Controlled release dosage form
View Patent ↗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 condition, disorder or disease that is therapeutically responsive to (R)-baclofen (ARBAC), the method comprising orally administering to a subject in need thereof at least one controlled release oral dosage form comprising: a) a core comprising ARBAC, at least one disintegrant, 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 different grades of cellulose acetate polymer and at least one preformed passageway; wherein:
about 60 to about 100% wt of the drug is released over a period of about 6 to about 16 hours 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
following oral administration to a subject, the dosage form provides a majority of drug release from the core downstream of the stomach and upstream of the colon.
2. 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 no 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.
3. The method of claim 1 , wherein the dosage form exhibits a sigmoidal in vitro release profile 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.
Dissolution (% wt)
Time (hr)
Maximum
Minimum
0
0
0
2
20
5
4
50
20
6
80
40
8
100
55
12
70.
4. The method of claim 1 , wherein the membrane ruptures from 0.1 to 1.5 hours after exposure of the device to an environment of use.
5. The method of claim 4 , wherein the core comprises an edge, seam or shoulder and the rupture occurs adjacent an edge, seam or shoulder of the core.
6. The method of claim 1 , wherein the core: a) further comprises at least one filler; b) further comprises at least one antioxidant; c) further comprises at least one glidant; d) further comprises at least one lubricant; e) comprises about 5 to about 25 mg of ARBAC; f) excludes a composition or coat or layer between the core and the semipermeable membrane; or g) a combination thereof.
7. The method of claim 1 , wherein the dosage form exhibits a positive food effect in pharmacokinetic performance.
8. The method of claim 7 , wherein the dosage form exhibits a positive food effect in terms of bioavailability, Tmax, Cmax, AUC 0-t , AUC 0-inf or a combination thereof when comparing oral administration of the dosage form in the fed and fasting states.
9. The method of claim 1 , wherein, the subject exhibits less adverse events caused by ARBAC than if the subject is orally administered an equivalent daily dose of arbaclofen, present as part of racemic baclofen, in a rapid release or immediate release dosage form.
10. The method of claim 1 , wherein the dosage form provides a reduced Cmax, reduced AUC, or a combination thereof as compared to oral administration of a reference immediate release dosage form comprising the same dose of ARBAC.
11. The method of claim 1 , wherein the release dosage form provides a Cmax and AUC for ARBAC that is lower than that provided by oral administration of an immediate release dosage form comprising rac-BAC but the same molar amount of ARBAC and still provides the same or an improved clinical benefit over the immediate release dosage form.
12. The method of claim 1 , wherein the dosage form provides a plasma profile as depicted in FIG. 2 .
13. The method of claim 1 , wherein the dosage form provides a dissolution profile as depicted in FIG. 1 inclusive of the area defined by minimum and maximum profiles.
14. The method of claim 1 , wherein oral administration of a single controlled release dosage form, in the fed state, comprising a 20 mg dose 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.
15. The method of claim 1 , wherein oral administration of a single controlled release dosage form, in the fasting state, comprising a 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.
16. The method of claim 1 , wherein chronic oral administration of a controlled release dosage form in the fed state comprising a 20 mg dose 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.
17. The method of claim 1 , wherein chronic oral administration of a controlled release dosage form in the fasting state comprising a 20 mg dose 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.
18. The method of claim 1 , wherein oral administration of a single controlled release dosage form in the fasting state comprising the 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. A method of treating a condition, disorder or disease that is therapeutically responsive to (R)-baclofen (ARBAC), the method comprising orally administering to a subject in need thereof at least one controlled release oral dosage form comprising:
a core comprising ARBAC, at least one disintegrant, at least one osmotic agent, at least one binder, at least one water swellable hydroxypropylcellulose polymer (HPC) and at least one water swellable polyethylene oxide polymer (PEO), wherein the amount of PEO polymer exceeds the amount of HPC polymer; and
a semipermeable membrane surrounding the core, said membrane comprising: a first grade of cellulose acetate polymer having hydroxyl content of 7-10% wt, an acetyl content of 30-36% wt and a viscosity of 200-280 sec; a second grade of cellulose acetate polymer having hydroxyl content of 3-5% wt, an acetyl content of 37-43% wt and a viscosity of 100-240 sec; and at least one preformed passageway;
wherein the dosage form exhibits a sigmoidal in vitro release profile 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.
Dissolution (% wt)
Time (hr)
Maximum
Minimum
0
0
0
2
20
5
4
50
20
6
80
40
8
100
55
12
70;
and
following oral administration to a subject, the dosage form provides a majority of drug release from the core downstream of the stomach and upstream of the colon.
20. The method of claim 19 , wherein the membrane ruptures from 0.1 to 1.5 hours after exposure of the device to an environment of use.
21. The method of claim 20 , wherein the core comprises an edge, seam or shoulder and the rupture occurs adjacent an edge, seam or shoulder of the core.
22. The method of claim 19 , wherein the core: a) further comprises at least one filler; b) further comprises at least one antioxidant; c) further comprises at least one glidant; d) further comprises at least one lubricant; e) comprises about 5 to about 25 mg of ARBAC; f) excludes a composition or coat or layer between the core and the semipermeable membrane; or g) a combination thereof.
23. The method of claim 19 , wherein the dosage forms exhibits a positive food effect in pharmacokinetic performance.
24. The method of claim 23 , wherein the dosage form exhibits a positive food effect in terms of bioavailability, Tmax, Cmax, AUC 0-t , AUC 0-inf or a combination thereof when comparing oral administration of the dosage form in the fed and fasting states.
25. The method of claim 19 , wherein, the subject exhibits less adverse events caused by ARBAC than if the subject is orally administered an equivalent daily dose of arbaclofen, present as part of racemic baclofen, in a rapid release or immediate release dosage form.
26. The method of claim 19 , wherein the dosage form provides a reduced Cmax, reduced AUC, or reduced Cmax and reduced AUC as compared to oral administration of a reference immediate release dosage form comprising the same dose of ARBAC.
27. The method of claim 19 , wherein the release dosage form provides a Cmax and AUC for ARBAC that is lower than that provided by an orally administered immediate release dosage form comprising rac-BAC but the same molar amount of ARBAC and still provides the same or an improved clinical benefit over the immediate release dosage form.
28. The method of claim 19 , wherein following oral administration the dosage form provides a plasma profile as depicted in FIG. 2 .
29. The method of claim 19 , wherein the dosage form provides a dissolution profile as depicted in FIG. 1 inclusive of the area defined by minimum and maximum profiles.
30. The method of claim 19 , wherein oral administration of a single controlled release dosage form, in the fed state, comprising a 20 mg dose 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.
31. The method of claim 19 , wherein oral administration of a single controlled release dosage form, in the fasting state, comprising a 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.
32. The method of claim 19 , wherein chronic oral administration of a controlled release dosage form in the fed state comprising a 20 mg dose 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.
33. The method of claim 19 , wherein chronic oral administration of a controlled release dosage form in the fasting state comprising a 20 mg dose 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.
34. The method of claim 19 , wherein oral administration of a single controlled release dosage form in the fasting state comprising the 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.
35. The method of claim 19 , wherein condition, disorder or disease is spasticity or spasticity associated with multiple sclerosis.
36. The method of claim 1 , wherein condition, disorder or disease is spasticity or spasticity associated with multiple sclerosis.