Description

The present invention relates to a stable oral pharmaceutical composition of Sodium oxybate or free base thereof. In particular  present invention relates to a pharmaceutical composition of sodium oxybate comprising one or more preservatives and optionally with other pharmaceutically acceptable excipients. The invention also includes process of preparing such composition.

Sodium oxybate  also known as sodium salt of gamma-hydroxybutyrate (GHB)  is a central nervous system depressant. Chemically  sodium oxybate is sodium 4-hydroxybutyrate  with the following structure:

Sodium oxybate is approved in United States under the proprietary name Xyrem® as oral solution and marketed by Jazz Pharms. Sodium oxybate is a white to off-white  crystalline powder that is very soluble in aqueous solutions. Xyrem® oral solution contains 500 mg of sodium oxybate per milliliter of USP purified water  neutralized to pH 7.5 with malic acid.

The Xyrem® oral solution is prescribed for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy.

GHB is the pharmacologically active metabolite of both gamma-butyrolactone (GBL) and 1  4-butanediol (1  4-BD)  both of which have been abused recreationally." It is also known that GHB and GBL are interconverted in aqueous solution via hydrolysis and intramolecular esterification reactions.

U.S. Patent No. 6 780 889 discloses a pharmaceutical composition comprising an aqueous solution of 500 mg/ml sodium gamma-hydroxybutyrate  and malic acid as a pH adjusting agent. The composition has a pH of about 7.5  chemically stable  resistant to microbial growth and the composition is free of preservatives.

U.S. Patent No. 6  472 431 discloses a method of preparing an aqueous medium resistant to microbial growth comprising adding the gamma-hydroxybutyrate salt to the aqueous medium  adjusting the concentration of the gamma-hydroxybutyrate salt in the aqueous medium to a final concentration of at least about 250 mg/ml and the pH of the medium to of about 6 to about 10.

The Patent No. 6 780 889 discloses that use of preservative in sodium oxybate composition may adversely affect the pH of the composition and thus gamma-hydroxybutyrate’s stability.

Thus  the prior arts disclosure suggests that use of preservative sodium oxybate formulations may adversely affect the pH of the composition and thus  may result ultimately in unstable formulations of gamma-hydroxybutyrate.

Thus  there still exists an enduring need to develop an improved  stable pharmaceutical composition of sodium oxybate which will provides an alternative to existing formulation of sodium oxybate.

The inventors of the present invention have surprisingly found that by using one or more preservative(s) in sodium oxybate compositions  level of impurities can be controlled significantly. Thus the present invention provides a stable pharmaceutical composition of sodium oxybate comprising one or more preservative(s) in legitimate amount and optionally other pharmaceutically acceptable excipients  which exhibits excellent storage stability.

The inventors of the present invention further empirically found that using low amount of preservative has a direct effect on the formulation stability. In particular  the inventors have found that judicial amount of the preservative  particularly  paraben can effectively curb the degradation of sodium oxybate and eventually control generation of gamma-butyrolactone (GBL) with a wide range of several other gamma-hydroxybutyrate (GHB) impurities. As a result  inventors of the present invention have found a novel way of preparing the pharmaceutical composition of sodium oxybate which can exhibit excellent storage stability.

The compositions of the present invention are stable compositions of gamma-hydroxybutyrate that improve shelf-life  and provide a titratable formulation of gamma-hydroxybutyrate for easy dose measurement.

In one general aspect  there is provided a stabilized oral pharmaceutical composition comprising sodium oxybate and one or more preservative(s) and optionally with one or more pharmaceutically acceptable excipients  wherein the amount of preservatives in the composition ranges from about 0.006% to about 0.2% w/v.

In another general aspect  there is provided a stabilized oral pharmaceutical composition comprising sodium oxybate  butylparaben  and optionally one or more pharmaceutically acceptable excipients  wherein the amount of butylparaben in the composition range from about 0.006 % to 0.05 % w/v.

In another general aspect  there is provided a stabilized oral pharmaceutical composition comprising sodium oxybate  one or more preservative and optionally other pharmaceutically acceptable excipients  wherein the amount of preservatives comprising butylparaben in the composition range from about 0.006 % to 0.05 % by weight/volume (w/v)  characterized in that the level of total impurity in the said composition is not more than 1.5%

In another general aspect  there is provided a stabilized oral pharmaceutical composition comprising sodium oxybate and butylparaben  wherein the amount of butylparaben in the composition ranges from about 0.006 % to 0.05 % by w/v and characterized in that the level of individual impurity in the said composition is not more than 0.1%.

In another general aspect  there is provided a stabilized oral pharmaceutical composition comprising sodium oxybate and one or more preservative(s)  wherein the ratio of the amount of sodium oxybate or free base thereof to preservative(s) in the composition ranges from about 1:0.0006 to about 1: 0.000075 by weight.

In another general aspect  the composition contains sodium oxybate or free base thereof having purity equal to or greater than 90%.

In another general aspect  there is provided a stabilized oral pharmaceutical composition comprising sodium oxybate and one or more preservative(s)  wherein the amount of preservative(s) in the composition ranges from about 0.006% to about 0.2% w/v  and characterized in that said composition contains retains at least 90% w/w of total potency of sodium oxybate or its free base when stored for real time study condition at 25°C and 40% relative humidity or for accelerated study condition at 400C and 25% relative humidity.

In another general aspect  there is provided a stabilized oral pharmaceutical composition comprising sodium oxybate and one or more preservative(s)  one or more pH adjusting agents  aqueous vehicle  sweetening agent  flavoring agent and optionally one or more other pharmaceutically acceptable excipients  wherein the amount of preservatives in the composition ranges from about 0.006% to about 0.2% by weight/volume (w/v).

In another general aspect  there is provided a process for preparation of stable oral pharmaceutical composition comprising sodium oxybate  which process comprises of mixing sodium oxybate solution and one or more preservatives and optionally with one or more pharmaceutically acceptable excipients  wherein the amount of preservative(s) in the composition ranges from about 0.006% to about 0.2% w/v.

The term "Sodium oxybate" used throughout the specification refers to not only sodium oxybate per se  but also its free base  other pharmaceutically acceptable salts  pharmaceutically acceptable solvates  pharmaceutically acceptable hydrates  pharmaceutically acceptable enantiomers  pharmaceutically acceptable derivatives  pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.

The term "stable composition" or “stabilized composition” used throughout the specification refers to composition resistant to degradation of GHB into its known or unknown decomposition elements.

The term "preservative" used throughout the specification refers to substances that inhibit chemical change or microbial inhibition. Such preservatives may include  but are not limited to  parabens  xylitol  sodium benzoate  propyl gallate  sorbic acid  chlorobutanol  dihydroacetic acid  monothioglycerol  potassium benzoate  benzoic acid  benzalkonium chloride  alcohol  benzoic acid  benzalkonium chloride  benzethonium chloride  benzyl alcohol  butylparaben  cetylpyridinium chloride  ethylenediamine  ethyl vanillin  glycerin  hypophophorus acid  phenol  phenylethyl alcohol  phenymercuric nitrate  sassafras oil  sodium benzoate  sodium propionate  thimerosal and potassium sorbate. Preferred preservatives may be selected from the group comprising parabens but not limited to  methylparaben  ethylpareben propylparaben and butylparaben.

The stabilized oral pharmaceutical composition of the present invention may be characterized by sodium oxybate having purity equal to or greater than 90% by weight.

The stabilized oral pharmaceutical composition of the present invention is further characterized by containing total impurity of not more than 1.5% and any individual impurity of not more than 0.1%.

In an embodiment  the pharmaceutical composition of the present invention retains at 90% w/w of total potency of sodium oxybate or its free base when stored for real time study condition at 25°C and 40% relative humidity or for accelerated study condition at 400C and 25% relative humidity for at least 3 months.

In a further embodiment  the composition comprises total impurity of about 1.5% or less when stored at 25°C and 40% relative humidity or at 400C and 25% relative humidity for 3 months.

Various methods of analyzing (characterization and quantification) the impurities are well established in the art. Various spectroscopic techniques  such as NMR  MS  IR etc. and chromatographic techniques  such as HPLC  HPLC-TLC  HPLC-CE and hyphenated methods  such as LC-MS-MS  HPLC-DAD-MS  HPLC-NMR  GC-MS & LC-MS can be used for analyzing impurities.

The pharmaceutical composition of the present invention may be developed in the form of a dosage form suitable of oral administration.

Suitable dosage form includes  but not limited to a solution  suspension  dry powder for solution or suspension or syrup.

The pharmaceutical composition of the present invention may also be developed in the form of a dosage form suitable of parenteral administration. The parenteral route of administration of the compositions comprises subcutaneous  intramuscular  intravenous  transdermal  intradermal  intranasal  intraarterial and intraperitoneal injection or infusion.
The pharmaceutical composition of the present invention further comprises various pharmaceutically acceptable excipients suitable for oral administration. Such excipient includes  but not limited to pH adjusting agents or buffers  co-solvents  chelating agents/sequestering agents  sweetening agents  flavoring agents  antioxidant and aqueous vehicle.

Examples of suitable pH adjusting agents includes  but not limited to hydrochloric acid  citric acid  ascorbic acid  acetic acid  tartaric acid  phosphoric acid  metaphosphoric acid  polymetaphosphoric acid  carbonic acid  sodium hydroxide  potassium hydroxide  sodium citrate  potassium citrate  sodium bicarbonate  potassium bicarbonate  ammonium carbonate  sodium hydrogen phosphate  potassium hydrogen phosphate  ethanolamine  diethanolamine  triethanolamine  hexane-1 2-diamine  sodium carbonate  sodium potassium tartrate  potassium metaphosphate  potassium polymetaphosphate  and sodium metaphosphate. The pH of the pharmaceutical composition preferably ranges from about 6 to about 10.

Examples of suitable buffers includes  but not limited to pharmaceutically acceptable salts and acids of acetate  glutamate  citrate  tartrate  benzoate  lactate  histidine or other amino acids  gluconate  phosphate  malate  succinate  formate  propionate  and carbonate.

Examples of suitable co-solvents includes  but not limited to ethanol  glycerol  propylene glycol  polyethylene glycol  and different oils.

Examples of suitable chelating agents/ sequestering agents includes  but not limited to ethylenediaminetetraacetic acid (EDTA)  diethylenetriaminepentaacetic acid (DTPA)  hydroxyethylenediaminetriacetic acid (HEDTA)  ethylene glycol-bis-(2-aminoethyl)-N N N"" N""-tetraacetic acid (EGTA)  nitrilotriacetic acid (NTA)  citrate and alkaline salt derivatives thereof.

Examples of suitable antioxidants include  but are not limited to  asocrbyl palmitate  butylated hydroxyanisole  butylated hydroxytoluene  potassium metabisulfite  sodium metabisulfite  anoxomer and maleic acid.

The present invention further provides a process of manufacturing sodium oxybate compositions. The present process involves mixing sodium oxybate solution and one or more preservatives and optionally pharmaceutically acceptable excipients  wherein the amount of preservatives in the composition ranges from about 0.006% to about 0.2% w/v.

The process also involves preparing sodium oxybate in liquid or solid form  mixed/dissolved with one or more preservatives and optionally other pharmaceutically acceptable excipients with said sodium oxybate.

The present invention further refers to the use of the above defined composition for the preparation of medicaments useful for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example 1: Preparation of Sodium oxybate [liquid form]

Sr. No. Ingredients Quantity in mg/ mL % weight/ volume (w/v)
1. Gamabutyrolactone 340.62 34.062
2. Sodium Hydroxide 158.26 15.826
3. Purified water 401.12 40.112
4. Subtotal 900.00 90%

Process: The specified amount of water was transferred in jacketed tank. To this Sodium Hydroxide was added slowly to dissolve and form clear solution. The solution was mixed for specified time. This step involved exothermic reaction and temperature of the bulk solution raised to 90ºC-95ºC. The obtained solution was cooled to 20ºC-25ºC. To this Gama-butyrolactone was added slowly and mixed with well. Temperature of bulk solution was maintained and mixed the contents for specified time. The obtained bulk solution was cooled and checked for the pH and visual clarity of solution.

Example 2: Sodium oxybate oral solution 500.0 mg/mL

Sr. No. Ingredients Quantity in (mg) % weight/ volume (w/v)
1. Sodium oxybate [liquid form] 900.00 90.00
2. Butylparaben Sodium 0.075 0.0075
3. Malic acid (In the form of 10 % aqueous Solution) q.s to adjustpH-7.5 q.s to adjustpH-7.5
4. Purified water q.s.to 1.000 mL 100.00 %

Example 3: Sodium oxybate oral solution 500.0 mg/mL

Sr. No. Ingredients Quantity in (mg) % weight/ volume (w/v)
1. Sodium oxybate [liquid form] 900.00 90.00
2. Butylparaben Sodium 0.113 0.00375
3. Malic acid (In the form of 10 % aqueous Solution) q.s to adjustpH-7.5 q.s to adjustpH-7.5
4. Purified water q.s.to 1.000 mL 100.00 %

Example 4: Sodium oxybate oral solution 500.0 mg/mL
Sr. No. Ingredients Quantity in (mg) % weight/ volume (w/v)
1. Sodium oxybate [liquid form] 900.00 90.00
2. Propylparaben Sodium 0.225 0.0225
3. Malic acid q.s to adjustpH-7.5 q.s to adjustpH-7.5
4. Purified water q.s.to 1.000 mL 100.00 %

Example 5: Sodium oxybate oral solution 500.0 mg/mL

Sr. No. Ingredients Quantity in (mg) % weight/ volume (w/v)
5. Sodium oxybate [liquid form] 900.00 90.00
6. Propylparaben Sodium 0.112 0.0112
7. Malic acid q.s to adjustpH-7.5 q.s to adjustpH-7.5
8. Purified water q.s.to 1.000 mL 100.00 %

Example 6: Sodium oxybate oral solution 500.0 mg/mL

Sr. No. Ingredients Quantity in (mg) % weight/ volume (w/v)
1 Sodium oxybate [liquid form] 900.00 50.000
2 Propylparaben Sodium 0.225 0.0225
3 Butylparaben Sodium 0.0025 0.0075
4 Malic acid q.s to adjustpH-7.5 q.s to adjustpH-7.5
5 Purified water 1.000mL Qs to 100.0 %
Process: The weighed amount of preservative(s) was dissolved in water to form clear solution. To this measured amount of bulk solution obtained in Example 1 was added and mixed for specified time. The pH adjusted using acid solution. Make up volume and mixed further for time. The obtained solution filtered  checked for the yield and finally packed.

We claim:

1. A stabilized pharmaceutical composition of sodium oxybate or free base thereof comprising one or more preservatives and optionally one or more pharmaceutically acceptable excipients.

2. The stabilized pharmaceutical composition of claim 1  wherein the amount of preservative in the composition ranges from about 0.006% to about 0.2% w/v.

3. The stabilized pharmaceutical composition of claim 1  wherein the level of total impurities in the said composition is less than 1.5%.

4. The stabilized pharmaceutical composition of claim 1  wherein the level of individual impurities in the said composition is less than 0.1%.

5. The stabilized pharmaceutical composition of claim 1  wherein the ratio of the amount of sodium oxybate or free base thereof to preservatives in the composition ranges from about 1:0.0006 to about 1: 0.000075 by weight.

6. The stabilized pharmaceutical composition of claim 1  wherein the composition retains at least 90% w/w of the total potency of sodium oxybate or its free base when stored at 25°C and 40% relative humidity or at 400C and 25% relative humidity for 3 months.

Dated this 20th day of December 2012 For Wockhardt Limited

(Dr. Mandar Kodgule)
Authorized Signatory