Controlled release dosage form with enhanced pharmacokinetics
The present invention provides a simple and improved dosage 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 that is therapeutically responsive to arbaclofen, the method comprising orally administering to a subject in need thereof a daily dose of arbaclofen (ARBAC) in one or more extended release dosage forms, wherein said one or more extended release dosage forms provides at least the same therapeutic efficacy and reduced adverse events as compared to one or more immediate release reference dosage forms containing the same daily dose of ARBAC, and:
a) said one or more extended release dosage forms provides a higher AUC 0-inf and higher Cmax and a longer Tmax than that provided by said one or more immediate release reference dosage forms; or
b) said one or more extended release dosage forms provides an AUC 0-inf and a Cmax that are at least the same as the AUC 0-inf and Cmax, respectively, provided by said one or more immediate release reference dosage forms and a longer Tmax than that provided by said one or more immediate release reference dosage forms.
2. The method of claim 1 , wherein the condition is spasticity or spasticity associated with multiple sclerosis.
3. The method of claim 2 , wherein the reduced adverse events is reduced drowsiness and/or reduced dizziness.
4. The method of claim 1 , wherein the extended release dosage form excludes a gastroretentive dosage form.
5. The method of claim 1 , wherein the extended release dosage form releases a majority of the ARBAC downstream of the stomach and upstream of the colon.
6. The method of claim 5 , wherein the extended release dosage form releases a majority of the ARBAC release downstream of the stomach in the upper portion of the GI tract following oral administration thereof.
7. The method of claim 1 , wherein extended release dosage form exhibits a substantial positive food effect in terms of bioavailability, AUC, Cmax, AUC 0-t or AUC 0-inf when comparing oral administration of the extended release dosage form in the fed and fasting states.
8. The method of claim 1 , wherein the daily dose of ARBAC is divided into two portions in respective extended release dosage forms, and one portion is administered in the fasting state, and another portion is administered in the fed state, wherein the portions are administered within a 24-hour period or are administered about 8 hours to about 16 hours apart.
9. The method of claim 1 , wherein the extended release dosage form provides a controlled release of ARBAC for a period of at least 8 and up to about 24 hours.
10. The method of claim 1 , where the extended release dosage form comprises:
a) a core comprising the ARBAC, at least two water-swellable excipients, at least one osmotic salt, and at least one binder; and
b) a semipermeable membrane surrounding the core and comprising at least one film-forming cellulose ester; wherein
c) the at least two water-swellable excipients comprise a combination of a cellulose derivative and polyalkylene oxide;
d) the at least two water-swellable excipients comprise a major portion of a first type and a minor portion of a second type of polymer;
e) the first type of polymer is a polyalkylene oxide polymer and the second type of polymer is a hydroxyalkyl alkylcellulose derivative or a hydroxyalkylcellulose derivative; and
f) the polyalkylene oxide has a molecular weight of about 1,000,000 or less.
11. The method of claim 10 , wherein the membrane comprises at least a majority of a single grade of film-forming cellulose ester.
12. The method of claim 11 , wherein the cellulose ester is cellulose acetate.
13. The method of claim 1 , where the extended release dosage form comprises:
a) a core comprising 2.5-50 mg of the ARBAC, water-swellable hydroxyalkyl alkylcellulose derivative or a hydroxyalkylcellulose derivative, water swellable polyalkylene oxide, at least one osmotic salt, and at least one binder, the polyalkylene oxide has a molecular weight of about 1,000,000 or less, and
b) semipermeable membrane surrounding the core comprising at least one film-forming cellulose ester, and plasticizer.
14. The method of claim 13 , wherein:
the weight ratio of polyalkylene oxide to cellulose derivative is in the range of about 10:1 to about 25:1, about 13:1 to about 17:1 or about 17:1 to about 22:1;
the weight ratio of uncoated core to membrane applied to the core ranges from about 10:1 to about 15:1 or about 5:1 to about 10:1; and/or
the weight ratio of total water swellable polymer to total binder in the core ranges from about 6:1 to about 2:1 or about 5:1 to about 1:1.
15. The method of claim 10 , wherein the weight ratio of uncoated core to membrane applied to the core ranges from about 10:1 to about 15:1 or about 5:1 to about 10:1.
16. The method of claim 10 , wherein the semipermeable membrane comprises plasticizer and about 80% wt to less than 100% wt of a single cellulose ester based upon the final weight of the membrane.
17. The method of claim 16 , wherein the cellulose ester comprises at least one of the following grades of cellulose acetate:
Hydroxyl Content
Acetyl Content
Cellulose Acetate
(% by wt.)
(% by wt.)
Viscosity*
Grade 1
8.7
32
2.4
P
Grade 2
3.5
39-40, 39.8
38
P
Grade 3
7-10
30-36
200-280
sec*
Grade 4
3-5
37-43
6-45
sec*
Grade 5
3-5
37-43
100-240
sec*
wherein * indicates determination of viscosity as set forth in ASTM D817 (Formula A) and D1343.
18. The method of claim 10 , wherein the dosage form comprises a dose of 2.5 mg to 50 mg of the ARBAC.
19. The method of claim 10 , wherein the osmotic salt is present at a concentration ranging from about 5 to about 45% wt based upon the weight of the uncoated core, or wherein the weight ratio of total water swellable polymer and to osmotic salt is about 1.5:1 to about 1:1.5 or about 0.7:1 to about 1:1.
20. The method of claim 1 , wherein the extended release dosage form exhibits a mean 3-phase sigmoidal in vitro release profile as follows under conditions defined in USP <711>, wherein the first phase lasts no more than about 2 hours, the second phase lasts about 4 to 8 hours, and the third phase lasts about 2 hours or more.
21. The method of claim 10 , wherein the membrane ruptures from 0.1 to 1.5 hours after exposure of the extended release dosage form to an aqueous environment of use.
22. The method of claim 1 , wherein the extended release dosage form provides a dissolution profile according to any one of the following:
a) about 40 to about 80% wt of the drug is released by about six hours, about 55 to about 100% of the drug is released by about 8 hours, and no less than 70% of the drug is released by about 12 hours after placement in an aqueous environment of use or after oral administration;
b) about 50 to about 100% wt of the drug is released by about six hours, about 65 to about 100% of the drug is released by about 8 hours, and no less than 90% of the drug is released by about 12 hours after placement in an aqueous environment of use or after oral administration;
c) about 60 to about 100% wt of the drug is released by about six hours, about 75 to about 100% of the drug is released by about 8 hours, and no less than 90% of the drug is released by about 10 hours after placement in an aqueous environment of use or after oral administration;
d) about 45 to about 85% wt of the drug is released by six hours, about 65 to about 100% of the drug is released by 8 hours, and no less than 75% of the drug is released by 12 hours after placement in an aqueous environment of use or after oral administration;
e) about 50 to about 85% wt of the drug is released by six hours, about 70 to about 100% of the drug is released by 8 hours, and no less than 85% of the drug is released by 10 hours after placement in an aqueous environment of use or after oral administration;
f) about 5 to about 40% wt of the drug is released by 2 hours, 45 to about 85% wt of the drug is released by six hours, about 65 to about 100% of the drug is released by 8 hours, and no less than 75% of the drug is released by 12 hours after placement in an aqueous environment of use or after oral administration;
g) about 10 to about 20% wt of the drug is released by 2 hours, about 25 to about 50% is released by 4 hours, about 60 to about 90% wt of the drug is released by 8 hours, and no less than 75% of the drug is released by 12 hours after placement in an aqueous environment of use or after oral administration;
h) about 10 to about 20% wt of the drug is released by 2 hours, about 25 to about 50% is released by 4 hours, 60 to about 90% wt of the drug is released by 8 hours, and no less than 80% of the drug is released by 12 hours after placement in an aqueous environment of use or after oral administration;
i) about 7 to about 20% wt of the drug is released by 2 hours, about 25 to about 45% is released by 4 hours, about 55 to about 80% wt of the drug is released by 6 hours, and no less than 70% of the drug is released by 8 hours after placement in an aqueous environment of use or after oral administration;
j) no more than about 20% wt of the drug is released by 2 hours, about 20 to about 45% is released by 4 hours, about 55 to about 90% wt of the drug is released by 8 hours, and no less than 80% of the drug is released by 12 hours after placement in an aqueous environment of use or after oral administration;
k) no more than about 20% wt of the drug is released by 2 hours, about 30 to about 60% is released by 4 hours, about 50 to about 70% wt of the drug is released by 6 hours, no less than 70% of the drug is released by 8 hours and no less than 80% of the drug is released by 12 hours after placement in an aqueous environment of use or after oral administration;
l) no more than about 10% of the drug is released by 1 hour, no more than about 20% wt of the drug is released by 2 hours, about 30 to about 50% is released by 4 hours, about 40 to about 70% wt of the drug is released by 6 hours, no less than 60% of the drug is released by 8 hours and no less than 75% of the drug is released by 12 hours after placement in an aqueous environment of use or after oral administration;
m) no more than about 10% of the drug is released by 1 hour, no more than about 20% wt of the drug is released by 2 hours, about 30 to about 50% is released by 4 hours, about 40 to about 70% wt of the drug is released by 6 hours, about 60% to about 85% of the drug is released by 8 hours and no less than 75% of the drug is released by 12 hours after placement in an aqueous environment of use or after oral administration;
n) about 70 to about 95% wt of the drug is released by six hours, about 80 to about 100% of the drug is released by 8 hours, and no less than 90% of the drug is released by 12 hours; or
o) about 15 to about 35% wt of the drug is released by 2 hours, about 50 to about 85% is released by 4 hours, about 80 to about 100% of the drug is released by 8 hours, and no less than 90% of the drug is released by 12 hours after placement in an aqueous environment of use or after oral administration.
23. The method of claim 1 , wherein the extended release dosage form provides a plasma profile as described herein or as depicted in FIG. 2 or FIG. 6 .
24. The method of claim 1 , wherein the extended release dosage form provides a dissolution profile as depicted in FIG. 1 or FIG. 5 inclusive of the area defined by minimum and maximum profiles.
25. The method of claim 1 , wherein oral administration in the fasting state of a single extended release dosage form comprising a 20 mg dose of ARBAC provides a pharmacokinetic profile defined as follows:
a mean Tmax of about 4.8 hrs±20%, a mean Cmax of about 240 ng/ml±30%, an AUC 0-t of about 1460 ng/ml*h±30%, an AUC 0-inf of about 1560 ng/ml*hr±30%, and a mean residence time of about 9.3 hrs±30%.
26. The method of claim 1 , wherein the extended release dosage form provides a plasma concentration of ARBAC that is at least 4-fold higher than its cerebrospinal fluid concentration.
27. The method of claim 1 , wherein the extended release dosage form exhibits in vitro dissolution profile approximating any of those depicted in FIG. 5 and exhibits in vivo single dose plasma profile approximating that depicted in FIG. 6 for formulation T2.
28. The method of claim 1 , wherein a single dose of the extended release dosage form containing 20 mg of ARBAC provides a pharmacokinetic plasma profile as follows:
Mean values
Parameter
Fed
Fasting
Tmax (hr)
about 4-6
about 3.5-5.5
Cmax (ng/ml)
about 110-190
about 80-150
AUC 0-t (ng · h/ml)
about 1400-1900
about 550-1080
AUC 0-inf (ng · h/ml)
about 1400-1900
about 550-1080
when orally administered in the fed or fasting state.
29. The method of claim 1 , wherein the extended release dosage form provides a dissolution profile according to any of the following:
Dissolution (% wt)
Time
Median or
(hr)
mean
Max
Min
0
0
0
0
2
11
20
5
4
35
50
20
6
61
80
40
8
78
100
55
12
88
70
Dissolution (% wt)
Time
Median or
(hr)
mean
Max
Min
0
0
0
0
2
11
20
5
4
35
50
25
6
61
80
45
8
78
100
65
12
88
80
Dissolution (% wt)
Time
Median or
(hr)
mean
Max
Min
0
0
0
0
2
12
20
5
4
40
50
30
6
65
80
50
8
85
100
70
12
95
90
Dissolution (% wt)
Time
Median or
(hr)
mean
Max
Min
0
0
0
0
2
12
20
5
4
42
50
35
6
67
80
55
8
87
100
75
12
97
100
Dissolution (% wt)
Time
Median or
(hr)
mean
Max
Min
0
0
0
0
1
11
15
5
2
20
30
11
4
50
72
35
6
80
100
61
8
100
78
Dissolution (% wt)
Time
Median or
(hr)
mean
Max
Min
0
0
0
0
1
7
10
2
2
15
20
7
4
40
50
25
6
65
85
50
8
85
100
70
10
100
when determined as described herein.