DESC:FIELD OF THE INVENTION
The present invention relates to an oral liquid pharmaceutical composition of Valproic acid and/or its salts, esters or amides and a process of preparing the same.

BACKGROUND OF THE INVENTION
Valproic acid and/or its salts, esters or amides are anti-epileptic drugs which are primarily used in the treatment of seizures and bipolar disorder besides being used for the prophylaxis of migraine headaches.
Valproic acid and its sodium salt are most frequently prescribed in the clinical settings. Further, liquid compositions are preferred dosage forms, for certain patient populations such as children and psychiatric patients who have difficulty in swallowing solid oral dosage forms, since these dosage forms offer ease of administration and can be made palatable to mask objectionable taste of certain drugs. Valproic acid is liquid in nature while its sodium salt is a hygroscopic solid exhibiting poor stability. Consequently, both forms of the active substance are reported to be unsuitable for the preparation of oral liquid pharmaceutical compositions.
With regards to certain patient populations, there exists a need in the pharmaceutical art to provide oral liquid pharmaceutical compositions of Valproic acid and/or its salts, esters or amides. One of the major factor in the development of liquid pharmaceutical compositions is the stability of the formulation since most of the drugs are reported to exhibit decreased stability when formulated as liquid compositions. Additionally, there exists a need to provide oral liquid pharmaceutical compositions of Valproic acid and/or its salts which are not only palatable but also offer desirable stability.
The Applicants have successfully developed an oral liquid pharmaceutical composition comprising Valproic acid and/or its salts, esters or amides, prepared by a process which is not only simple, robust, but is also commercially viable. The oral liquid pharmaceutical composition prepared by the process of the invention is stable when subjected to stability testing at a temperature of 40°C ± 2°C. and relative humidity ("RH") of 75% ± 5% for a period of at least three months.

SUMMARY OF THE INVENTION
It is a principal object of the present invention to provide an oral liquid pharmaceutical composition of Valproic acid and/or its salts, esters or amides.
Further object of the present invention is to provide an oral liquid pharmaceutical composition of Valproic acid and/or its salts, esters or amides and pharmaceutically acceptable excipients, wherein said composition has a pH more than 7.
Another object of the present invention is to provide a process for preparing an oral liquid pharmaceutical composition of Valproic acid and/or its salts, esters or amides, wherein said composition exhibits palatability and storage stability, which is either superior or comparable to the marketed products, by virtue of selection of excipients and manufacturing process.
The following embodiments further describe the objects of the present invention. However, the disclosed invention is not restricted to the particular embodiments hereinafter described and extends to cover the modifications obvious to one of ordinary skill in the art.
In a preferred embodiment, the oral liquid pharmaceutical composition comprises therapeutically effective amount of Valproic acid and/or its salts, esters or amides with at least one pharmaceutically acceptable excipient, wherein the composition has a pH more than 7.
In another preferred embodiment, the oral liquid pharmaceutical composition comprises Valproic acid and/or its salts, esters or amides in an amount of about 3.00 w/v to about 13.00 w/v.
In an another preferred embodiment, the oral liquid pharmaceutical composition comprises therapeutically effective amount of Valproic acid and/or its salts, esters or amides with at least one pharmaceutically acceptable excipient, wherein the composition is stable when subjected to testing at a temperature of 40°C ± 2°C. and relative humidity ("RH") of 75% ± 5% for a period of at least three months.
Another embodiment of the present invention provides a process for the preparation of an oral liquid pharmaceutical composition of Valproic acid and/or its salts, esters or amides, comprising the steps of preparing solution of sweetening agent, optional addition of syrup base to the solution of sweetening agent followed by addition of preservative solution, subsequent addition of drug solution and eventual addition of coloring and flavoring agent.
In the pharmaceutical composition or dosage form or formulation of the present invention, pharmaceutically acceptable salts of Valproic acid include but are not limited to divalproex, Valproic acid, Sodium valproate, valpromide and the like.
In the oral liquid pharmaceutical composition of the present invention, the pharmaceutically acceptable excipient comprises sucrose as syrup base, sweetening agent, preservative, colorant, flavoring agent, pH modifier and solubilizing agent.

DETAILED DESCRIPTION OF THE INVENTION
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
As used herein, the term “composition”, as in pharmaceutical composition, is intended to encompass a drug product comprising Valproic acid and/or its salts, esters or amides and other inert ingredient(s). Such pharmaceutical compositions are synonymous with “formulation” and “dosage form”. Pharmaceutical compositions of the invention include, but are not limited to, solutions, syrups, emulsion, suspension and the like. Preferably, the pharmaceutical composition refers to syrup dosage form.
The term “Valproic acid” as used herein, is synonymous to “Sodium valproate", "Divalproex sodium" and "Valpromide”.
The term "about" as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.
The present invention relates to a stable oral liquid pharmaceutical composition of Valproic acid or its pharmaceutically acceptable salts, esters or amides.
A first aspect of the present invention provides an oral liquid pharmaceutical composition comprising Valproic acid and/or its salts, esters or amides, wherein the composition comprises:
a) Syrup base
b) sweetening agent
c) preservative
d) pH modifier
e) vehicle
f) optionally flavoring agent
g) optionally coloring agent
It was found by inventors of the present invention that an oral liquid pharmaceutical composition comprising Valproic acid and/or its salts, esters or amides having pH more than 7 exhibited excellent storage stability.
The term “storage stability” as used herein, refers to the physical and chemical stability of Valproic acid with no significant change in pH and assay value, when stored at conditions specified by ICH guidelines for stability testing for not less than three months.
According to one embodiment of the above aspect, the oral liquid pharmaceutical composition is an immediate release composition.
According to another embodiment of the above aspect, the pharmaceutically acceptable salts of Valproic acid include but are not limited to divalproex, Valproic acid, Sodium valproate, valpromide and the like. Preferably, the pharmaceutically acceptable salt of Valproic acid is Sodium valproate.
According to another embodiment of the above aspect, the oral liquid pharmaceutical composition is in the form of solution, syrup, emulsion, suspension and the like. In a preferred embodiment, the oral liquid pharmaceutical composition is in the form of a syrup.
According to yet another embodiment of the above aspect, the oral liquid pharmaceutical composition comprises a therapeutically effective amount of Valproic acid and/or its salts, esters or amides. Valproic acid and/or its salts, esters or amides as per the composition of the present invention is present in an amount of about 10 mg/mL to about 100 mg/mL of the composition.
According to yet another embodiment of the above aspect, the oral liquid pharmaceutical composition comprises Valproic acid and/or its salts, esters or amides in an amount of more than about 3% w/v of the composition.
According to yet another embodiment of the above aspect, the oral liquid pharmaceutical composition comprises 100 mg to 1000 mg of Valproic acid and/or its salts, esters or amides.
According to yet another embodiment of the above aspect, the particle size distribution of Valproic acid and/or its salts, esters or amides is such that D10 is not more than about 40µm, D50 is not more than about 200µm and D90 is not more than about 300µm.
According to yet another embodiment of the above aspect, the oral liquid pharmaceutical composition comprises syrup base in an amount of about 65.00 w/v to about 75.00 w/v of the composition.
In accordance with still another embodiment of the above aspect, there is provided an oral liquid pharmaceutical composition comprising a therapeutically effective amount of Valproic acid and/or its salts, esters or amides prepared by a process comprising the steps of preparing solution of sweetening agent, optional addition of syrup base to the solution of sweetening agent followed by addition of preservative solution, subsequent addition of drug solution and eventual addition of coloring and flavoring agent.
The term "pharmaceutically acceptable excipients," as used herein, refers to excipients that are routinely used in pharmaceutical compositions. The pharmaceutically acceptable excipients may comprise sweetening agent, preservative, colorant, flavoring agent, pH modifier, solubilizing agent, and the like.
Suitable sweetening agent or sweetner is selected from the group comprising maltitol, lactose, sucrose, dextrose, fructose, glucose, glycerin, inulin, isomalt, lactitol, maltose, maltol, mannitol, xylitol, erythritol, sucralose, trehalose, propylene glycol, sorbitol, sodium saccharin, thaumatin, sodium cyclamate, aspartame, acesulfame-K, mogroside, saccharin, glycyrrhizin, monosodium glycyrrhizinate, monoamonium glycyrrhizinate, glycerine, dextrose and the like, or mixtures thereof. In a preferred embodiment, sweetening agent is sucrose.
According to yet another embodiment of the above aspect, sweetening agent is present in an amount more than 30% w/v of the composition. Preferably, sweetening agent is present in an amount more than 20% w/v of the composition.
Suitable preservative is selected from the group comprising benzoic acid, sodium benzoate, boric acid, sorbic acid and salts thereof, benzyl alcohol, benzalkonium chloride, parahydroxybenzoic acids and their alkyl esters sorbates, EDTA, domiphen bromide, butylparaben, propylparaben, ethylparaben, methylparaben, paraben salts and mixtures thereof and the like. In a preferred embodiment, the pharmaceutically acceptable preservative comprises methylparaben and propylparaben.
According to yet another embodiment of the above aspect, preservative is present in an amount of about 0.01% w/v to about 0.2% w/v of the composition. Preferably, preservative is present in an amount of about 0.015% w/v to about 0.15% w/v of the composition.
Suitable pH modifier is selected from the group comprising ascorbic acid, acetic acid, tartaric acid, citric acid monohydrate, trisodium citrate dehydrate, sodium citrate, potassium citrate, sodium phosphate, tricalcium phosphate, calcium carbonate, sodium bicarbonate, calcium phosphate, carbonated calcium phosphate, magnesium hydroxide, hydrochloric acid, sodium hydroxide and the like or combinations thereof. In a preferred embodiment, the pharmaceutically acceptable pH modifier is hydrochloric acid/sodium hydroxide.
Pharmaceutically acceptable flavoring agents and/ or coloring agents known to a person skilled in the art may be added to impart organoleptic properties such as flavor and color to the pharmaceutical composition. Suitable flavor is selected from the group comprising orange, banana, strawberry, cherry, wild cherry, lemon, cardamom, anis, mint, menthol, vanillin and the like or combinations thereof. In a preferred embodiment, the pharmaceutically acceptable flavoring agent is cherry flavor.
Pharmaceutically acceptable vehicle is selected from the group comprising water, glycerin, ethanol, propylene glycol, polyethylene glycol, benzyl alcohol, isopropyl alcohol and the like or mixtures thereof. In a preferred embodiment, the pharmaceutically acceptable vehicle is water.
According to yet another embodiment of the above aspect, the oral liquid pharmaceutical composition is stable when subjected to stability testing at a temperature of 40°C ± 2°C. and relative humidity ("RH") of 75% ± 5% for a period of at least three months.
A second aspect of the present invention provides a process for the preparation of an oral liquid pharmaceutical composition comprising Valproic acid and/or its salts, esters or amides, wherein the process comprises the following steps:
a) preparing a solution of sweetening agent in a suitable vehicle;
b) preparing a solution of preservative in a suitable vehicle;
c) adding solution of step b) to solution prepared in step a);
d) preparing a solution of Valproic acid and/or its salts, esters or amides in a suitable vehicle;
e) adding solution of step d) to solution prepared in step c);
f) preparing a solution of colorant in a suitable vehicle;
g) adding solution of step f) to solution prepared in step e);
h) preparing a solution of flavoring agent in a suitable vehicle;
i) adding solution of step h) to solution prepared in step g);
j) preparing a solution of pH modifier in a suitable vehicle;
k) adjusting the pH of the solution prepared in step i) with solution of step j);
l) making up the required volume by adding suitable amount of vehicle
m) optionally filtering the solution of step l) through a suitable filter

According to yet another embodiment of the above aspect, the process is carried out at a relative humidity in the range of 30% to 70%. Preferably, the process is carried out at a relative humidity in the range of 40% to 50%.

According to yet another embodiment of the above aspect, the process is carried out in presence of sodium vapor lamp.

According to yet another embodiment of the above aspect, the process is carried out at a temperature not more than 25°C.

The process of the invention makes it possible to prepare an oral liquid pharmaceutical composition of Valproic acid and/or its salts, esters or amides, wherein the composition is stable and the process is consistent as well as economical and therefore feasible for industrial production.

A third aspect of the present invention relates to an oral liquid pharmaceutical composition comprising Valproic acid and/or its salts, esters or amides, prepared by a process comprising the following steps:
a) preparing a solution of sweetening agent in a suitable vehicle;
b) preparing a solution of preservative in a suitable vehicle;
c) adding solution of step b) to solution prepared in step a);
d) preparing a solution of Valproic acid and/or its salts, esters or amides in a suitable vehicle;
e) adding solution of step d) to solution prepared in step c);
f) preparing a solution of colorant in a suitable vehicle;
g) adding solution of step f) to solution prepared in step e);
h) preparing a solution of flavoring agent in a suitable vehicle;
i) adding solution of step h) to solution prepared in step g);
j) preparing a solution of pH modifier in a suitable vehicle;
k) adjusting the pH of the solution prepared in step i) with solution of step j);
l) making up the required volume by adding suitable amount of vehicle
m) optionally filtering the solution of step l) through a suitable filter
According to yet another embodiment of the above aspect, the process is carried out at a relative humidity in the range of 20% to 80%. Preferably, the process is carried out at a relative humidity in the range of 30% to 70%. More preferably, the process is carried out at a relative humidity in the range of 40% to 50%.
A fourth aspect of the present invention provides an oral liquid pharmaceutical composition comprising:
a) Sodium valproate in an amount of about 4% w/v of the composition
b) Sweetening agent in an amount of about 96% w/v of the composition
c) Preservative in an amount of about 0.2% w/v of the composition
d) Colorant in an amount of about 0.1% w/v of the composition
e) Flavoring agent an amount of about 0.4% w/v of the composition
f) pH modifier to adjust the pH of the composition to about 7.5±0.5
wherein the composition is stable when stored at a temperature of 40°C ± 2°C. and relative humidity ("RH") of 75% ± 5% for a period of at least three months.
In accordance with yet another embodiment of the above aspects, the oral liquid pharmaceutical composition comprising Sodium valproate is filled into light resistant High density polyethylene (HDPE) bottles or amber colored glass bottles.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail process for the preparation and testing of pharmaceutical composition comprising Valproic acid and/or its salts, esters or amides. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES
Following examples are set out to illustrate the invention and do not limit the scope of the present invention.
Example I to IV
Oral syrup of Sodium valproate (200 mg/5 ml) was prepared using the quantitative formula as given in Table 1:
TABLE 1
Ingredient Function Ex 1
(% w/v) Ex 2
(% w/v) Ex 3
(% w/v) Ex 4
(% w/v)
Sodium valproate Active 4.00 4.00 4.00 4.00
Sucrose Syrup base / Sweetening agent 72.00 60.00 72.00 55.00
Sorbitol solution Sweetening agent 24.3 25.00 24.00 30.00
Methyl paraben Preservative q.s. q.s. q.s. q.s.
Propyl paraben Preservative q.s. q.s. q.s. q.s.
Ponceau Coloring agent q.s. q.s. q.s. q.s.
Cherry flavour Flavouring agent q.s. q.s. q.s. q.s.
Hydrochloric acid pH modifier q.s. q.s. q.s. q.s.
Sodium hydroxide pH modifier q.s. q.s. q.s. q.s.
Purified water Vehicle q.s. q.s. q.s. q.s.

Procedure:
a) A solution of sucrose is prepared in purified water;
b) Sorbitol solution is added to solution prepared in step a) with continuous stirring till a clear solution is obtained;
c) a solution of preservative is prepared in purified water and added to solution prepared in step b) with continuous stirring till a clear solution is obtained;
d) a solution of Sodium valproate is prepared in purified water and added to solution prepared in step c) with continuous stirring till a clear solution is obtained;
e) a solution of Ponceau is prepared in purified water and added to solution prepared in step d) with continuous stirring till a clear solution is obtained;
f) a solution of flavoring agent is prepared in purified water and added to solution prepared in step e) with continuous stirring till a clear solution is obtained;
g) a solution of pH modifier is prepared in purified water;
h) pH of the solution prepared in step f) is adjusted to 7.5±0.5 with the help of solution prepared in step g);
i) volume is made up to 5 ml by adding suitable amount of purified water;
j) solution of step i) is filtered through a suitable filter.

Example V
Sodium valproate syrup prepared as per Example I was subjected to stability testing at a temperature/relative humidity of 40°±2°C / 75%±5% RH for 6 months. The results obtained are reported in Table 2. Currently marketed Sodium valproate syrup by Sanofi by the name of Epilim Syrup (200 mg/5 ml) was also subjected to stability testing at a temperature/relative humidity of 40°±2°C / 75%±5% RH for 6 months. The results obtained are reported in Table 3.

Table 2
Parameter Initial 3 months 6 months
Assay of sodium valproate 103.20 100.00 100.4
Assay of sodium methyl paraben 97.5 58.6 46.5
Related substances (Single maximum unknown impurity) BDL BDL BDL
Related substances (Total impurity) NA NA NA
pH 7.66 7.54 7.08
BDL: Below disregard limit (0.05%); NA: Not Applicable
Table 3
Parameter Initial 3 months 6 months
Assay of sodium valproate 100.20 100.60 100.50
Assay of sodium methyl paraben 0.42 mg/mL (Eq to. 100 %) 0.15 mg/mL (Eq to. 35.71 % from initial) 0.09 mg/mL (Eq to. 21.43 % from initial)
Related substances (Single maximum unknown impurity) 0.068 ND 0.012
Related substances (Total impurity) 0.076 0.013 0.035
pH 7.87 7.15 7.25
ND: Not detected; NLT: Not less than; NMT: Not more than
It can be seen from the data reported in Table 2 that the content of single maximum unknown impurity at the end of six months was below disregard limit (BDL) and that of total impurity was not applicable in case of the formulation prepared as per the present invention whereas as per the data reported in Table 3, content of single maximum unknown impurity was 0.012 % at the end of six months and content of total impurity was 0.035% at the end of six months. Thus, the formulation prepared as per the present invention exhibits better stability attribute in comparison to the commercially available formulation Epilim Syrup (200 mg/5 ml).
Similarly, it can be seen from the data reported in Table 2 that at the end of six months approximately 46.5% of the preservative remains in the formulation prepared as per the present invention whereas as per the data reported in Table 3, approximately 21.30% of the preservative remains in the reference formulation Epilim Syrup (200 mg/5 ml) at the end of six months. Thus, the formulation prepared as per the present invention is capable of preventing microbial growth even while consuming lesser amount of preservative. It can be inferred from this observation that the formulation prepared as per the present invention is more robust as compared to the commercially available formulation Epilim Syrup (200 mg/5 ml).

While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope, and spirit of this invention.

CLAIMS:We claim:
1. An oral liquid pharmaceutical composition comprising Valproic acid and/or its salts, esters or amides, wherein the composition comprises:
a) Syrup base
b) sweetening agent
c) preservative
d) pH modifier
e) vehicle
f) optionally flavoring agent
g) optionally coloring agent.
2. The oral liquid pharmaceutical composition as claimed in Claim 1 wherein, the composition has a pH more than 7.
3. The oral liquid pharmaceutical composition as claimed in Claim 1 wherein, pharmaceutically acceptable salts of Valproic acid are selected from the group consisting of divalproex, valproic acid, sodium valproate and valpromide.
4. The oral liquid pharmaceutical composition as claimed in Claim 1 wherein, the composition is in the form of solution, syrup, emulsion or suspension.
5. The oral liquid pharmaceutical composition as claimed in Claim 1 wherein, valproic acid and/or its salts, esters or amides is present in an amount of more than about 3% w/v of the composition.
6. The oral liquid pharmaceutical composition as claimed in Claim 1 wherein, the particle size distribution of Valproic acid and/or its salts, esters or amides is such that D10 is not more than about 40µm, D50 is not more than about 200µm and D90 is not more than about 300µm.
7. The oral liquid pharmaceutical composition as claimed in Claim 1 wherein, the composition is stable when subjected to stability testing at a temperature of 40°C ± 2°C. and relative humidity ("RH") of 75% ± 5% for a period of at least three months.
8. A process for the preparation of an oral liquid pharmaceutical composition comprising Valproic acid and/or its salts, esters or amides, wherein the process comprises the following steps:
a) preparing a solution of sweetening agent in a suitable vehicle;
b) preparing a solution of preservative in a suitable vehicle;
c) adding solution of step b) to solution prepared in step a);
d) preparing a solution of Valproic acid and/or its salts, esters or amides in a suitable vehicle;
e) adding solution of step d) to solution prepared in step c);
f) preparing a solution of colorant in a suitable vehicle;
g) adding solution of step f) to solution prepared in step e);
h) preparing a solution of flavoring agent in a suitable vehicle;
i) adding solution of step h) to solution prepared in step g);
j) preparing a solution of pH modifier in a suitable vehicle;
k) adjusting the pH of the solution prepared in step i) with solution of step j);
l) making up the required volume by adding suitable amount of vehicle
m) optionally filtering the solution of step l) through a suitable filter
9. An oral liquid pharmaceutical composition comprising Valproic acid and/or its salts, esters or amides, prepared by a process comprising the following steps:
a) preparing a solution of sweetening agent in a suitable vehicle;
b) preparing a solution of preservative in a suitable vehicle;
c) adding solution of step b) to solution prepared in step a);
d) preparing a solution of Valproic acid and/or its salts, esters or amides in a suitable vehicle;
e) adding solution of step d) to solution prepared in step c);
f) preparing a solution of colorant in a suitable vehicle;
g) adding solution of step f) to solution prepared in step e);
h) preparing a solution of flavoring agent in a suitable vehicle;
i) adding solution of step h) to solution prepared in step g);
j) preparing a solution of pH modifier in a suitable vehicle;
k) adjusting the pH of the solution prepared in step i) with solution of step j);
l) making up the required volume by adding suitable amount of vehicle
m) optionally filtering the solution of step l) through a suitable filter
10. An oral liquid pharmaceutical composition comprising:
a) Sodium valproate in an amount of about 4% w/v of the composition,
b) Sweetening agent in an amount of more than about 20% w/v of the composition,
c) pH modifier to adjust the pH of the composition to about 7.5±0.5
wherein the composition is stable when stored at a temperature of 40°C ± 2°C. and relative humidity ("RH") of 75% ± 5% for a period of at least three months.