WO2007107835A2

WO2007107835A2 - Stable liquid formulations of antiepileptic agents

Info

Publication number: WO2007107835A2
Application number: PCT/IB2007/000652
Authority: WO
Inventors: Vikas Yande; Shailesh Kulkarni; Srichakravarthy Narasimharaghavan; Sivakumaran Meenakshisunderam
Original assignee: Aurobindo Pharma Ltd
Current assignee: Aurobindo Pharma Ltd
Priority date: 2006-03-17
Filing date: 2007-03-14
Publication date: 2007-09-27
Anticipated expiration: 2008-09-17
Also published as: WO2007107835A3

Abstract

The present invention relates to a stable and taste masked oral liquid formulation comprising GABA analogues and a polyhydric alcohol containing 2 to 6 carbon atoms, wherein the content of polyhydric alcohol is equal to or less than 20% weight/volume (w/v) of the composition.

Description

STABLE LIQUID FORMULATIONS OF ANTIEHLEPTIC AGENTS

Field of the invention

The present invention relates to a stable oral liquid formulation of antiepileptic drug. More particularly, the present invention relates to a stable oral liquid formulation of GABA analogues.

The present invention also relates to preparation of a stable oral liquid formulation of GABA analogues.

Background of the invention Gamma amino butyric acid (GABA) is an inhibitory amino acid found in the mammalian central nervous system (CNS). It has been reported that dysfunctions with GABA neurotransmission in the CNS may contribute or even cause psychiatric and neurological diseases such as epilepsy, schizophrenia, Parkinson's disease, Huntington's chorea and dyskinesia (Saletu B., et al., International Journal of Clinical Pharmacology, Therapy, and Toxicology, 1986; 24:362-373).

Two GABA analogues viz. Gabapentin and Pregabalin have been approved for the treatment of epilepsy and other related disorders.

Gabapentin is chemically known as l-(aminomethyl)-cyclohexaneacetic acid. It was designed as a GABA analogue that would cross the blood-brain barrier. Gabapentin was found to have anticonvulsant and antispastic activity with extremely low toxicity in man. Gabapentin is commercially marketed as oral tablet, capsule and solution under the trade name NEURONTIN^® in the US for the treatment of partial seizures in patients with epilepsy. Pregabalin is chemically known as S-enantiomer of 3-aminomethyl-5- methyl-hexanoic acid and is disclosed in US 5,563,175 for the treatment of partial seizures in patients with epilepsy. It is commercially marketed as oral capsule under the trade name LYRICA^® in the US. Being a GABA analog, it shows a phenomenon identical to that of gabapentin as regards its degradation in aqueous solution into lactam molecules. US patent Nos. 4,024,175 and 4,087,544 disclose the use of gabapentin for the treatment of certain forms of epilepsy, faintness attacks, hypokinesia, and cranial traumas.

US patent No. 6,054,482 discloses a stable pharmaceutical composition in unit dry medicinal dosage form consisting essentially of: (i) an active ingredient which is gabapentin in the free amino acid, crystalline anhydrous form containing less than 0.5% by weight of its corresponding lactam and less than 20 ppm of an anion of a mineral acid and (ii) one or more pharmaceutically acceptable adjuvants that do not promote conversion of more than 0.2% by weight of the gabapentin to its corresponding lactam form when stored at 25°C and an atmospheric humidity of 50% for one year.

It was found that liquid formulations of gabapentin undergo cyclization to form lactam much more readily than in the solid state. For safety reasons, levels of lactam compound must be reduced to a minimum. Further, Gabapentin has a very bitter taste and there is a need to administer high doses of gabapentin in the treatment of certain diseases. To overcome these issues, US 2004/0072904 disclosed a liquid pharmaceutical composition of a GABA analogue comprising at least one polyhydric alcohol containing 2 to 6 carbon atoms having a pH of about 5.5 to about 7.0, wherein the content of polyhydric alcohol is about 25% to about 75% weight/volume (w/v).

US 2002/0012679 described a process for manufacturing coated particles of GABA analogue, whose lactam content by weight relative to the weight of

GABA analogue is less than 0.5%. The process is characterized in that a coating solution of at least one polymer in an organic solvent is sprayed onto the particles of GABA.

WO 99/59573 discloses stabilized pharmaceutical preparation of a 4- amino-3-substituted-butanoic acid derivative obtained by incorporating an amino acid as a stabilizer.

Both gabapentin and prgabalin are bitter in taste, thereby making it difficult to use in the native form in pharmaceutical formulations. To address the problem of bitter taste, EP O 458 751 proposed gabapentin in the form of particles coated with a hydrophilic first layer of a water-insoluble polymer and a hydrophobic second layer. Even though satisfactory masking of the taste is obtained, the process of coating the first layer requires the presence of water, such that an intramolecular cyclization of gabapentin can be expected, leading to the formation of lactam inside the finished product itself.

In view of this, there is a need to develop stable oral liquid formulation of GABA analogues. The inventors of the present invention found that stability of GABA analogues can be maintained using low concentrations of polyhydric alcohols containing 2 to 6 carbon atoms.

Objective of the present invention

Accordingly, the main objective of the present invention is to provide simple, stable and taste masked oral liquid formulation of GABA analogue.

Summary of the invention Accordingly, the present invention provides a stable and taste masked oral liquid formulation comprising GABA analogue and polyhydric alcohol containing 2 to 6 carbon atoms, wherein the content of polyhydric alcohol is equal to or less than 20% weight/volume (w/v) of the composition.

Detailed description of the invention The polyhydric alcohol are known to be highly safe as they are in hydrogenated form of the carbohydrate where the carbonyl group has been reduced to primary or secondary hydroxyl group. Various polyhydric alcohols containing 2 to 6 carbon atoms useful according to the present invention are glycerol, xylitol, sorbitol, mannitol and mixture thereof. In yet another embodiment of the present invention, polyhdric alcohol used is equal to or less than 20% w/v, preferably in the range of 5 to 20% w/v of the composition.

GABA analogues of the present invention include gabapentin, pregabalin.

In yet another embodiment, the stable oral liquid formulation of GABA analogue further comprises pharmaceutically acceptable excipients such as colorants, liquid carriers, flavors, preservatives, antioxidants, sweetener, buffers, solubilizing agents and the like.

Suitable sweetener used according to the present invention is selected from the group consisting of sucrose, maltose, sodium saccharin, aspartame, lactitol, maltitol, acesulfame potassium and the like or mixture thereof.

Suitable preservatives used according to the present invention are selected from methyl paraben, propyl paraben, alkyl hydroxybenzoates; sorbic acid or a salt thereof; benzoic acid or a salt thereof; sodium metabisulfite, and mixtures thereof. Suitable buffering systems according to the present invention include combinations of citric acid and salts and solvates thereof, for example citric acid (anhydrous or monohydrate) combined with sodium citrate dihydrate.

Suitable flavoring aids according to the present invention are selected from strawberry, cherry, grape, anise, menthol and vanillin. Suitable liquid carriers according to the present invention are selected from water, ethanol, polyethylene glycols, propylene glycol and the like or mixtures thereof.

Suitable solubilizers according to the present invention include polysorbate 80, sodium lauryl sulfate, poloxamer and the like. The amount of solubilizer used may range from about 0.1 to about 50 mg/ml of the composition, preferably, from 0.1 to 30.0 mg/ml of the composition.

Suitable antioxidant according to the present invention include butylated hydroxy anisole (BHA), butylated hydroxytoulene (BHT), ascorbic acid, benzoic acid, cysteine hydrochloride, isoascorbic acid and sodium metabisulfite and the like or mixtures thereof.

In yet another embodiment, the oral liquid formulation is in the form of a solution, suspension or emulsion.

The pH of the oral liquid formulation of GABA analogue is in the range of 5.0 to 8.0, preferably in the range of 5.0 to 7.0. In yet another embodiment, the oral liquid formulation of GABA analogues has less than 0.5% by weight of the corresponding lactam analogue after storage at about 2⁰C to about 1O⁰C, preferable about 2⁰C to about 8⁰C. for 18 months to 2 years, preferable 18 months. In yet another embodiment of the present invention, there is provided a process for the preparation of stable and taste masked oral liquid formulation comprising GABA analogue and polyhydric alcohol containing 2 to 6 carbon atoms, wherein the content of polyhydric alcohol is equal to or less than 20% weight/volume (w/v) of the composition, comprises the steps of i). preparing a clear solution by dissolving polyhydric alcohol containing 2 to 6 carbon atom in the water, ii). dissolving GABA analogue in the solution obtained from step (1) by stirring for a period of 30 min, iii). adding one or more sweetener, flavoring agent, preservatives under stirring and iv). finally making up the volume with purified water.

In yet another embodiment, there is provided a method for the treatment of a subject suffering from cerebral diseases, including epilepsy, faintness attacks, hypokinesia and cranial traumas, neurodegenerative disorders, depression, mania and bipolar disorders, anxiety, panic, inflammation, renal colic, insomnia, gastrointestinal damage, incontinence, pain, including neuropathic pain, muscular pain, skeletal pain, and migraine, by administering liquid formulation of gabapentin of the present invention.

The following example further exemplifies the invention and is not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry. Example 1

The processing steps involved are:

1. a clear solution was prepared by dissolving xylitol in purified water,

2. gabapentin was dissolved in the clear solution obtained in step (1) under stirring for about 30 minutes,

3. sodium saccharin and artificial strawberry was added to the solution obtained in step (2) under stirring,

4. finally the volume was made with purified water under stirring.

The stable and taste masked oral liquid formulations of gabapentin disclosed in example 2 and 3 were prepared by a similar procedure described in example 1.

Example 2

Example 3

Gabapentin oral solution prepared according the present invention was found to be stable. The 3 months stability carried out at 25 ⁰C, 60 % relative humidity is shown in table 1.

Table 1

Claims

Claims:

1. A stable oral liquid formulation comprising GABA analogue and polyhydric alcohol containing 2 to 6 carbon atoms, wherein the content of polyhydric alcohol is equal to or less than 20% weight/volume (w/v) of the composition.

2. The stable oral liquid formulation of GABA analogue as claimed in claim 1, wherein the polyhydric alcohol containing 2 to 6 carbon atoms are selected from glycerol, xylitol, sorbitol, mannitol and mixture thereof.

3. The stable oral liquid formulation of GABA analogue as claimed in claim 1, wherein the said composition has less than 0.5% by weight of the corresponding lactam analogue.

4. The stable oral liquid formulation of GABA analogue as claimed in claim 1, wherein the pH of the solution is in the range of 5.0 to 7.0.

5. The stable oral liquid formulation as claimed in claim 1, further comprises one or more pharmaceutically acceptable excipients such as colorants, liquid carriers, flavors, preservatives, antioxidants, sweetener, buffers and solubilizing agents.

6. The stable oral liquid formulation as claimed in claim 5, wherein the sweetener is selected from the group consisting of sucrose, maltose, sodium saccharin, aspartame, lactitol, maltitol, acesulfame potassium and the like or mixture thereof.

7. The stable oral liquid formulation as claimed in claim 5, wherein the antioxidant is selected from the group consisting of butylated hydroxy anisole (BHA), butylated hydroxytoulene (BHT), ascorbic acid, benzoic acid, cysteine hydrochloride, isoascorbic acid and sodium metabisulfite and the like or mixtures thereof.

8. The stable oral liquid formulation as claimed in claim 5, wherein the flavouring agent is selected from the group consisting of strawberry, cherry, grape, anise, menthol, and vanillin.

9. The stable oral liquid formulation as claimed in claim 5, wherein the liquid carriers are selected from the group consisting of water, ethanol, polyethylene glycols, propylene glycol and the like or mixtures thereof.

10. The stable oral liquid formulation as claimed in claim 5, wherein the solubilizer is selected from the group consisting of polysorbate 80, poloxamer, sodium lauryl sulfate and mixture thereof.

11. A process for the preparation of stable oral liquid formulation comprising GABA analogue and polyhydric alcohol containing 2 to 6 carbon atoms, wherein the content of polyhydric alcohol is equal to or less than 20% weight/volume (w/v) of the composition, comprises the steps of i). preparing a clear solution by dissolving polyhydric alcohol containing 2 to 6 carbon atom in the water, ii). dissolving GABA analogue in the solution obtained from step (1) by stirring for a period of 30 min, iii). adding one or more sweetener, flavouring agent, preservatives under stirring and iv). finally making up the volume with purified water.