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 controlled release oral dosage form comprising: a) a core comprising at least one GABA B receptor agonist and at least two water-swellable excipients; and b) a semipermeable membrane surrounding the core, said membrane comprising at least two film-forming cellulose esters; wherein the at least one GABA B receptor agonist is (R)-baclofen (ARBAC); and following oral administration of said dosage form, the dosage form releases a majority of ARBAC downstream of the stomach and upstream of the colon.
2. The dosage form of claim 1 , wherein: a) the core further comprises at least one osmotic salt.
3. The dosage form of claim 2 , wherein: a) the core further comprises at least one binder.
4. The dosage form of claim 3 , wherein the at least two water-swellable excipients comprise a combination of a cellulose derivative and polyalkylene oxide.
5. The dosage form of claim 1 , wherein the at least two water-swellable excipients comprise a majority of a first type of polymer and a minority of a second type of polymer.
6. The dosage form of claim 1 , wherein the at least two film-forming cellulose esters are present as: a) a combination of at least two different grades of the same type of cellulose ester polymer; or b) a combination of two different types of cellulose ester polymer.
7. The dosage form 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., wherein about 60 to about 100% wt of the drug is released over a period of about 6 to about 16 hours.
8. The dosage form of claim 7 , wherein about 40% to about 80% wt of the drug is released after six hours, about 55% to about 100% wt of the drug is released after 8 hours, and no less than 70% wt 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% wt of the drug is released after 8 hours, and no less than 75% wt of the drug is released after 12 hours.
9. The dosage form 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.
Time
Dissolution (% wt)
(hr)
Maximum
Minimum
0
0
0
2
20
5
4
50
20
6
80
40
8
100
55
12
70.
10. The dosage form of claim 1 , wherein the membrane ruptures from 0.1 hours to 1.5 hours after exposure of the device to an aqueous environment of use.
11. The dosage form claim 10 , wherein the core comprises an edge, seam or shoulder and the rupture occurs adjacent the edge, seam or shoulder of the core.
12. The dosage form of claim 1 , wherein the core: a) further comprises at least one binder; b) further comprises at least one filler; c) further comprises at least one antioxidant; d) further comprises at least one glidant; e) further comprises at least one lubricant; f) comprises about 5 mg to about 25 mg of ARBAC; g) is a unitary core; h) excludes a composition or coat or layer between the core and the semipermeable membrane; or i) a combination thereof.
13. The dosage form of claim 1 , wherein the dosage form provides a controlled release of the GABA B receptor agonist for a period of at least 8 and up to about 24 hours.
14. The dosage form of claim 1 , wherein the dosage form exhibits a positive food effect in terms of bioavailability, Tmax, Cmax, AUC 0-t and/or AUC 0-inf when comparing oral administration of the dosage form in the fed and fasting states.
15. The dosage form of claim 1 , wherein a batch of the dosage forms exhibits a standard deviation in the range of ±0.05% to ±10% in the release profile of active agent from the core on a point-to-point or overall basis.
16. The dosage form of claim 1 , wherein, following oral administration to a subject in need thereof, the subject exhibits less adverse events associated with 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.
17. The dosage form of claim 1 , wherein, following oral administration to a subject in need thereof, the 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.
18. The dosage form of claim 1 , wherein following oral administration to a subject in need thereof, the extended release dosage form provides a Cmax and AUC for ARBAC that is lower than that provided by an immediate release dosage form comprising rac-BAC but the same molar amount of (R)-BAC and still provides substantially the same or an improved clinical benefit over the immediate release dosage form.
19. The dosage form of claim 1 , wherein, following oral administration to a subject in need thereof, the dosage form provides a plasma profile as depicted in FIG. 2 .
20. The dosage form 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.
21. A controlled release oral dosage form comprising: a) a core comprising arbaclofen and at least two water-swellable excipients; and b) a semipermeable membrane surrounding the core, said membrane comprising at least two film-forming cellulose esters; wherein chronic oral administration of said controlled release dosage form, to a subject in need thereof in the fed state, comprising a 20 mg dose of arbaclofen 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.
22. The dosage form of claim 21 , wherein chronic oral administration of said controlled release dosage form to the subject in the fasting state 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 dosage form of claim 1 , wherein oral administration of a single dose of said controlled release dosage form in the fasting state comprising the specified dose of GABA B receptor agonist 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.
24. The dosage form of claim 1 , wherein following oral administration the dosage form provides a majority of drug release in the upper portion of the GI tract.
25. The dosage form of claim 1 , wherein following oral administration 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 arbaclofen which may be present as racemic baclofen.
26. A controlled release oral dosage form comprising: a) a core comprising (R)-baclofen (ARBAC), at least one osmotic salt, at least one binder and at least two water-swellable excipients; and b) a semipermeable membrane surrounding the core, said membrane comprising at least two film-forming cellulose esters; wherein chronic oral administration, to a subject in need thereof in the fed or fasting state, of a 20 mg dose of ARBAC in said dosage form 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.
27. The controlled release oral dosage form of claim 26 , wherein a) the at least two water-swellable excipients is 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) the at least two film-forming cellulose esters is at least two different grades of cellulose acetate polymer; c) the dosage form provides an in vitro release profile, 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 d) 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.
28. The controlled release oral dosage form of claim 4 , wherein the amount of polyalkylene oxide polymer exceeds the amount of cellulose derivative polymer; and the dosage form exhibits a drug release profile defined as follows when placed in an aqueous environment of use: about 40% to about 80% wt of the drug is released after six hours, about 55% to about 100% wt of the drug is released after 8 hours, and no less than 70% wt 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% wt of the drug is released after 8 hours, and no less than 75% wt of the drug is released after 12 hours.