# US 2019/0167618 A1 · Controlled Release Dosage Form

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- Number: US 2019/0167618 A1
- Document ID: US20190167618A1
- Status: Published application
- Kind: A1
- Application number: 16/270,837
- Filed: 2019-02-08
- Published: 2019-06-06
- Earliest claimed: 2015-02-20
- Assignees: Osmotica Kereskedelmi Es Szolgaltato Kft
- Applicants: Osmotica Kereskedelmi Es Szolgaltato Kft
- Inventors: Glenn A. MEYER; Cristian R. FRANCO; Gustavo A. FISCHBEIN; Alejandro A. AGUILAR; Claude E. WRIGHT
- Web page: https://patentgrep.com/patent/US20190167618A1

## CPC

- A61K 31/197: the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid (carnitine A61K31/205)
- A61K 9/0004: {Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/006: {Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays}
- A61K 9/145: {with organic compounds}
- A61K 9/146: {with organic macromolecular compounds}
- A61K 9/20: Pills, tablets, {discs, rods (A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095)}
- A61K 9/2031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers}
- A61K 9/2866: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/4866: {Organic macromolecular compounds}
- A61K 9/5042: {Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose}
- A61K 31/222: with compounds having aromatic groups, e.g. dipivefrine, ibopamine
- A61K 31/325: Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof (thiurams A61K31/145)
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides a simple and improved dose form that is capable of providing a controlled release of GABAB 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 GABAB receptor agonist.

## Claims

### Claim 1

1) 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 ARBAC, wherein the dosage form exhibits a positive food effect in terms of bioavailability, Tmax, Cmax, AUC0-t and/or AUC0-inf of ARBAC when comparing oral administration of the dosage form in the fed and fasting states, and the dosage form comprises: a) a core comprising ARBAC, 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.

### Claim 2 (depends on 1)

2) 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.

### Claim 3 (depends on 1)

3) The method of claim 1, wherein the dosage form provides a controlled release of ARBAC for a period of at least 8 and up to about 24 hours.

### Claim 4 (depends on 1)

4) 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 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.

### Claim 5 (depends on 1)

5) The method of claim 1, wherein the dosage form exhibits an 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.

### Claim 6 (depends on 1)

6) The method of claim 1, wherein said dosage form exhibits an in vitro release profile 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

### Claim 7 (depends on 1)

7) The method of claim 1, wherein said dosage form provides a dissolution profile as depicted in FIG. 1 inclusive of the area 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.

### Claim 8 (depends on 1)

8) The method of claim 1, wherein the subject exhibits less adverse events associated with ARBAC than if the subject is administered an equivalent daily dose of ARBAC, present as part of racemic baclofen, in a rapid release or immediate release dosage form.

### Claim 9 (depends on 8)

9) The method of claim 8, wherein said subject experiences less drowsiness and/or less dizziness.

### Claim 10 (depends on 1)

10) The method of claim 1, wherein said dosage form is administered once, twice or three times daily.

### Claim 11 (depends on 1)

11) The method of claim 1, wherein said 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.

### Claim 12 (depends on 11)

12) The method of claim 11, wherein said 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 the immediate release dosage form.

### Claim 13 (depends on 1)

13) The method of claim 1, wherein said 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.

### Claim 14 (depends on 1)

14) The method of claim 1, wherein said dosage form provides a plasma profile approximately as depicted in FIG. 2.

### Claim 15 (depends on 1)

15) The method of claim 1, wherein oral administration in the fed state of a single dose of said 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

### Claim 16 (depends on 15)

16) The method of claim 15, wherein said single dose is in a single said dosage form.

### Claim 17 (depends on 1)

17) The method of claim 1, wherein oral administration in the fed state of multiple daily doses of said dosage form comprising a total dose of about 20 mg of ARBAC provides a steady state pharmacokinetic profile defined as follows:
Mean values
Tmaxss (hr)
4-6
Cmaxss (ng/ml)
about 120-220
Cminss (ng/ml)
about 10-100
AUCss (ng · h/ml)
about 1000-1700

### Claim 18 (depends on 17)

18) The method of claim 17, wherein said multiple daily doses is twice daily doses.

### Claim 19 (depends on 18)

19) The method of claim 18, wherein said daily doses are administered about every twelve hours for five days.

### Claim 20 (depends on 1)

20) The method of claim 1, wherein oral administration in the fasting state of said dosage form comprising a total dose 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
AUC0-inf (ng · h/ml)
About 575
About 700
About 1090

### Claim 21 (depends on 20)

21) The method of claim 20, wherein each said below-specified dose is in its respective single said dosage form.

### Claim 22 (depends on 1)

22) The method of claim 1, wherein oral administration in the fasting state of a single dose of said dosage form comprising a total dose of about 20 mg 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

### Claim 23 (depends on 22)

23) The method of claim 22, wherein said single dose is in a single said dosage form.

### Claim 24 (depends on 1)

24) The method of claim 1, wherein oral administration in the fasting state of multiple daily doses of said dosage form comprising a total dose of about 20 mg of ARBAC provides a steady state pharmacokinetic profile defined as follows:
Mean values
Tmaxss (hr)
3.5-5.5
Cmaxss (ng/ml)
about 80-150
Cminss (ng/ml)
about 5-80
AUCss (ng · h/ml)
about 600-1150

### Claim 25 (depends on 24)

25) The method of claim 24, wherein said multiple daily doses is twice daily doses.

### Claim 26 (depends on 25)

26) The method of claim 25, wherein said daily doses are administered about every twelve hours for five days.

### Claim 27 (depends on 1)

27) The method of claim 1, wherein said dosage form provides a plasma concentration of ARBAC that is at least 4-fold higher than the cerebrospinal fluid concentration of ARBAC.

### Claim 28 (depends on 1)

28) The method of claim 1, wherein said dosage form provides a majority of drug release in the upper portion of the GI tract.

### Claim 29 (depends on 1)

29) The method of claim 1, wherein said 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 ARBAC which may be present as racemic baclofen.

### Claim 30 (depends on 1)

30) The method of claim 1, wherein said dosage form provides a majority of drug release downstream of the stomach and upstream of the colon.

### Claim 31

31) 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 therapeutically effective dose of ARBAC, wherein the controlled release dosage form provides an in vitro dissolution profile approximately as depicted in FIG. 1 inclusive of the area 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., and the dosage form comprises: a) a core comprising ARBAC, 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.

### Claim 32

32) 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 therapeutically effective dose of ARBAC, wherein the dosage form provides a majority of drug release in the upper portion of the GI tract downstream of the stomach, and the dosage form comprises: a) a core comprising ARBAC, 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.

### Claim 33 (depends on 32)

33) The method of claim 32, wherein said dosage form provides a majority of drug release downstream of the stomach and upstream of the colon.

### Claim 34

34) 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 therapeutically effective dose of ARBAC, wherein 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 ARBAC which may be present as racemic baclofen, and the dosage form comprises: a) a core comprising ARBAC, 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.

### Claim 35 (depends on 34)

35) The method of claim 34, wherein said dosage form provides reduced sleepiness and/or reduced drowsiness.

### Claim 36 (depends on 34)

36) The method of claim 34, wherein oral administration in the fed state of multiple daily doses of said dosage form comprising a total dose of about 20 mg of ARBAC provides a steady state pharmacokinetic profile defined as follows:
Mean values
Tmaxss (hr)
4-6
Cmaxss (ng/ml)
about 120-220
Cminss (ng/ml)
about 10-100
AUCss (ng · h/ml)
about 1000-1700

### Claim 37 (depends on 36)

37) The method of claim 36, wherein said multiple daily doses is twice daily doses.

### Claim 38 (depends on 37)

38) The method of claim 37, wherein said daily doses are administered about every twelve hours for five days.

### Claim 39 (depends on 34)

39) The method of claim 34, wherein oral administration in the fasting state of multiple daily doses of said dosage form comprising a total dose of about 20 mg of ARBAC provides a steady state pharmacokinetic profile defined as follows:
Mean values
Tmaxss (hr)
3.5-5.5
Cmaxss (ng/ml)
about 80-150
Cminss (ng/ml)
about 5-80
AUCss (ng · h/ml)
about 600-1150

### Claim 40 (depends on 39)

40) The method of claim 39, wherein said multiple daily doses is twice daily doses.

### Claim 41 (depends on 40)

41) The method of claim 40, wherein said daily doses are administered about every twelve hours for five days.