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 of treating a human patient in need of treatment for spasticity associated with multiple sclerosis, comprising administering twice-daily a composition comprising drug and excipients, said drug consisting of about 2.5 mg to about 50 mg of arbaclofen (ARBAC), and/or a corresponding amount of one or more pharmaceutically acceptable salt(s) of ARBAC, said composition providing the following in vitro release under conditions defined in USP <711> using a Type H apparatus with 900 ml 0.1 N HCl stirred at 50 rpm and maintained at a temperature of 370.5° C.: about 40% by wt to about 80% by wt of the drug is released after six hours, about 55% by wt to about 100% by wt 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% by wt to about 85% by wt of the drug is released after six hours, about 65% by wt to about 100% of the drug is released after 8 hours, and no less than 75% by wt of the drug is released after 12 hours.
2. The method of claim 1 , wherein said composition exhibits an in vitro release profile of the drug 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
3. The method of claim 1 , wherein said composition provides an in vitro drug release profile as depicted in FIG. 1 inclusive of the region 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.
4. The method of claim 1 , wherein said composition exhibits a positive food effect for the drug in terms of bioavailability, 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.
5. The method of claim 1 , wherein the subject exhibits less adverse events associated with ARBAC than if the subject is administered an equivalent total daily dose of ARBAC, present as part of racemic baclofen, in a rapid release or immediate release dosage form.
6. The method of claim 1 , wherein administration of said composition provides for a statistically significant improvement of spasticity compared to a placebo.
7. The method of claim 6 , wherein said method affords no statistically significant difference in sleepiness compared to placebo.
8. The method of claim 6 , wherein sleepiness is measured using the Epworth Sleepiness Scale.
9. The method of claim 1 , wherein said composition 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.
10. The method of claim 9 , wherein said composition 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.
11. The method of claim 1 , wherein said composition provides a plasma profile corresponding to that depicted in FIG. 2 .
12. The method of claim 1 , wherein oral administration in the fed state of a single dose of said composition 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
13. The method of claim 12 , wherein said single dose is in a single tablet.
14. The method of claim 1 , wherein chronic twice-daily oral administration in the fed state of a dose of the composition, said dose comprising a total 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
15. The method of claim 14 , wherein said dose comprises a total of 20 mg of ARBAC.
16. The method of claim 14 , wherein each said dose is in a single tablet.
17. The method of claim 1 , wherein oral administration in the fasting state of a single dose of the composition comprising a total 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
18. The method of claim 1 , wherein oral administration in the fasting state of a single dose of the composition comprising a total of 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
19. The method of claim 18 , wherein said single dose is in a single tablet.
20. The method of claim 1 , wherein oral administration in the fasting state of a single dose of the composition, said dose comprising a total of about 20 mg dose 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
21. The method of claim 20 , wherein said single dose is in a single tablet.
22. The method of claim 1 , wherein chronic twice-daily oral administration in the fasting state of a dose of the composition, said dose comprising a total 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
23. The method of claim 22 , wherein each said dose is in a single tablet.
24. The method of claim 1 , wherein the compositions provides a majority of drug release in the upper portion of the GI tract.
25. The method of claim 1 , wherein the composition provides a majority of drug release downstream of the stomach and upstream of the colon.
26. The method of claim 1 , wherein the composition is an osmotic device comprising: a) a core comprising the drug, 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.
27. The method of claim 26 , wherein the membrane ruptures from 0.1 hours to 1.5 hours after exposure of the device to an aqueous medium which is water or buffer.
28. The method of claim 27 , wherein the core comprises an edge, seam or shoulder and the rupture occurs adjacent the edge, seam or shoulder of the core.
29. The method of claim 1 , wherein oral administration in the fed state of said composition comprising a total of about 20 mg of ARBAC provides an AUC of about 1400-1900 ng.h/ml, and oral administration in the fasting state of said composition comprising a total of about 20 mg of ARBAC provides an AUC of about 550-1080 ng.h/ml.
30. The method of claim 1 , wherein oral administration in the fed state of said composition comprising a total of 20 mg of ARBAC provides an AUC of about 1400-1900 ng.h/ml, and oral administration in the fasting state of said composition comprising a total of 20 mg of ARBAC provides an AUC of about 550-1080 ng.h/ml.
31. The method of claim 1 , wherein chronic twice-daily oral administration in the fed state of a dose of said composition, each said dose comprising a total of about 20 mg of ARBAC, provides a steady state AUC of about 1000-1700 ng.h/ml, and chronic twice-daily oral administration in the fasting state of a dose of said composition, each said dose comprising a total of about 20 mg of ARBAC, provides a steady state AUC of about 600-1150 ng.h/ml.
32. The method of claim 31 , wherein each said dose is in a single tablet.
33. The method of claim 1 , wherein chronic twice-daily oral administration in the fed state of a dose of said composition, each said dose comprising a total of 20 mg of ARBAC, provides a steady state AUC of about 1000-1700 ng.h/ml, and chronic twice-daily oral administration in the fasting state of a dose of said composition, each said dose comprising a total of 20 mg of ARBAC, provides a steady state AUC of about 600-1150 ng.h/ml.
34. The method of claim 33 , wherein each said dose is in a single tablet.
35. The method of claim 1 , wherein chronic twice-daily oral administration, to a subject in need thereof in the fed or fasting state, of a dose of said composition, each said dose comprising a total of about 20 mg of ARBAC, provides a steady state pharmacokinetic profile defined as follows
Mean values
Parameter
Fed state
Fasting State
Tmax ss (hr)
about 5
about 4.5
Cmax ss (ng/ml)
about 170
about 130
Cmin ss (ng/ml)
about 55
about 40
AUC ss (ng · h/ml)
about 1250
about 890
36. The method of claim 35 , wherein each said dose is in a single tablet.
37. The method of claim 1 , wherein chronic twice-daily oral administration, to a subject in need thereof in the fed or fasting state, of a dose of said composition, each said dose comprising a total of 20 mg of ARBAC, provides a steady state pharmacokinetic profile defined as follows
Mean values
Parameter
Fed state
Fasting State
Tmax ss (hr)
about 5
about 4.5
Cmax ss (ng/ml)
about 170
about 130
Cmin ss (ng/ml)
about 55
about 40
AUC ss (ng · h/ml)
about 1250
about 890
38. The method of claim 37 , wherein each said dose is in a single tablet.
39. The method of claim 1 , wherein said composition is not gastroretentive.