Oral administration of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)alkyl] phosphonic acid and derivatives

• US 20050142192A1
• Filed: 10/08/2004
• Published: 06/30/2005
• Est. Priority Date: 10/15/2003
• Status: Abandoned Application

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Islam, Mohammed, Tremblay, Gerald F., Cloud, William F., Benjamin, Eric J., Ashraf, Muhammad, Brandt, Michael R.
• Application Number:
  US10/961,871
• Publication Number:
  US 20050142192A1
• Time in Patent Office: Days
• US Class Current: 424/464
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

Solid, pharmaceutical dosage forms of [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en-2-yl)alkyl]phosphonic acid and derivatives thereof are disclosed. In addition, methods of use are disclosed for the treatment, inter alia, of cerebral vascular disorders, anxiety disorders; mood disorders; schizophrenia; schizophreniform disorder; schizoaffective disorder; cognitive impairment; chronic neurodegenerative disorders; inflammatory diseases; fibromyalgia; complications from herpes zoster; prevention of tolerance to opiate analgesia; withdrawal symptoms from addictive drugs; and pain.

Claims

1. A solid, pharmaceutical dosage form, comprising:

at least one compound of formula (I) or a pharmaceutically acceptable salt thereof;

wherein;

R₁ is hydrogen, a C₁ to C₆ alkyl group, a C₂ to C₇ acyl group, a C₁ to C₆ alkanesulfonyl group, or a C₆ to C₁₄ aroyl group;

A is alkylenyl of 1 to 4 carbon atoms or alkenylenyl of 2 to 4 carbon atoms;

R₂ and R₃ are independently selected from hydrogen,

with the proviso that at least one of R₂ and R₃ is other than hydrogen;

R₄ and R₅ are independently selected from hydrogen, a C₁ to C₄ alkyl group, a C₅ to C₇ aryl group, a C₆ to C₁₅ aralkyl group having 5 to 7 carbon atoms in the aryl ring, a C₂ to C₇ alkenyl group, or C₂ to C₇ alkynyl group, or R₄ and R₅ may together form a spiro C₃ to C₈ carbocyclic ring;

R₆ is a C₁ to C₁₂ linear or branched alkyl group, a C₂ to C₇ linear or branched alkenyl or alkynyl group, a C₅ to C₁₃ aryl group, a C₆ to C₂, aralkyl group having 5 to 13 carbon atoms in the aryl moiety;

a 5 to 13 membered heteroaryl group, a 6 to 21 membered heteroaralkyl group having 5 to 13 members in the heteroaryl moiety, a C₄ to C₈ cycloalkyl group, a C₅ to C₁₆ cycloalkylalkyl group having 4 to 8 carbon atoms in the cycloalkyl ring;

R₇ and R₈ are independently selected from hydrogen, a C₁ to C₁₂ linear or branched alkyl group, a C₂ to C₇ linear or branched alkenyl or alkynyl group, a C₅ to C₁₃ aryl group, a C₆ to C₂, aralkyl group having 5 to 13 carbon atoms in the aryl moiety, a 5 to 13 membered heteroaryl group, a 6- to 21-membered heteroaralkyl group having 5 to 13 members in the heteroaryl moiety, or R₇ and R₈ may together form a cycloalkyl or heterocycloalkyl group having in the ring 4 to 8 carbon atoms and optionally one to two atoms selected from nitrogen, oxygen or sulfur;

wherein any R₁ to R₈ group having an aryl, heteroaryl, cycloalkyl or heterocycloalkyl moiety may optionally be substituted on the aryl, heteroaryl, cycloalkyl or heterocycloalkyl moiety with 1 to about 5 substituents independently selected from a halo, a cyano, nitro or hydroxyl group, a C₁ to C₆ alkyl group, or a C₁ to C₆ alkoxy group; and

at least one pharmaceutically acceptable absorption enhancer.

3. A dosage form according to claim 1 or 2 that is a powder, a capsule or a tablet.

4. A dosage form according to claim 1 or 2 that is an enteric-coated capsule or an enteric-coated tablet.

5. A dosage form according to claim 4 that comprises an anionic polymer selected from the group consisting of a methacrylic acid copolymer, cellulose acetate phthalate, hydroxpropylmethylcellulose phthalate, polyvinyl acetate phthalate, shellac, hydroxpropylmethylcellulose acetate succinate, and carboxy-methylcellulose.

6. A dosage form according to claim 1 or 2 that is an immediate release capsule or an immediate release tablet.

7. A dosage form according to claim 1 or 2 comprising about 25% by weight to about 99.5% by weight, based on the total weight of said dosage form, of said compound of formula (I).

8. A dosage form according to claim 7 comprising about 50% by weight to about 99.5% by weight, based on the total weight of said dosage form, of said compound of formula (I).

9. A dosage form according to claim 8 comprising about 60% by weight to about 99.5% by weight, based on the total weight of said dosage form, of said compound of formula (I).

10. A dosage form according to claim 9 comprising about 70% by weight to about 99.5% by weight, based on the total weight of said dosage form, of said compound of formula (I).

11. A dosage form according to claim 1, wherein R₁ is H or a C₁ to C₄ alkyl group.

12. A dosage form according to claim 1, wherein A is an alkylenyl group having the formula —

(CH₂)_n—

, where n is 1 to 3.

13. A dosage form according to claim 1, wherein R₂ is H.

14. A dosage form according to claim 1, wherein R₄ and R₅ are independently H or a C₁ to C₄ alkyl group, and R₆ is a C₃ to C₁₀ linear or branched alkyl group, a C₅ to C₇ aryl group, a 5- to 7-membered heteroaryl group, or a cycloalkyl group having in the ring 5 to 7 carbon atoms.

15. A dosage form according to claim 14, wherein R₆ is a C₅ to C₇ aryl group.

16. A dosage form according to claim 1, wherein R₂ and R₃ are both hydrogen.

17. A dosage form according to claim 1, wherein at least one of said compounds of formula (I) is:

3-{2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}-3-oxido-7-oxo-7-phenyl-2,4,6-trioxa-3-phosphahept-1-yl benzoate;

3-{2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}-3-oxido-7-oxo-8-propyl-2,4,6-trioxa-3-phosphaundec<sup>−

1</sup>-yl 2-propylpentanoate;

2,2-dimethyl-propionic acid (2,2-dimethyl-propionyloxymethoxy)-[2-(8,9-dioxo-2,6-diaza-bicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]-phosphinoyloxymethyl ester;

7-cyclohexyl-3-{2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}-1,5-dimethyl-3-oxido-7-oxo-2,4,6-trioxa-3-phosphahept-1-yl cyclohexanecarboxylate;

7-cyclohexyl-3-{2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}-3-oxido-7-oxo-2,4,6-trioxa-3-phosphahept-1-yl cyclohexanecarboxylate;

[2-(8,9-dioxo-2,6-diaza-bicyclo[5.2.0]non-1-(7)-en-2-yl)-ethyl]-phosphonic acid diisopropoxycarbonyl oxymethyl ester;

[2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl]-phosphonic acid bis [1-(benzoyloxy)ethyl] ester;

benzoic acid [2-(8,9-dioxo-2,6-diaza-bicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]-hydroxy-phosphinoyloxymethyl ester;

[2-(8,9-dioxo-2,6-diaza-bicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]-phosphonic acid di-dimethylcarbamoyloxymethyl ester;

or a pharmaceutically acceptable salt thereof.

18. A dosage form according to claim 1 comprising about 0.25 weight % to about 50 weight %, based on the total weight of said dosage form, of said absorption enhancer.

19. A dosage form according to claim 1 or 2, wherein said pharmaceutically acceptable absorption enhancer is surfactant, bile salt, fatty acid, fatty acid salt, chelating agent, acyl carnitine, acyl choline, or a mixture thereof.

20. A dosage form according to claim 19, wherein said surfactant is ionic surfactant, nonionic surfactant, or a mixture thereof.

21. A dosage form according to claim 20, wherein said ionic surfactant is sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or a mixture thereof.

22. A dosage form according to claim 20, wherein said nonionic surfactant is polyoxyethylene alkyl ether, polyoxyethylene alkyl ester, polysorbate, or a mixture thereof.

23. A dosage form according to claim 22, wherein said polyoxyethylene alkyl ester is polyethylene glycol-20 sorbitan monooleate.

24. A dosage form according to claim 19, wherein said bile salt is sodium cholate, sodium deoxycholate, or a mixture thereof.

25. A dosage form according to claim 19, wherein said fatty acid is oleic acid.

26. A dosage form according to claim 19, wherein said fatty acid salt is sodium caprate.

27. A dosage form according to claim 19, wherein said chelating agent is ethylenediaminetetraacetic acid.

28. A dosage form according to claim 19, wherein said acyl carnitine is palmitoyl carnitine.

29. A dosage form according to claim 19, wherein said acyl choline is lauroyl choline.

30. A dosage form according to claim 1 or 2, further comprising a filler, disintegrant, binder, lubricant, or a mixture thereof.

31. A dosage form according to claim 30, wherein said filler is lactose, microcrystalline cellulose, mannitol, calcium phosphate, pregelatinized starch, pregelatinized sucrose, or a mixture thereof.

32. A dosage form according to claim 30, wherein said disintegrant is croscarmellose sodium, starch, sodium starch glycolate, pregelatinized starch, crospovidone, or a mixture thereof.

33. A dosage form according to claim 30, wherein said binder is povidone, hydroxypropylmethylcellulose, gelatin, gum, or a mixture thereof.

34. A dosage form according to claim 30, wherein said lubricant is magnesium stearate, sodium stearyl fumarate, or a mixture thereof.

35. A single dosage form, comprising the dosage form according to claim 1 or 2.

36. A multiple dosage form, comprising the dosage form according to claim 1 or 2.

37. A method for treating at least one condition in a mammal selected from a cerebral vascular disorder selected from cerebral ischemia, cerebral infarction or cerebral vasospasm;

cerebral trauma;

muscular spasm;

a convulsive disorder selected from epilepsy or status epilepticus;

hypoglycemia;

cardiac arrest;

asphyxia anoxia;

or spinal chord injury, comprising the step of;

administering orally to a mammal in need thereof an effective amount of the dosage form according to claim 1 or 2.

38. A method for treating at least one condition in a mammal selected from glaucoma or diabetic end organ complications, comprising the step of:

administering orally to a mammal in need thereof an effective amount of the dosage form according to claim 1 or 2.

39. A method for treating at least one condition in a mammal selected from anxiety disorders;

mood disorders;

schizophrenia;

schizophreniform disorder;

or schizoaffective disorder, comprising the step of;

administering orally to a mammal in need thereof an effective amount of the dosage form according to claim 1 or 2.

40. A method as claimed in claim 39, wherein the anxiety disorder is selected from panic attack, agoraphobia, panic disorder, specific phobia, social phobia, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, separation anxiety disorder, or substance-induced anxiety disorder;

or the mood disorder is selected from bipolar disorders, depressive disorders selected from major depressive disorder, dysthymic disorder, or substance-induced mood disorder, or mood episodes selected from major depressive episode, manic episode, mixed episode, or hypomanic episode.

41. A method for treating at least one neurodegenerative disorder in a mammal selected from Huntingdon'"'"'s disease, Alzheimer'"'"'s disease, amyotrophic lateral sclerosis, chronic dementia, or cognitive impairment, comprising the step of:

administering orally to a mammal in need thereof an effective amount of the dosage form according to claim 1 or 2.

42. A method for treating Parkinson'"'"'s disease, comprising the step of:

administering orally to a mammal in need thereof an effective amount of the dosage form according to claim 1 or 2.

43. A method for treating at least one condition in a mammal selected from inflammatory diseases;

fibromyalgia;

complications from herpes zoster;

prevention of tolerance to opiate analgesia;

or withdrawal symptoms from addictive drugs, comprising the step of;

administering orally to a mammal in need thereof an effective amount of the dosage form according to claim 1 or 2.

44. A method for treating pain in a mammal, comprising the step of:

administering orally to a mammal in need thereof an effective amount of the dosage form according to claim 1 or 2.

45. A method according to claim 44 further comprising administering a therapeutically effective amount of at least one pain relieving agent.

46. A method according to claim 44, wherein the pain is at least one of neuropathic pain;

cancer pain;

visceral pain associated with pancreatitis or abdominal, pelvic or perineal regions;

musculoskeletal pain associated with lower or upper back, spine, fibromylagia, temporomandibular joint, or myofascial pain syndrome;

bony pain associated with bone or joint degenerating disorders;

headaches;

or pain associated with infections, sickle cell anemia, autoimmune disorders, multiple sclerosis, dental procedures, burns or inflammation.

47. A method according to claim 46, wherein the pain comprises neuropathic pain and is associated with at least one of diabetic neuropathy, peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, casualgia, thalamic syndrome, nerve root avulsion, or nerve damage cause by injury selected from phantom limb pain, reflex sympathetic dystrophy or postthoracotomy pain, cancer, chemical injury, toxins, nutritional deficiencies, or viral or bacterial infections.

48. A method according to claim 46, wherein said pain is small fiber neuropathy.

49. A method according to claim 46, wherein said pain is large fiber neuropathy.

50. A method according to claim 46, wherein said pain is peripheral neuropathy.

51. A method according to claim 46, wherein said pain is central neuropathy.

52. A method according to claim 46, wherein said pain is post herpetic neuralgia.

53. A method according to claim 46, wherein said pain is post-surgical pain.

54. A solid, immediate release pharmaceutical composition, comprising:

at least one compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof wherein said composition has a bulk density of at least about 0.5 g/cm³.

55. A solid, immediate release pharmaceutical composition according to claim 54, wherein said composition has a bulk density of at least about 0.8 g/cm³.

56. A solid, immediate release pharmaceutical composition according to claim 54, wherein said composition is granular.

57. A solid, immediate release pharmaceutical composition according to claim 54,

wherein said solid composition further comprises at least one binder.

58. A solid, immediate release pharmaceutical composition according to claim 57,

wherein said binder is povidone.

59. A solid, immediate release pharmaceutical composition according to claim 58,

wherein said povidone is present at a level of at least about 1.5% by weight, based on the total weight of said composition.

60. A solid, immediate release pharmaceutical composition according to claim 59,

wherein said povidone is present at a level of at least about 2.5% by weight, based on the total weight of said composition.

61. A solid, immediate release pharmaceutical composition according to claim 54,

wherein said solid composition further comprises at least one disintegrant or filler.

62. A solid, immediate release pharmaceutical composition according to claim 61,

wherein said filler is microcrystalline cellulose.

63. A solid, immediate release pharmaceutical composition according to claim 61,

wherein said disintegrant is croscarmellose sodium.

64. A solid, pharmaceutical dosage form, comprising:

the solid, immediate release pharmaceutical composition according to claim 54.

65. A dosage form according to claim 64 that is a capsule or a tablet.

66. A single dosage form, comprising the dosage form according to claim 64.

67. A multiple dosage form, comprising the dosage form according to claim 64.

68. A capsule, comprising:

granular particles comprising the solid, immediate release pharmaceutical composition according to claim 54.

69. A tablet, comprising:

granular particles comprising the solid, immediate release pharmaceutical composition according to claim 54.

70. A method for treating at least one condition in a mammal selected from a cerebral vascular disorder selected from cerebral ischemia, cerebral infarction or cerebral vasospasm;

cerebral trauma;

muscular spasm;

a convulsive disorder selected from epilepsy or status epilepticus;

hypoglycemia;

cardiac arrest;

asphyxia anoxia;

or spinal chord injury, comprising the step of;

administering orally to a mammal in need thereof an effective amount of the solid, immediate release pharmaceutical composition according to claim 54.

71. A method for treating at least one condition in a mammal selected from glaucoma or diabetic end organ complications, comprising the step of:

administering orally to a mammal in need thereof an effective amount of the solid, immediate release pharmaceutical composition according to claim 54.

72. A method for treating at least one condition in a mammal selected from anxiety disorders;

mood disorders;

schizophrenia;

schizophreniform disorder;

or schizoaffective disorder, comprising the step of;

administering orally to a mammal in need thereof an effective amount of the solid, immediate release pharmaceutical composition according to claim 54.

73. A method as claimed in claim 72, wherein the anxiety disorder is selected from panic attack, agoraphobia, panic disorder, specific phobia, social phobia, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, separation anxiety disorder, or substance-induced anxiety disorder;

or the mood disorder is selected from bipolar disorders, depressive disorders selected from major depressive disorder, dysthymic disorder, or substance-induced mood disorder, or mood episodes selected from major depressive episode, manic episode, mixed episode, or hypomanic episode.

74. A method for treating at least one neurodegenerative disorder in a mammal selected from Huntingdon'"'"'s disease, Alzheimer'"'"'s disease, amyotrophic lateral sclerosis, chronic dementia, or cognitive impairment, comprising the step of:

administering orally to a mammal in need thereof an effective amount of the solid, immediate release pharmaceutical composition according to claim 54.

75. A method for treating Parkinson'"'"'s disease, comprising the step of:

administering orally to a mammal in need thereof an effective amount of the solid, immediate release pharmaceutical composition according to claim 54.

76. A method for treating at least one condition in a mammal selected from inflammatory diseases;

fibromyalgia;

complications from herpes zoster;

prevention of tolerance to opiate analgesia;

or withdrawal symptoms from addictive drugs, comprising the step of;

administering orally to a mammal in need thereof an effective amount of the solid, immediate release pharmaceutical composition according to claim 54.

77. A method for treating pain in a mammal, comprising the step of:

administering orally to a mammal in need thereof an effective amount of the solid, immediate release pharmaceutical composition according to claim 54.

78. A method according to claim 77 further comprising administering a therapeutically effective amount of at least one pain relieving agent.

79. A method according to claim 77, wherein the pain is at least one of neuropathic pain;

cancer pain;

visceral pain associated with pancreatitis or abdominal, pelvic or perineal regions;

musculoskeletal pain associated with lower or upper back, spine, fibromylagia, temporomandibular joint, or myofascial pain syndrome;

bony pain associated with bone or joint degenerating disorders;

headaches;

or pain associated with infections, sickle cell anemia, autoimmune disorders, multiple sclerosis, dental procedures, burns or inflammation.

80. A method according to claim 79, wherein the pain comprises neuropathic pain and is associated with at least one of diabetic neuropathy, peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, casualgia, thalamic syndrome, nerve root avulsion, or nerve damage cause by injury selected from phantom limb pain, reflex sympathetic dystrophy or postthoracotomy pain, cancer, chemical injury, toxins, nutritional deficiencies, or viral or bacterial infections.

81. A method according to claim 79, wherein said pain is small fiber neuropathy.

82. A method according to claim 79, wherein said pain is large fiber neuropathy.

83. A method according to claim 79, wherein said pain is peripheral neuropathy.

84. A method according to claim 79, wherein said pain is central neuropathy.

85. A method according to claim 79, wherein said pain is post herpetic neuralgia.

86. A method according to claim 79;

wherein said pain is post-surgical pain.

87. A solid, immediate release pharmaceutical composition according to claim 54,

wherein said composition exhibits a plasma C_max, upon administration to a subject in need thereof, for the compound of formula (I) of about 80 ng/mL to about 4200 ng/mL.

88. A solid, immediate release pharmaceutical composition according to claim 54,

wherein said composition exhibits a plasma T_max, upon administration to a subject in need thereof, for the compound of formula (I) of about 0.5 hours to about 4.0 hours.

89. A solid, immediate release pharmaceutical composition according to claim 54,

wherein said composition exhibits an AUC_{t=0 to 12 hours} upon administration to a subject in need thereof, for the compound of formula (I) of about 250 ng·

h/mL to about 6000 ng·

h/mL.

90. A solid, immediate release pharmaceutical composition according to claim 54,

wherein said composition is in the form of a capsule or a tablet.

91. A solid, immediate release pharmaceutical composition according to claim 90,

wherein said capsule or said tablet comprises about 200 mg to about 4000 mg of said compound of formula (I).

92. A solid, immediate release pharmaceutical composition according to claim 90,

wherein said composition is in the form a single dosage unit or multiple dosage unit.

93. A solid, immediate release pharmaceutical composition according to claim 92,

wherein said single dosage unit or said multiple dosage unit comprises from about 200 mg of said compound of formula (I) or a pharmaceutically acceptable salt thereof to about 4000 mg of said compound of formula (I) or a pharmaceutically acceptable salt thereof.

94. A solid, immediate release pharmaceutical composition according to claim 93,

wherein said single dosage unit or said multiple dosage unit comprises at least about 400 mg of said compound of formula (I) or a pharmaceutically acceptable salt thereof.

95. A solid, immediate release pharmaceutical composition according to claim 94,

wherein said single dosage unit or said multiple dosage unit comprises at least about 600 mg of said compound of formula (I) or a pharmaceutically acceptable salt thereof.

96. A process, comprising the steps of:

forming a wet granulation comprising;

at least one binder;

optionally at least one filler;

optionally at least one disintegrant; and

at least one compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof; and

forming a solid dosage form.

97. A process according to claim 96,

wherein said wet granulation is formed by:

dry blending at least one filler or disintegrant with said compound of formula (I) or a pharmaceutically acceptable salt thereof; and

granulating said dry blend with a solution of at least one binder to form a wet granulation.

98. A process according to claim 96,

wherein said binder is povidone.

99. A process according to claim 96,

wherein said filler is microcrystalline cellulose.

100. A process according to claim 96,

wherein said disintegrant is croscarmellose sodium.

101. A process according to claim 96,

further comprising the steps of:

drying said wet granulation;

milling said dried granulation; and

optionally blending said milled, dried granulation with one or more extragranulation components.

102. A process according to claim 96,

wherein said solid dosage form is a tablet.

103. A process according to claim 96,

wherein said solid dosage form is a capsule.

104. A product produced by the process of claim 96.

2. A solid, pharmaceutical dosage form, comprising:

at least one compound of formula (I) or a pharmaceutically acceptable salt thereof;

wherein;

R₁ is hydrogen;

A is —

(CH₂)_n—

, where n is 2; and

R₂ and R₃ are hydrogen; and

at least one pharmaceutically acceptable absorption enhancer.

105. An immediate release solid pharmaceutical composition in single dosage unit or multiple dosage unit form, comprising:

[2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid or a pharmaceutically acceptable salt thereof;

wherein said composition exhibits a plasma C_max, upon administration to a subject in need thereof, for the compound of formula (I) of about 80 ng/mL to about 4200 ng/mL.

106. An immediate release solid pharmaceutical composition in single dosage unit or multiple dosage unit form, comprising:

[2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid or a pharmaceutically acceptable salt thereof;

wherein said composition exhibits an AUC_{t=0 to 12 hours} upon administration to a subject in need thereof, for the compound of formula (I) of about 250 ng·

h/mL to about 6000 ng·

h/mL.

107. A method for treating pain in a mammal, comprising the step of:

administering orally to a mammal in need thereof [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid or a pharmaceutically acceptable salt thereof in an amount to provide a plasma C_max, of about 80 ng/mL to about 4200 ng/mL of the [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid.

108. A method for treating pain in a mammal, comprising the step of:

administering orally to a mammal in need thereof [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid or a pharmaceutically acceptable salt thereof in an amount to provide an AUC_{t=0 to 12 hours} of about 250 ng·

h/mL to about 6000 ng·

h/mL of the [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid.