also provides use of provided compositions in combination with one or more additional therapeutic agents. In some embodiments, methods described herein further comprise administering provided compositions of acamprosate with one or more additional therapeutic agents, such as first-generation neuroleptic (antipsychotic) drugs, second generation neuroleptic drugs, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), anti-nausea drugs, NMDA modulators, and/or an α.sub.2A adrenergic receptor agonists, or any combination thereof. In some embodiments, an additional therapeutic agent is administered with acamprosate in a fixed dose form or in separate dosage forms simultaneously or sequentially, such as at a different time, and/or on the same or different dosing schedule. As noted above, combination therapy (e.g., administering acamprosate in combination with one or more additional therapeutic agents) can provide benefits, such as increased patient compliance, increased therapeutic effects, and reduced side effects.

[0255] In some embodiments, provided compositions comprise acamprosate in a dose of from about 500 mg to about 4000 mg or from about 800 mg to about 1200 mg, and an additional therapeutic agent in a dose ranging from half of the lower end of its usual dosage range to the upper end of its dosage range. In some embodiments, a total daily dosage of acamprosate is from about 500 mg to about 4000 mg, or from about 1000 mg to about 4000 mg, or from about 1600 mg to about 4000 mg.

[0256] In some embodiments, provided methods comprise administering a fixed dose combination, comprising acamprosate and an additional therapeutic agent, to a patient in need thereof. In some embodiments, a fixed dose combination is used for treating any of the disorders treated with, for example, neuroleptic drugs, including schizophrenia, schizoaffective disorder, bipolar disorder, major depression, delusional disorder, organic psychoses, delirious agitation, or nausea and vomiting. In some such embodiments, a fixed dose combination is administered once-daily or twice-daily, typically with a single tablet composition given each time.

[0257] Without wishing to be bound by theory, for a given dosage of neuroleptic, a fixed dose combination as described herein can give equal or greater benefit for the neuropsychiatric disorder or symptoms being treated, compared to administration of the neuroleptic alone. Compared with the same dose of a first-generation neuroleptic given without acamprosate, fixed dose combinations described herein entail a lower risk of tardive dyskinesia and other tardive movement disorders, and result in movement disorder of lesser severity, if they cause one at all. In contrast with second-generation neuroleptics of equal therapeutic efficacy, a combination comprising a first generation neuroleptic and acamprosate may carry less risk of significant metabolic disturbances including weight gain, glucose intolerance, and increased risk of atherosclerotic cardiovascular disease.

[0258] The present disclosure also provides methods of reducing risk or delaying onset of tardive dyskinesia, the method comprising administering to a patient in need thereof a combination as described herein. In some embodiments, the method comprises administering to a patient in need thereof a composition comprising acamprosate and a neuroleptic medication.

[0259] In some embodiments, a method comprises administering to a patient in need thereof a composition comprising acamprosate and a first generation neuroleptic medication. At present the first-generation, high-potency neuroleptic medications are avoided because they are more likely than second-generation neuroleptic drugs to produce tardive dyskinesia. Nevertheless, first-generation neuroleptic medications are generally no less efficacious in treating psychosis than second-generation neuroleptic medications. In addition, second-generation neuroleptic medications usually are more expensive and have serious metabolic side effects with potentially life-threatening consequences. Accordingly, in some embodiments, a patient has tardive dyskinesia and requires continued neuroleptic therapy for a chronic mental disorder. In some embodiments, a patient has tardive dyskinesia and requires continued neuroleptic therapy with a first-generation neuroleptic medication for a chronic mental disorder.

[0260] In some embodiments, a method comprises administering to a patient in need thereof a composition comprising acamprosate and a second generation neuroleptic medication. Second-generation neuroleptic medications still carry some risk of TD. Accordingly, in some embodiments, a patient has tardive dyskinesia and requires continued neuroleptic therapy with a second-generation neuroleptic medication for a chronic mental disorder.

EXAMPLES

Example 1: Prior Fogel Formulations with Carbomer Homopolymer Type B

[0261] The present Example describes certain exemplary formulations described in the Prior Fogel Filings that utilize a carbomer homopolymer type B (specifically, Carbopol® 974) and achieve desirable manufacturability and delivery characteristics for a therapeutic agent (e.g., an acamprosate agent). These exemplary formulations were manufactured as 400 mg (Formulation 1) and 800 mg (Formulation 2) tablets. In some embodiments, these tablets were standard round bi-convex white tablets with beveled edges. Both tablet strengths were spray coated with Opadry® II White (Colorcon, Inc.) for ease of swallowing. Purified water is the vehicle for the Opadry; it evaporates during the coating process. The total weight of the coating was between 2% and 4% of the pre-coating weight.

[0262] The tablets prior to coating comprised the ingredients in the following table:

TABLE-US-00001 TABLE 1 Formu- Formu- lation 1 lation 2 Amount Amount Ingredient Function (mg) (mg) Acamprosate calcium Active ingredient 400 800 Povidone K-90 Binder 50 50 Microcrystalline cellulose Diluent 320 100 Colloidal silicon dioxide Glidant 10 10 Citric acid Acidulant 60 0 Carbopol ® 974P Polymer 60 60 Carboxymethyl cellulose Polymer 40 40 Starcap 1500 ® Disintegrant 40 40 Talc powder Filler 10 10 Magnesium stearate Lubricant 10 10 Total prior to coating 1000 1120

[0263] Dissolution profiles of these 400 mg and 800 mg acamprosate tablets were determined, and were reported in certain of the Prior Fogel Filings. Specifically, 400 mg or 800 mg tablets were dissolved in either acetate solution (pH 4.5) or 1N HCl (pH 1.0). The percentage of the active ingredient released into the solution was determined at 1, 2, 4, 6, 10, and 12 hours. Each release profile was assessed in six different test vessels. The following Tables 2-5 display the results, demonstrating that release is approximately linear with the square root of time, and furthermore demonstrating that the release is comparable across the pH range tested (i.e., pH 1.0 to pH 4.5). The fourth column in each Table displays the amount of drug that would be released if the release were exactly proportional to the square root of time, with a specified coefficient that ranges from 0.27 to 0.3.

TABLE-US-00002 TABLE 2 Release of Acamprosate from Formulation 1 in Acetate Solution (pH 4.5) (n = 6) Mean % S.D. of % Maxi- of Total 27% * of Total Minimum mum Time SQRT Drug SQRT Drug % % (hours) Time Released Time Released Released Released 0 0.0000 0.00 0.00 0.00 0 0 1 1.0000 24.09 27.00 1.40 23 27 2 1.4142 36.09 38.18 2.34 34 40 4 2.0000 54.39 54.00 4.02 49 60 6 2.4495 70.11 66.14 4.15 64 76 10 3.1623 87.67 85.38 4.21 83 95 12 3.4641 92.31 93.53 4.38 87 99

TABLE-US-00003 TABLE 3 Release of Acamprosate from Formulation 1 in 0.1N HCl (pH 1.0) (n = 6) Mean % S.D. of % Maxi- of Total 27% * of Total Minimum mum Time SQRT Drug SQRT Drug % % (hours) Time Released Time Released Released Released 0 0.0000 0.00 0.00 0.00 0 0 1 1.0000 31.60 27.00 1.58 24 27 2 1.4142 44.83 38.18 3.20 36 41 4 2.0000 63.20 54.00 4.42 56 62 6 2.4495 75.27 66.14 5.42 69 74 10 3.1623 91.31 85.38 3.59 85 91 12 3.4641 95.99 93.53 2.96 90 96

TABLE-US-00004 TABLE 4 Release of Acamprosate from Formulation 2 in Acetate Solution (pH 4.5) (n = 6) Mean % S.D. of % Maxi- of Total 30% * of Total Minimum mum Time SQRT Drug SQRT Drug % % (hours) Time Released Time Released Released Released 0 0.0000 0.00 0.00 0.00 0 0 1 1.0000 31.60 30.00 1.58 29 34 2 1.4142 44.83 42.43 3.20 42 51 4 2.0000 63.20 60.00 4.42 58 64 6 2.4495 75.27 73.48 5.42 70 84 10 3.1623 91.31 94.87 3.59 87 97 12 3.4641 95.99 100.00 2.96 91 100

TABLE-US-00005 TABLE 5 Release of Acamprosate from Formulation 2 in 0.1N HC1 (pH 1.0) (n = 6) Mean % S.D. of % Maxi- of Total 29% * of Total Minimum mum Time SQRT Drug SQRT Drug % % (hours) Time Released Time Released Released Released 0 0.0000 0.00 0.00 0.00 0 0 1 1.0000 28.11 29.00 1.21 26 29 2 1.4142 41.56 41.01 1.77 40 44 4 2.0000 61.48 58.00 2.38 57 63 6 2.4495 75.41 71.04 1.61 73 77 10 3.1623 92.24 91.71 0.55 92 93 12 3.4641 96.62 100.00 0.65 96 97

[0264] Table 6 describes % swelling and firmness characteristics of Formulation 2, evaluated as described in Example 5.

TABLE-US-00006 TABLE 6 % Swelling and firmness of tablets of Formulation 2 Property pH 1.0 pH 4.5 pH 6.8 % Swelling (length) 127% 119% 110% % Swelling (width) 158% 147% 150% Firmness 4.5 3 4

Example 2: Prior Fogel Formulations with Carbomer Homopolymer Type A

[0265] The present Example describes certain exemplary formulations described in the Prior Fogel Filings that utilize a carbomer homopolymer type A (specifically, Carbopol® 971) and achieve desirable manufacturability and delivery characteristics for a therapeutic agent (e.g., an acamprosate agent). In particular, Table 7 presents the ingredients included in tablets comprising various Prior Fogel Formulations.

TABLE-US-00007 TABLE 7 Amount (mg) Formu- Formu- Formu- lation lation lation Component Function 2 3 4 Acamprosate Active ingredient 800 800 800 Microcrystalline Diluent 100 — — Cellulose Carbopol ® 971P Polymer — 60 80 (Type A) Carbopol ® 974P Polymer 60 — — (Type B) Povidone K-90 Binder 50 50 50 CMC 7HF Polymer 40 40 20 Starcap 1500 ® Disintegrant 40 40 40 Colloidal Silicon Glidant 10 — — Dioxide Talc Powder Filler 10 10 10 Magnesium stearate Lubricant 10 10 10 Avicel ® PH102 Binder — 100 100 Cabosil Glidant — 10 10 Total prior to coating 1120 1120 1120

[0266] Table 8 displays the results of contacting the tablets described in Example 2 with either acetate solution (pH 4.5) or 0.1 N HCl (pH 1.0). In particular, (i) the swelling results are similar to those of Formulation 2 in Example 1; (ii) no erosion was observed; (iii) the % swelling is greater in Formulation 4 than in Formulation 3; and (iv) the swollen tablets are intact and firm for 6 hours during the swelling test. The results in Table 9 show that the dissolution profile is substantially proportional to the square root of time and is equivalent to the reference 800 mg tablets (Formulation 2) of Example 1.

TABLE-US-00008 TABLE 8 Swell test of 800 mg tablets of Formulations 3 and 4 Formulation 3 Formulation 4 Property HCl Acetate HCl Acetate Initial Length (cm) 1.28 1.28 1.28 1.28 Length 5 min (cm) 1.4 1.4 1.45 1.45 Length 30 min (cm) 1.5 1.5 1.55 1.5 Length 1 hr (cm) 1.55 1.52 1.6 1.52 Length 2 hr (cm) 1.65 1.55 1.7 1.55 Length 6 hr (cm) 1.9 1.65 1.95 1.7 % Swelling (length) 148% 129% 152% 133% Firmness Rating 4.5 4 4.8 4 Initial Thickness (cm) 0.77 0.78 0.78 0.78 Final Thickness (cm) 1.5 1.3 1.55 1.3 % Swelling (width) 195% 167% 199% 167%

Firmness Rating System:

[0267] 1. Shapeless after 6 hours in acid [0268] 2. Loosely retains shape, very soft [0269] 3. Retains shape, but offers no resistance [0270] 4. Can be picked up, slight resistance [0271] 5. Very firm and elastic

TABLE-US-00009 TABLE 9 Release Profiles at pH 1.0 and pH 4.5 Formu- Formu- Formu- lation lation lation pH Release Profile 2 3 4 1.0 % Dissolution (t = 1 h) 29.6 30.21 29.27 % Dissolution (t = 2 h) 42.1 42.22 44.21 % Dissolution (t = 4 h) 58.9 58.63 62.71 % Dissolution (t = 6 h) 71.3 70.15 74.75 % Dissolution (t = 10 h) 87 84.94 89.04 % Dissolution (t = 12 h) 91 88.14 92.79 f2 86.8 78.28 4.5 % Dissolution (t = 1 h) 30.9 36.41 34.24 % Dissolution (t = 2 h) 44.3 49.75 47.42 % Dissolution (t = 4 h) 61.6 68.76 64.53 % Dissolution (t = 6 h) 74.4 80.72 77.94 % Dissolution (t = 10 h) 89 93.94 92.93 % Dissolution (t = 12 h) 92 96.34 95.68 f2 61.9 72.29

Example 3: Preparation of Tablet Compositions

[0272] In work documented in the present Examples, tablet compositions prior to coating were prepared according to the following general two-step process: [0273] 1. Wet granulation step: Materials (“granular materials”) were weighed, sieved, and blended. Then, granulation was effected using purified water as the granulating agent to form wet granules. The wet granules were sieved and dried until the % LOD (loss on drying) was no more than 2%, resulting in the dry granules. [0274] 2. Extra-granulation step: The dry granules were sieved and blended with the additional materials (“extra-granular materials”). The final blend of the granules and extra-granular materials was compressed into tablets. In some cases, oval punches 0.758″×0.350″ embossed with “BK” on one side were used for compression.

[0275] The compressed tablets were evaluated for various parameters, including target weight, hardness, thickness, and friability.

[0276] In some aspects, the process further comprised a coating step. The coating step was performed on the compressed tablets. Various coating parameters for a pan coater (pan size: 12 inch) were used for coating: [0277] (1) Coating system: 20% Opadry® II white [0278] (2) Spray rate: 8 gm/min [0279] (3) Pan speed: 18 rpm [0280] (4) Pan load: 900 g [0281] (5) Air flow rate: 200 CFM [0282] (6) Pan differential pressure: −0.1 psi [0283] (7) Atomic air pressure: 30 psi [0284] (8) Pattern air pressure: 20 psi [0285] (9) Setting temperature: 48-58° C.; Inlet temperature: 44.0-63.0° C.; Exhaust temperature: 39.0-49.0° C.; and [0286] (10) Target weight gain: 2-4%.

Example 4: Preparation of Tablet Compositions as Single Oval Tablets

[0287] The process of Example 3 was used for preparing the Prior Fogel Formulations (Formulations 1 and 2 of Example 1 and Formulations 3 and 4 of Example 2). The tablets were standard round bi-convex white tablets with beveled edges. While this process can usefully provide desirable formulations for the preparation of round tablets, the present disclosure identifies a source of variability with the process when the process is used to prepare oval tablets. As disclosed above, oval tablets are desirable for a number of reasons, including ease of swallowing and increased patient compliance.

[0288] Attempts to make oval tablets using equivalent manufacturing process parameters for the preparation of Prior Fogel Formulations did not result in oval tablets with acceptable physical properties, i.e., the resulting oval tablets did not possess acceptable hardness (<2-3 kp) or friability (>3%).

[0289] The source of the problem was traced to the wet granulation step. In particular, granulation with purified water provided a wet powder mass that did not bind well and, as a result, led to overwetting of the material and routine clogging of the screen during sieving. Various modifications of the process parameters (e.g., reducing the speed of the granulator impeller and chopper, reducing the rate of water addition, etc.) did not lead to acceptable tablets.

[0290] Two alternative methods were then used to prepare granules: (i) extrusion or (ii) milling (e.g., with a Fitzmill) without a screen. Oval tablets prepared using either (i) extrusion or (ii) milling (e.g., with a Fitzmill) without a screen provided tablets with a hardness in an acceptable range of 15-18 kp and friability <1.0%. However, dissolution profiles of the resulting oval tablets from either of these processes indicated that, although physical properties comparable to the round tablets were achieved, the dissolution profile was somewhat faster (6-8 hours for 100% active agent release) with the oval tablets compared to the round tablets (8-10 hours for 100% active agent release) at both pH 1.0 (FIG. 1A) and pH 4.5 (FIG. 1B).

[0291] In addition to the use of (i) extrusion or (ii) milling (e.g., with a Fitzmill) without a screen, further modifications to the process were evaluated: [0292] (a) Addition of 40 mg carboxymethyl cellulose (CMC 7HF) to the granular materials instead of to the extra-granular materials resulted in a formulation that compressed well and provided tablets with acceptable physical properties, but still exhibited a faster release profile than that of Formulation 2. [0293] (b) Addition of 40 mg carboxymethyl cellulose (CMC 7HF) and 60 mg carbomer homopolymer type B to the granular materials instead of to the extra-granular materials resulted in a formulation that compressed well and provided tablets with acceptable physical properties. [0294] (c) Addition of 60 mg carbomer homopolymer type B to the granular materials instead of the extra-granular materials resulted in a formulation that did not compress well and provided tablets with poor physical properties. [0295] (d) Addition of an additional 40 mg carboxymethyl cellulose (CMC 7HF) to the formulation used to prepare Formulation 2, such that 40 mg CMC 7HF remained in the extra-granular materials and an additional 40 mg CMC 7HF was added to the granular materials, resulted in an oval tablet with acceptable physical properties and a release profile that closely matched that of Formulation 2.

[0296] The tablet resulting from modification (d) has an increased tablet weight of 1,160 mg absent any coating, as compared to 1,120 mg absent any coating for tablets of Formulation 2. Oval tablets prepared using modification (d) exhibited dissolution profiles at pH 1.0 (FIG. 2A) and pH 4.5 (FIG. 2B) that closely match those of Formulation 2.

[0297] Table 10 presents Formulation 5, the oval tablets prepared according to modification (d), described above.

TABLE-US-00010 TABLE 10 Formulation 5 Amount Component Function (mg) Granular Acamprosate Active 800 Materials Calcium ingredient (mg) Avicel ® Ph 102 (Microcrystalline Diluent 100 cellulose) Povidone K90 Binder 50 CMC 7HF Polymer 40 Colloidal Silicon Glidant 10 Dioxide Extra- Carbopol ® 974 P Polymer 60 Granular CMC 7HF Polymer 40 Materials Starcap 1500 Disintegrant 40 (mg) Talc powder Filler 10 Magnesium Stearate Lubricant 10 Total prior to coating 1160 Tablet Shape oval

[0298] Among other things, the present disclosure provides a solution to the above-identified problem and, furthermore, provides methodologies for developing and/or preparing formulations with acceptable physical properties and release profiles. For example, in some embodiments, the present disclosure describes a process in which granules are prepared and then combined with extra-granular materials before compression into tablets. In some embodiments, the present disclosure describes a process for formulating the Prior Fogel Formulations as oval tablets. In some embodiments, a process for formulating the Prior Fogel Formulations as oval tablets comprises the addition of 40 mg CMC 7HF to the granular materials, according to modification (d).

Example 5: Testing of Formulations

[0299] The Examples herein describe formulations of the present disclosure and demonstrate the physical characteristics of the tablets produced using such formulations. Characteristics assessed include, for example, dissolution profiles, erosion properties of the tablets, and swelling properties of the tablets.

[0300] The dissolution profiles of prepared formulations were compared to the reference product 800 mg tablets of Example 1 (Formulation 2). The prepared formulations were tested at pH 1.0 (0.1 N HCl), pH 4.5 (acetate buffer), and pH 6.8 (phosphate buffer) for up to 12 hrs. The f2 similarity factor was calculated using the following equation to determine the equivalent performance with the reference product Formulation 2:

f2=50.Math.log{[I+(1/n)l:t=1n(Rt−Tt)2]−0.5.Math.100}

The similarity factor is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) of dissolution between the two curves, where n is the number of time points, Rt is the dissolution value of the reference batch at time t, and Tt is the dissolution value of the test batch at time t.

[0301] The erosion properties of prepared formulations were assessed (n=4) as follows: initial weights of the individual tablets (Wi) were recorded and erosion studies were performed at pH 1.0 (0.1 N HCl), pH 4.5 (acetate buffer), and pH 6.8 (phosphate buffer) for 2 hr and/or 6 hr. Tablets were carefully removed from the medium and dried at 55° C. overnight. The individual dried final weights were recorded (Wt). The % of the material eroded is calculated by the following formula:

% Erosion=(Wf−Wi)/Wi*100%

[0302] The swelling properties of prepared formulations were assessed (n=3) as follows: the initial length and thickness were recorded and the swelling test was performed at pH 1.0 (0.1 N HCl), pH 4.5 (acetate buffer), and pH 6.8 (phosphate buffer) for up to 6 hr. % Swelling of the length and thickness were recorded. Firmness was determined on a 1-5 scale, as described in Example 2.

[0303] The results of the above assessments are included and described in the following examples which detail provided formulations with carbomer homopolymers.

Example 6: Formulations with Carbomer Homopolymer Type B

[0304] This Example summarizes exemplary useful compositions provided by the present disclosure that meet certain performance requirements as described herein.

[0305] In particular, Table 11 presents the ingredients included in various provided formulations, prepared according to a two-step procedure as described above in Example 3. Release profiles for 800 mg tablets prepared from Formulations 6-8 were obtained and the data are presented in Tables 11-15. The data were consistent with the release data for the reference Formulation 2 at the three pH values tested. Additionally, the 800 mg tablets prepared from Formulations 6-8 demonstrated suitable swelling properties and firmness as is shown in Table 15.

TABLE-US-00011 TABLE 11 Amount (mg) Formulation Formulation Formulation Component Function 6 7 8 Granular Acamprosate Active 800 800 800 Materials Calcium ingredient (mg) Avicel ® Ph 102 — 100 — (Microcrystalline Diluent cellulose) Povidone K90 Binder 50 40 40 EUDRAGIT ® Polymer — 10 10 FS 30D* Sugar Spheres Carrier 100 — 100 Colloidal Silicon Glidant 10 10 10 Dioxide Extra- Carbopol ® 974P Polymer 90 90 90 Granular CMC 7HF Polymer 10 — — Materials Starcap 1500 Disintegrant — 10 10 (mg) Gelatin Type B Polymer 40 40 40 Talc powder Filler 10 10 10 Magnesium Stearate Lubricant 10 10 10 Total prior to coating (mg) 1120 1120 1120 Tablet Shape oval oval oval

TABLE-US-00012 TABLE 12 Release profiles of tablets in 0.1N HCl (pH 1.0) Formu- Formu- Formu- Release Profile (pH 1.0) lation 6 lation 7 lation 8 % Erosion (t = 2 h) 26.25 29.88 28.76 % Dissolution (t = 1 h) 28.47 31.12 28.78 % Dissolution (t = 2 h) 42.02 44.06 40.51 % Dissolution (t = 4 h) 61 62.46 57.94 % Dissolution (t = 6 h) 77.24 78.25 77.41 % Dissolution (t = 10 h) 92.3 93.85 90.95 % Dissolution (t = 12 h) 95.12 98.33 95.75 f2 71.59 64.4 72.4 Y-intercept, SQRT 1.5699 2.4211 0.9569 Slope, SQRT 28.551 28.993 28.513 R{circumflex over ( )}2, SQRT 0.9902 0.9929 0.9917

TABLE-US-00013 TABLE 13 Release profiles of tablets in acetate solution (pH 4.5) Formu- Formu- Formu- Release Profile (pH 4.5) lation 6 lation 7 lation 8 % Erosion (t = 2 h) 27.21 43.44 28.42 % Dissolution (t = 1 h) 34.98 38.05 36.44 % Dissolution (t = 2 h) 51.44 52.42 51.93 % Dissolution (t = 4 h) 73.55 74.03 73.16 % Dissolution (t = 6 h) 88.39 87.87 90.32 % Dissolution (t = 10 h) 95.36 96.5 96.6 % Dissolution (t = 12 h) 96.71 98.1 98.63 f2 52.88 51.25 50.64 Y-intercept, SQRT 7.4475 8.3906 7.5718 Slope, SQRT 28.784 28.779 29.212 R{circumflex over ( )}2, SQRT 0.9529 0.9568 0.9556

TABLE-US-00014 TABLE 14 Release profiles of tablets in phosphate solution (pH 6.8) Formu- Formu- Formu- Release Profile (pH 6.8) lation 6 lation 7 lation 8 % erosion (t = 2 h) 20.67 34.52 20.75 % Dissolution (t = 1 h) 27.3 28 28.47 % Dissolution (t = 2 h) 35.59 37.23 37.85 % Dissolution (t = 4 h) 41.68 44.75 45.49 % Dissolution (t = 6 h) 46.93 51.57 52.43 % Dissolution (t = 10 h) 54.6 59.62 60.61 % Dissolution (t = 12 h) 58.54 65.6 66.7 f2 75.43 83.77 77.6 Y-intercept, SQRT 7.5381 6.8017 6.9146 Slope, SQRT 15.706 17.728 18.024 R{circumflex over ( )}2, SQRT 0.9431 0.9618 0.9618

TABLE-US-00015 TABLE 15 % Swelling and firmness of tablets Property Conditions Formulation 6 Formulation 7 Formulation 8 % 0.1N HCl, pH 1.0 127% 130% 127% Swelling Acetate Buffer, pH 4.5 112% 115% 117% (length) Phosphate Buffer, pH 6.8 115% 116% 121% % 0.1N HCl, pH 1.0 167% 166% 165% Swelling Acetate Buffer, pH 4.5 140% 154% 138% (thickness) Phosphate Buffer, pH 6.8 140% 152% 150% Firmness 0.1N HCl 4.50 4.80 4.50 Acetate Buffer, pH 4.5 3.80 3.80 3.80 Phosphate Buffer, pH 6.8 4.20 4.20 4.20

Example 7: Formulations with Carbomer Homopolymer Type C

[0306] This Example summarizes exemplary useful compositions provided by the present disclosure that meet certain performance requirements as described herein.

[0307] In particular, Table 16 presents the ingredients included in various provided formulations, prepared according to a two-step procedure as described above in Example 3. As can be seen in the release profile data in Table 17, Formulations 9-11 have release data that were equivalent to the reference Formulation 2. Formulation 12, which uses 140 mg carbomer homopolymer type C had a slower release rate as compared to the reference. Further release profile data were obtained for Formulation 9 at pH 4.5 and 6.8; these data were also equivalent to the reference Formulation 2, as shown in Tables 18 and 19. In addition, the tablet of Formulation 9 demonstrated acceptable swelling and firmness as shown in Table 20.

TABLE-US-00016 TABLE 16 Carbomer Type C Formulations Amount (mg) Formu- Formu- Formu- Formu- Component Function lation 9 lation 10 lation 11 lation 12 Granular Acamprosate Active 800 800 800 800 Materials Calcium ingredient Avicel ® Ph 102 Diluent 100 100 100 100 Povidone K90 Binder 50 50 50 50 Colloidal Silicon Glidant 10 10 10 10 Dioxide Extra- Carbopol ® 980P Polymer 60 90 30 140 Granular CMC 7 HF Polymer 40 40 40 — Materials Starcap 1500 ® Disintegrant 40 10 70 — Talc Filler 10 10 10 10 Magnesium Lubricant 10 10 10 10 Stearate Tablet Shape Circular Circular Circular Circular Tablet prior to coating 1120 1120 1120 1120

TABLE-US-00017 TABLE 17 Release Profiles of Tablets at pH 1.0 Formu- Formu- Formu- Formu- lation lation lation lation Release Profile 9 10 11 12 % Erosion (t = 2 h) 31.7 — — — % Erosion (t = 6 h) 48.6 — — — % Dissolution (t = 1 h) 31.47 30.84 35.62 24.69 % Dissolution (t = 2 h) 45.51 42.08 49.91 33.99 % Dissolution (t = 4 h) 62.64 58.28 68.28 45.41 % Dissolution (t = 6 h) 75.03 72.24 80.64 55.22 % Dissolution (t = 10 h) 90.22 88.31 93.03 69.85 % Dissolution (t = 12 h) 95.15 93.24 97.32 77.93 f2 73.34 92.2 56.06 44.1 Y-intercept, SQRT 3.8629 2.7275 6.5376 1.5118 Slope, SQRT 27.648 27.123 28.097 21.98 R{circumflex over ( )}2, SQRT 0.9904 0.9951 0.9774 0.9984

TABLE-US-00018 TABLE 18 Release Profiles of Tablets at pH 4.5 Release Profile Formulation 9 % Erosion (t = 2 h) 37.9 % Erosion (t = 6 h) 61.5 % Dissolution (t = 1 h) 36.58 % Dissolution (t = 2 h) 50.13 % Dissolution (t = 4 h) 66.59 % Dissolution (t = 6 h) 77.53 % Dissolution (t = 10 h) 95.12 % Dissolution (t = 12 h) 98.92 f2 63.26 Y-intercept, SQRT 6.0574 Slope, SQRT 28.352 R{circumflex over ( )}2, SQRT 0.9857

TABLE-US-00019 TABLE 19 Release Profiles of Tablets at pH 6.8 Release Profile Formulation 9 % Erosion (t = 2 h) 38.28 % Erosion (t = 6 h) 58.45 % Dissolution (t = 1 h) 26.92 % Dissolution (t = 2 h) 31.17 % Dissolution (t = 4 h) 36.78 % Dissolution (t = 6 h) 42.01 % Dissolution (t = 10 h) 50.6 % Dissolution (t = 12 h) 53.87 f2 58.6 Y-intercept, SQRT 6.8707 Slope, SQRT 14.326 R{circumflex over ( )}2, SQRT 0.9451

TABLE-US-00020 TABLE 20 % Swelling and Firmness of Tablets Conditions Formulation 9 % Swelling 0.1N HCl, pH 1.0 129% (length) Acetate Buffer, pH 4.5 117% Phosphate Buffer, pH 6.8 114% % Swelling 0.1N HCl, pH 1.0 172% (thickness) Acetate Buffer, pH 4.5 146% Phosphate Buffer, pH 6.8 148% Firmness 0.1N HCl, pH 1.0 4.5 Acetate Buffer, pH 4.5 3.8 Phosphate Buffer, pH 6.8 4.0

Example 8: Formulations with Polyethylene Oxide

[0308] This Example summarizes the failure of compositions utilizing polyethylene oxide to meet certain performance requirements as described herein.

[0309] In particular, Table 21 presents the ingredients included in various provided formulations, prepared according to a two-step procedure as described above in Example 3.

TABLE-US-00021 TABLE 21 Amount (mg) Formu- Formu- Component Function lation 13 lation 14 Granular Acamprosate Active 800 800 Materials Calcium Avicel ® Ph 102 Diluent 100 100 Povidone K90 Binder 50 50 Colloidal Silicon Glidant 10 10 Dioxide Extra- CMC 7 HF Polymer 40 Granular Starcap 1500 Disintegrant 40 Materials PEO 303 Polymer 60 140 Talc Filler 10 10 Magnesium Lubricant 10 10 Stearate Tablet Shape oval oval Tablet prior to coating 1120 1120

[0310] Formulations 13 and 14 failed to meet the performance requirements at pH 1.0. Formulation 13 rapidly eroded in 0.1 N HCl, and % Erosion at t=2 h could not be measured. The dissolution profile of Formulation 13 also could not be measured over 12 hours, as only about 10% of the solid remained after 2 hours. Similarly, the dissolution profile of Formulation 14 could not be measured either, and after only 1 hour in 0.1 N HCl, the tablet fell apart when picked up. As a result, Formulations 13 and 14 were not further tested. These results demonstrate that not all polymers provide suitable formulations for the production of extended release tablets.

Example 9: Formulations with Methylcellulose

[0311] This Example summarizes the failure of compositions utilizing methylcellulose to meet certain performance requirements as described herein.

[0312] In particular, Table 22 presents the ingredients included in various formulations, prepared according to a two-step procedure as described above in Example 3. As can be seen in the release profile data in Table 23, the 800 mg tablets from Formulation 15 performed similarly to the reference Formulation 2 with a dissolution f2 of 64.6. However, the tablet's gel was much weaker than the reference tablet and therefore Formulation 15 failed to meet the performance requirements. As a result, the 800 mg tablets of Formulation 15 were not further tested. The result below demonstrates that although a polymer may provide release data equivalent to the reference tablet, it may fail in other aspects of the requirements such as gel formation and therefore be unsuitable for the production of extended release tablets.

TABLE-US-00022 TABLE 22 Amount (mg) Component Function Formulation 15 Granular Acamprosate Calcium Active 800 Materials Avicel ® Ph 102 Diluent 100 Povidone K90 Binder 50 Colloidal Silicon Glidant 10 Dioxide Extra- METHOCEL ® K100M Polymer 140 Granular Talc Filler 10 Materials Magnesium Stearate Lubricant 10 Tablet Shape oval Tablet prior to coating 1120

TABLE-US-00023 TABLE 23 Release Profile of Tablet at pH 1.0 Release Profile Formulation 15 % Erosion (t = 2 h) 35.88 % Erosion (t = 6 h) (weak gel) % Dissolution (t = h) 35.08 % Dissolution (t = 2 h) 48.82 % Dissolution (t = 4 h) 65.24 % Dissolution (t = 6 h) 76.77 % Dissolution (t = 10 h) 89.44 % Dissolution (t = 12 h) 92.49 f2 64.56 Y-intercept, SQRT 6.9063 Slope, SQRT 26.649 R{circumflex over ( )}2, SQRT 0.9752

Example 10: Additional Formulations

[0313] This Example summarizes results obtained with compositions prepared with various polymer components (e.g., in a polymer matrix); as can be seen, several such compositions failed one or more performance parameters. For example, several compositions could not be effectively formulated into tablets with appropriate properties. For example, several compositions could not be effectively formulated into tablets that showed a release profile comparable to that of Formulation 2. Alternatively or additionally, several compositions could not be effectively formulated into tablets with appropriate erosion characteristics (e.g., prepared tablets showed significant erosion within 2 hours when placed under acidic conditions in 0.1 N HCl).

[0314] For example, certain compositions utilizing carbomer homopolymer type B and Poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1, (i.e., Eudragit® FS 30 D) failed to meet certain performance requirements as described herein. Multiple different formulations were tested with various combinations of carbomer homopolymer type B and Poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1, (i.e., Eudragit® FS 30 D). It was found that most such combinations failed due to unacceptable swelling and erosion results of the resulting tablets. Further, it was found that the above tested formulations failed to provide suitable dissolution profiles. It is worth noting that carbomer homopolymer type B was always present in an amount that was less than about 5.4 wt % of the tablet (and in a ratio of less than about 0.075:1 with respect to acamprosate calcium) in these failing tablets.

[0315] For example, certain compositions utilizing poly(ethylene) oxide (i.e., Polyox™ WSR-303) or cellulose ethers (i.e., METHOCEL™ K15M or METHOCEL™ K100M) failed to meet certain performance requirements as described herein. Multiple different formulations were tested with poly(ethylene) oxide (i.e., PEO 303 or Polyox™ WSR-303) or cellulose ethers (i.e., METHOCEL™ K15M or METHOCEL™ K100M). It was found that most of the formulations failed due to unacceptable swelling and erosion results of the resulting tablets. Further, it was found that the above tested formulations failed to provide suitable dissolution profiles. It is worth noting that the polyethylene oxide (i.e., PEO 303 or Polyox™ WSR-303) or cellulose ethers (i.e., METHOCEL™ K15M or METHOCEL™ K100M) was always present in an amount that was less than about 12.5 weight percent of the tablet (and in a ratio of less than 0.175:1 with respect to acamprosate) in these failing tablets.

[0316] In general, tablet compositions were considered to have failing swelling and erosion characteristics if the tablet did not remain intact over 12 hours in 0.1 N HCl (pH 1.0), acetate buffer (pH 4.5), and phosphate buffer (pH 6.8).

[0317] In general, compositions were considered to have failing release profile characteristics if they failed to provide a release profile comparable to 800 mg tablets of Example 1 (Formulation 2).

Example 11: Preparation of Tablet Compositions Comprising Mini-Tablets

[0318] The process of Example 3 will be used to prepare mini-tablets comprising formulations described herein: [0319] 1. Wet granulation step: Materials (“granular materials”) will be weighed, sieved, and blended. Then, granulation will be effected using purified water as the granulating agent to form wet granules. The wet granules will be sieved and dried until the % LOD (loss on drying) is no more than 2%, resulting in the dry granules. [0320] 2. Extra-granulation step: The dry granules will be sieved and blended with the additional materials (“extra-granular materials”). The final blend of the granules and extra-granular materials will be compressed into mini-tablets.

[0321] The compressed mini-tablets will be evaluated for various parameters, including target weight, hardness, thickness, and friability.

[0322] In some embodiments, the process will further comprise a coating step.

[0323] In some embodiments, the process will further comprise an encapsulation step to provide a capsule comprising a plurality of mini-tablets.

EQUIVALENTS

[0324] The herein described subject matter sometimes illustrates different methods, compositions and/or components contained within, or combined with, different other methods, compositions and/or components. It is to be understood that the various described methods, compositions, components, and combinations of the same are merely provided as non-limiting examples, and that in fact many others can be implemented which achieve the same purposes and/or functionality. Additional non-limiting examples of polymers that can be utilized with the formulations and compositions described herein are found in PHARMACEUTICAL POLYMERS in MARTIN'S PHYSICAL PHARMACY AND PHARMACEUTICAL SCIENCES, Sixth Edition 2010, by Patrick J. Sinko and published by Wolters Kluwer, ISBN: 9780781797665, at Chapter 20, pp 492-515; which is incorporated herein by reference in its entirety.

[0325] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity.

[0326] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and/or “an” should typically be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should typically be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, typically means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”

[0327] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the embodiments of the technology.

[0328] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present embodiments are not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed. The subject matter disclosed in the publications, including any methods, compositions, excipients (including ranges and dosages of the same), etc., are incorporated herein by reference in their entireties.

[0329] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. The scope of the present invention is not intended to be limited to the above Description, but rather is as set forth in the following claims: