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 the drug arbaclofen (ARBAC), the method comprising orally administering, to a subject in need thereof, at least one controlled release dosage form comprising: a) a core comprising ARBAC 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.
2. The method of claim 1 , wherein the core further comprises at least one osmotic salt.
3. The method of claim 1 , wherein the core further comprises at least one binder.
4. The method of claim 3 , wherein the at least two water-swellable excipients comprise a combination of a cellulose derivative and polyalkylene oxide.
5. The method 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 method 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 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.
8. The method of claim 1 , wherein said at least one controlled release dosage form provides a controlled release of ARBAC for a period of at least 8 and up to about 24 hours.
9. The method of claim 1 , wherein said at least one controlled release dosage form exhibits a sigmoidal 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.
10. The method of claim 9 , 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.
11. The method of claim 1 , wherein said at least one controlled release dosage form exhibits an in vitro release profile defined 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
12. The method of claim 1 , wherein said at least one controlled release dosage form provides an in vitro drug release profile for ARBAC 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.
13. The method 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.
14. The method of claim 13 , wherein the core comprises an edge, seam or shoulder and the rupture occurs adjacent the edge, seam or shoulder of the core.
15. 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 mg to about 25 mg of ARBAC; f) is a unitary core; g) excludes a composition or coat or layer between the core and the semipermeable membrane; or h) a combination thereof.
16. The method of claim 1 , wherein said at least one controlled release dosage form 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.
17. 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.
18. The method of claim 17 , wherein a) said subject experiences less drowsiness and/or less dizziness; b) administration of said at least one controlled release dosage form provides for a statistically significant improvement of spasticity compared to a placebo; or c) said method affords no statistically significant difference in sleepiness compared to placebo.
19. The method of claim 18 , wherein sleepiness is measured using the Epworth Sleepiness Scale (ESS).
20. The method of claim 1 , wherein said at least one controlled release dosage form is administered once, twice or three times daily.
21. The method of claim 1 , wherein said at least one controlled release 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.
22. The method of claim 21 , wherein said at least one controlled release 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 said immediate release dosage form.
23. The method of claim 1 , wherein said at least one controlled release 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.
24. The method of claim 1 , wherein said at least one controlled release dosage form provides a plasma profile corresponding to that depicted in FIG. 2 .
25. The method of claim 1 , wherein oral administration in the fed state of a single dose of said at least one controlled release 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
26. The method of claim 1 , wherein oral administration in the fasting state of a single dose of said at least one controlled release dosage form, 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
27. The method of claim 1 , wherein chronic twice-daily oral administration in the fed state of a dose of said at least one controlled release dosage form, 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
28. The method of claim 1 , wherein chronic twice-daily oral administration in the fasting state of a dose of said at least one controlled release dosage form, 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
29. The method of claim 1 , wherein chronic oral administration in the fasting state of said at least one controlled release dosage form comprising a 20 mg dose 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
30. The method of claim 1 , wherein oral administration in the fasting state of a single dose of said at least one controlled release dosage form 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
31. The method of claim 1 , wherein said at least one controlled release dosage form provides a majority of drug release in the upper portion of the GI tract or provides a majority of drug release downstream of the stomach and upstream of the colon.
32. The method of claim 1 , wherein said at least one controlled release controlled release dosage form provides a plasma concentration of ARBAC that is at least 4-fold higher than the cerebrospinal fluid concentration of ARBAC.
33. 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) a core comprising ARBAC, at least one osmotic salt, at least one binder, at least two water swellable excipients, wherein said at least two water-swellable excipients comprise a majority of a first type of polymer and a minority of a second type of polymer; and b) a semipermeable membrane surrounding the core, said membrane comprising at least two different types or grades of film-forming cellulose ester; wherein following oral administration of said at least one controlled release dosage form, the dosage form releases a majority of ARBAC downstream of the stomach and upstream of the colon.
34. The method of claim 33 , wherein said at least one controlled release dosage form exhibits a positive food effect.
35. The method of claim 34 , wherein a) oral administration in the fed state of one of said controlled release dosage form comprising a 20 mg dose of ARBAC provides an AUC of about 1400-1900 ng·h/ml, and oral administration in the fasting state of one of said controlled release dosage form comprising a 20 mg dose of ARBAC provides an AUC of about 550-1080 ng·h/ml; or b) chronic oral administration in the fed state of a controlled release dosage form comprising a 20 mg dose of ARBAC provides a steady state AUC of about 1000-1700 ng·h/ml, and chronic oral administration in the fasting state of a controlled release dosage form comprising a 20 mg dose of ARBAC provides a steady state AUC of about 600-1150 ng·h/ml.
36. The method of claim 33 , 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.
37. 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) a core comprising ARBAC, at least one osmotic salt, at least one water swellable cellulose derivative, and at least one water swellable polyalkylene oxide; and b) a semipermeable membrane surrounding the core, said membrane comprising at least two different types or grades of film-forming cellulose ester; wherein following oral administration of said at least one controlled release dosage form, the dosage form releases a majority of ARBAC downstream of the stomach, upstream of the colon and in the upper portion of the GI tract; and 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.
38. The method of claim 37 , wherein said at least one controlled release dosage form exhibits a positive food effect.
39. The method of claim 38 , wherein a) oral administration in the fed state of one of said at least one controlled release controlled release dosage form comprising a 20 mg dose of ARBAC provides an AUC of about 1400-1900 ng·h/ml, and oral administration in the fasting state of one of said at least one controlled release controlled release dosage form comprising a 20 mg dose of ARBAC provides an AUC of about 550-1080 ng·h/ml; or b) chronic oral administration in the fed state of said at least one controlled release controlled release dosage form comprising a 20 mg dose of ARBAC provides a steady state AUC of about 1000-1700 ng·h/ml, and chronic oral administration in the fasting state of said at least one controlled release controlled release dosage form comprising a 20 mg dose of ARBAC provides a steady state AUC of about 600-1150 ng·h/ml.
40. The method of claim 37 , 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.
41. The method of claim 1 , wherein said at least one controlled release dosage form is not gastroretentive.