Liquid pharmaceutical compositions of baclofen for oral administration
The present invention relates to liquid pharmaceutical compositions of baclofen or a pharmaceutically acceptable salt thereof. More specifically, stable liquid pharmaceutical compositions of baclofen at concentrations of 5 mg/mL or more are provided. Preferably, the liquid pharmaceutical compositions are suitable for oral administration, and stable at pH ranges of 5-8 over a variety of storage conditions, including long-term storage for extended periods of time.
1. A liquid pharmaceutical composition, comprising baclofen, a solubilizer, and a pharmaceutically acceptable excipient selected from the group consisting of a sweetening agent, a flavoring agent, a preservative, an antioxidant, a viscosity modifier, a pH adjusting agent, a buffering agent, a coloring agent, a surfactant, and mixtures thereof, wherein baclofen is present at a concentration of about 2 mg/mL or more, wherein the pharmaceutical composition is an aqueous solution for oral administration, and wherein the liquid pharmaceutical composition is stable; and
wherein the solubilizer is at least one of cyclodextrin or a cyclodextrin derivative selected from the group consisting of hydroxypropyl-β-cyclodextrin (HP-β-CD), methyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin (SBE-β-CD), and hydroxypropyl-γ-cyclodextrin.
2. The liquid pharmaceutical composition according to claim 1 , wherein baclofen is present at a concentration from about 5 mg/mL to about 10 mg/mL.
3. The liquid pharmaceutical composition according to claim 2 , wherein the cyclodextrin or cyclodextrin derivative is present at a concentration of about 10 mg/mL to about 400 mg/mL, preferably from about 25 mg/mL to about 100 mg/mL, more preferably about 50 mg/mL.
4. The liquid pharmaceutical composition according to claim 2 , wherein the weight ratio of cyclodextrin or cyclodextrin derivative to baclofen is from about 1:1 to about 80:1, preferably from about 5:1 to about 20:1, more preferably about 10:1.
5. The liquid pharmaceutical composition according to claim 1 , wherein the liquid pharmaceutical composition has a pH in the range of about 5 to about 8, preferably between about 6 to about 7.
6. The liquid pharmaceutical composition according to the claim 1 , wherein the composition is stable for at least 6 months at 40° C./75% RH.
7. The liquid pharmaceutical composition according to the claim 1 , wherein the composition is stable for at least 12 months at about 2° C. to 8° C.
8. The pharmaceutical composition according to claim 1 , wherein a level of (4-(4-chlorophenyl)-2-pyrrolidinone is less than about 2% (w/w), preferably less than about 1.5% (w/w), more preferably less than about 1% (w/w) as measured by HPLC.
9. A pharmaceutical composition according to claim 1 , comprising:
(i) about 5 mg/mL of baclofen;
(ii) about 50 mg/mL of cyclodextrin or a cyclodextrin derivative;
(iii) about 2 mg/mL of a preservative;
(iv) water;
(v) a flavouring agent; and
(vi) a sweetener.
10. A process for the preparation of a stable, liquid pharmaceutical formulation for oral administration comprising baclofen according to claim 1 , the process comprising the steps of:
a) heating water to a temperature of up to about 60° C.;
b) adding cyclodextrin or the cyclodextrin derivative to the water to form a first solution;
c) stirring the first solution to obtain a first clear solution;
d) adding baclofen to the first clear solution to form a second solution;
e) stirring the second solution to obtain a second clear solution;
f) optionally, adding the pharmaceutically acceptable excipient; and
g) stirring to obtain a final clear solution.
11. A method for managing, treating or alleviating the signs and symptoms of spasticity resulting from multiple sclerosis, spinal cord damage or spinal cord disease in a patient by orally administering an effective amount of a liquid pharmaceutical composition according to claim 1 .
12. The method of claim 11 , wherein the patient is an adult, pediatric or geriatric patient.
13. A liquid pharmaceutical composition, comprising baclofen, a cyclodextrin, water, and a pharmaceutically acceptable excipient selected from the group consisting of a sweetening agent, a flavoring agent, a preservative, an antioxidant, a viscosity modifier, a pH adjusting agent, a buffering agent, a coloring agent, a surfactant, and mixtures thereof, wherein baclofen is present at a concentration of about 2 mg/mL or more, wherein the pharmaceutical composition is an aqueous solution for oral administration.
14. The liquid pharmaceutical composition according to the claim 13 , wherein the composition is stable for at least 6 months at 40° C./75% RH.