Controlled release dosage form
The present invention provides a simple and improved dose form that is capable of providing a controlled release of GABA B receptor agonist contained in the core thereof. The invention also provides methods of administering the dosage form and of treating conditions that are therapeutically responsive to GABA B receptor agonist.
1. A method for treating a condition, disorder or disease that is therapeutically responsive to arbaclofen (ARBAC), the method comprising orally administering to a subject in need thereof at least one controlled release dosage form comprising ARBAC, wherein the dosage form exhibits a positive food effect in terms of bioavailability, Tmax, Cmax, AUC 0-t and/or AUC 0-inf of ARBAC when comparing oral administration of the dosage form in the fed and fasting states, and the dosage form comprises: a) a core comprising ARBAC, at least one osmotic agent, at least one binder, at least one water swellable cellulose derivative (CD) polymer and at least one water swellable polyalkylene oxide (PAO) polymer, wherein the amount of PAO polymer exceeds the amount of CD polymer; and b) a semipermeable membrane surrounding the core, said membrane comprising at least two types or grades of film-forming cellulose ester polymer.
2. The method of claim 1 , wherein the condition, disorder or disease is selected from the group consisting of spasticity, spastic diplegia, spasticity associated with multiple sclerosis, amyotrophic lateral sclerosis, trigeminal and glossopharyngeal neuralgias, spinal cord injury, alcoholism, alcohol addiction, dependence or alcohol abuse, gastro-esophageal reflux disease, emesis, cough, narcotic addiction or abuse, nicotine addiction or abuse, neuropathic pain and musculoskeletal pain, nocturnal acid breakthrough, chronic hiccups, dyspepsia, non-nuclear dyspepsia, gastric motility disorder, migraine, Post-traumatic Stress Disorder, depression, anxiety, and lower urinary tract dysfunction.
3. The method of claim 1 , wherein the dosage form provides a controlled release of ARBAC for a period of at least 8 and up to about 24 hours.
4. The method of claim 1 , wherein about 40 to about 80% wt of the drug is released after six hours, about 55 to about 100% of the drug is released after 8 hours, and not less than 70% of the drug is released after 12 hours, or wherein about 45 to about 85% wt of the drug is released after six hours, about 65 to about 100% of the drug is released after 8 hours, and no less than 75% of the drug is released after 12 hours.
5. The method of claim 1 , wherein the dosage form exhibits an in vitro release profile for ARBAC as follows under conditions defined in USP <711> using a Type II apparatus with 0.1 N HCl stirred at 50 rpm and maintained at a temperature of 37±0.5° C., wherein about 60 to about 100% wt of the drug is released over a period of about 6 to about 16 hours.
6. The method of claim 1 , wherein said dosage form exhibits an in vitro release profile as follows:
Time
Dissolution (% wt)
(hr)
Maximum
Minimum
0
0
0
2
20
5
4
50
20
6
80
40
8
100
55
12
70.
7. The method of claim 1 , wherein said dosage form provides a dissolution profile as depicted in FIG. 1 inclusive of the area defined by minimum and maximum profiles, wherein the release profile is determined under conditions defined in USP <711> using a Type II apparatus with 0.1 N HCl stirred at 50 rpm and maintained at a temperature of 37±0.5° C.
8. The method of claim 1 , wherein the subject exhibits less adverse events associated with ARBAC than if the subject is administered an equivalent daily dose of ARBAC, present as part of racemic baclofen, in a rapid release or immediate release dosage form.
9. The method of claim 8 , wherein said subject experiences less drowsiness and/or less dizziness.
10. The method of claim 1 , wherein said dosage form is administered once, twice or three times daily.
11. The method of claim 1 , wherein said dosage form provides a reduced Cmax and/or AUC as compared to oral administration of a reference immediate release dosage form comprising the same dose of ARBAC.
12. The method of claim 11 , wherein said dosage form provides a Cmax and AUC for ARBAC that is lower than that provided by an immediate release dosage form comprising racemic baclofen but the same molar amount of ARBAC and still provides substantially the same or an improved clinical benefit over the immediate release dosage form.
13. The method of claim 1 , wherein said dosage form provides at least a minimum therapeutically effective concentration of ARBAC in the cerebrospinal fluid (CSF) of the subject, and: a) the minimum therapeutically effective concentration of ARBAC in the CSF of the subject is at least about 2, at least about 3 or at least about 4 ng/ml when a total daily dose of 20 mg of ARBAC is administered; b) the minimum therapeutically effective concentration of ARBAC in the CSF of the subject is at least about 3, at least about 4 or at least about 5 ng/ml when a total daily dose of 30 mg of ARBAC is administered; and/or c) the minimum therapeutically effective concentration of ARBAC in the CSF of the subject is at least about 5, at least about 6 or at least about 7 ng/ml when a total daily dose of 40 mg of ARBAC is administered.
14. The method of claim 1 , wherein said dosage form provides a plasma profile approximately as depicted in FIG. 2 .
15. The method of claim 1 , wherein oral administration in the fed state of a single dose of said dosage form comprising a total dose of about 20 mg of ARBAC provides a pharmacokinetic profile defined as follows:
Mean values
Tmax (hr)
about 4-6
Cmax (ng/ml)
about 110-190
AUC (ng · h/ml)
about 1400-1900.
16. The method of claim 15 , wherein said single dose is in a single said dosage form.
17. The method of claim 1 , wherein oral administration in the fed state of multiple daily doses of said dosage form comprising a total dose of about 20 mg of ARBAC provides a steady state pharmacokinetic profile defined as follows:
Mean values
Tmax ss (hr)
4-6
Cmax ss (ng/ml)
about 120-220
Cmin ss (ng/ml)
about 10-100
AUC ss (ng · h/ml)
about 1000-1700.
18. The method of claim 17 , wherein said multiple daily doses is twice daily doses.
19. The method of claim 18 , wherein said daily doses are administered about every twelve hours for five days.
20. The method of claim 1 , wherein oral administration in the fasting state of said dosage form comprising a total dose of about the below-specified dose of ARBAC provides a pharmacokinetic profile defined as follows:
Parameter
10 mg dose
15 mg dose
20 mg dose
Tmax (hr) (median
about 5
about 4.5
About 5
or mean)
Cmax (ng/ml)
about 77
about 100
About 142
AUC 0-inf (ng · h/ml)
About 575
About 700
About 1090.
21. The method of claim 20 , wherein each said below-specified dose is in its respective single said dosage form.
22. The method of claim 1 , wherein oral administration in the fasting state of a single dose of said dosage form comprising a total dose of about 20 mg of ARBAC provides a pharmacokinetic profile defined as follows
Mean values
Tmax (hr)
about 3.5-5.5
Cmax (ng/ml)
about 80-150
AUC (ng · h/ml)
about 550-1080.
23. The method of claim 22 , wherein said single dose is in a single said dosage form.
24. The method of claim 1 , wherein oral administration in the fasting state of multiple daily doses of said dosage form comprising a total dose of about 20 mg of ARBAC provides a steady state pharmacokinetic profile defined as follows:
Mean values
Tmax ss (hr)
3.5-5.5
Cmax ss (ng/ml)
about 80-150
Cmin ss (ng/ml)
about 5-80
AUC ss (ng · h/ml)
about 600-1150.
25. The method of claim 24 , wherein said multiple daily doses is twice daily doses.
26. The method of claim 25 , wherein said daily doses are administered about every twelve hours for five days.
27. The method of claim 1 , wherein said dosage form provides a plasma concentration of ARBAC that is at least 4-fold higher than the cerebrospinal fluid concentration of ARBAC.
28. The method of claim 1 , wherein said dosage form provides a majority of drug release in the upper portion of the GI tract.
29. The method of claim 1 , wherein said dosage form provides reduced adverse events as compared to oral administration of a rapid release or immediate release dosage form containing an equimolar amount of ARBAC which may be present as racemic baclofen.
30. The method of claim 1 , wherein said dosage form provides a majority of drug release downstream of the stomach and upstream of the colon.
31. A method for treating a condition, disorder or disease that is therapeutically responsive to arbaclofen (ARBAC), the method comprising orally administering to a subject in need thereof at least one controlled release dosage form comprising a therapeutically effective dose of ARBAC, wherein the controlled release dosage form provides an in vitro dissolution profile approximately as depicted in FIG. 1 inclusive of the area defined by minimum and maximum profiles, wherein the release profile is determined under conditions defined in USP <711> using a Type II apparatus with 0.1 N HCl stirred at 50 rpm and maintained at a temperature of 37±0.5° C., and the dosage form comprises: a) a core comprising ARBAC, at least one osmotic agent, at least one binder, at least one water swellable cellulose derivative (CD) polymer and at least one water swellable polyalkylene oxide (PAO) polymer, wherein the amount of PAO polymer exceeds the amount of CD polymer; and b) a semipermeable membrane surrounding the core, said membrane comprising at least two types or grades of film-forming cellulose ester polymer.
32. A method for treating a condition, disorder or disease that is therapeutically responsive to arbaclofen (ARBAC), the method comprising orally administering to a subject in need thereof at least one controlled release dosage form comprising a therapeutically effective dose of ARBAC, wherein the dosage form provides a majority of drug release in the upper portion of the GI tract downstream of the stomach, and the dosage form comprises: a) a core comprising ARBAC, at least one osmotic agent, at least one binder, at least one water swellable cellulose derivative (CD) polymer and at least one water swellable polyalkylene oxide (PAO) polymer, wherein the amount of PAO polymer exceeds the amount of CD polymer; and b) a semipermeable membrane surrounding the core, said membrane comprising at least two types or grades of film-forming cellulose ester polymer.
33. The method of claim 32 , wherein said dosage form provides a majority of drug release downstream of the stomach and upstream of the colon.
34. A method for treating a condition, disorder or disease that is therapeutically responsive to arbaclofen (ARBAC), the method comprising orally administering to a subject in need thereof at least one controlled release dosage form comprising a therapeutically effective dose of ARBAC, wherein the dosage form provides reduced adverse events as compared to oral administration of a rapid release or immediate release dosage form containing an equimolar amount of ARBAC which may be present as racemic baclofen, and the dosage form comprises: a) a core comprising ARBAC, at least one osmotic agent, at least one binder, at least one water swellable cellulose derivative (CD) polymer and at least one water swellable polyalkylene oxide (PAO) polymer, wherein the amount of PAO polymer exceeds the amount of CD polymer; and b) a semipermeable membrane surrounding the core, said membrane comprising at least two types or grades of film-forming cellulose ester polymer.
35. The method of claim 34 , wherein said dosage form provides reduced sleepiness and/or reduced drowsiness.
36. The method of claim 34 , wherein oral administration in the fed state of multiple daily doses of said dosage form comprising a total dose of about 20 mg of ARBAC provides a steady state pharmacokinetic profile defined as follows:
Mean values
Tmax ss (hr)
4-6
Cmax ss (ng/ml)
about 120-220
Cmin ss (ng/ml)
about 10-100
AUC ss (ng · h/ml)
about 1000-1700.
37. The method of claim 36 , wherein said multiple daily doses is twice daily doses.
38. The method of claim 37 , wherein said daily doses are administered about every twelve hours for five days.
39. The method of claim 34 , wherein oral administration in the fasting state of multiple daily doses of said dosage form comprising a total dose of about 20 mg of ARBAC provides a steady state pharmacokinetic profile defined as follows:
Mean values
Tmax ss (hr)
3.5-5.5
Cmax ss (ng/ml)
about 80-150
Cmin ss (ng/ml)
about 5-80
AUC ss (ng · h/ml)
about 600-1150.
40. The method of claim 39 , wherein said multiple daily doses is twice daily doses.
41. The method of claim 40 , wherein said daily doses are administered about every twelve hours for five days.