DESC:FIELD OF THE INVENTION
The present invention relates to an improved sustained release compact pharmaceutical dosage form suitable for a once daily administration.
alproic acid and its derivatives are indicated for the
treatment of different types of epilepsy, for the treatment
of acute manic or mixed episodes associated with bipolar
disorder, and for prophylaxis of migraine headaches.
Particularly, a complex constituted by a 1:1 molar
relationship of valproic acid and sodium valproate
(divalproex sodium) has recently reached some preference
in the market. Divalproex sodium is marketed by Abbott
Laboratories as conventional delayed-release (DR),
enteric-coated, dosage forms (Depakote tablets, and
Depakote sprinkle capsules), and as innovative extended-
release (ER) tablets (Depakote ER). Both tablets
(divalproex-DR and divalproex-ER) are supplied in dosage
strengths containing divalproex sodium equivalent to 250
and 500 mg of valproic acid, and the DR form is supplied
containing divalproex sodium equivalent to 125 of valproic
acid as well
76
INTRODUCTION
Valproic acid and its derivatives are indicated for the
treatment of different types of epilepsy, for the treatment
of acute manic or mixed episodes associated with bipolar
disorder, and for prophylaxis of migraine headaches.
Particularly, a complex constituted by a 1:1 molar
relationship of valproic acid and sodium valproate
(divalproex sodium) has recently reached some preference
in the market. Divalproex sodium is marketed by Abbott
Laboratories as conventional delayed-release (DR),
enteric-coated, dosage forms (Depakote tablets, and
Depakote sprinkle capsules), and as innovative extended-
release (ER) tablets (Depakote ER). Both tablets
(divalproex-DR and divalproex-ER) are supplied in dosage
strengths containing divalproex sodium equivalent to 250
and 500 mg of valproic acid, and the DR form is supplied
containing divalproex sodium equivalent to 125 of valproic
acid as well.
BACKGROUND OF THE INVENTION
Valproic acid and its derivatives are indicated for the treatment of different types of epilepsy, for the treatment of acute manic or mixed episodes associated with bipolar disorder, and for prophylaxis of migraine headaches. Particularly, a complex constituted by a 1:1 molar relationship of valproic acid and sodium valproate (divalproex sodium) has recently reached some preference in the market. Divalproex sodium is marketed by Abbott Laboratories as conventional delayed-release (DR), enteric-coated, dosage forms (Depakote® tablets, and Depakote™ sprinkle capsules), and as innovative extended release (ER) tablets (Depakote™ ER). Both tablets (divalproex-DR and divalproex-ER) are supplied in dosage strengths containing divalproex sodium equivalent to 250 and 500 mg of valproic acid. The main constraint of divalproex-ER is its lower bioavailability in comparison with divalproex-DR.
It is known that Divalproex sodium has narrow therapeutic window as the range between the effective valproic acid concentrations and the concentrations associated with serious toxicity is narrow; sub-optimal doses or concentrations lead to therapeutic failure or severe toxicity; valproic acid is subject to therapeutic monitoring based on pharmacokinetics measures; and valproic acid has low-to-moderate within-subject variability.
Hence, there is need for a formulation which has consistent release profile and has less within subject variability with regimen of better compliance to therapy. The present inventors found a sustained release pharmaceutical dosage form comprising divalproex or its salt that provides an increased oral bioavailability of divalproex or its salt, and therefore, it allows reduction in the total daily dose. More particularly, the present inventors have found a sustained release pharmaceutical dosage form comprising divalproex or its salt and rate controlling polymer, wherein when one or more units of the sustained release pharmaceutical dosage form comprising a reduced total daily dose of divalproex or its salt, is/are administered once daily, therapeutically effective levels of divalproex for treating acute manic or mixed episodes associated with bipolar disorders with or without pyschotic features, complex partial seizures and simple and complex absence seizures or migraine are obtained.
SUMMARY OF THE INVENTION
The present invention provides a sustained release pharmaceutical dosage form comprising divalproex or its salt and rate controlling polymer, wherein when one or more units of the sustained release pharmaceutical dosage form comprising a reduced total daily dose of divalproex or its salt, is/are administered once daily, therapeutically effective levels of divalproex for treating acute manic or mixed episodes associated with bipolar disorders with or without pyschotic features, complex partial seizures and simple and complex absence seizures or migraine are obtained.
The sustained release pharmaceutical dosage form of the present invention not only provides a reduced dose, but also provides reduced number of units of the dosage form that are to be consumed as compared to that of the commercially available product.
DESCRIPTION OF THE FIGURE
Figure 1 describes the graph of percentage drug released Vs time in hours when tablet of Example 1 is subjected to in vitro dissolution test in 500 ml of 0.1 N hydrochloric acid for 45 minutes followed by 900 ml of pH 5.5 phosphate buffer with sodium lauryl sulphate 75 mM in USP II apparatus at 100 rotations per minute. The dosage form releases more than 20 % and less than 40 % at the end of 3 hours; releases more than 55 % and less than 65 % at the end of 9 hours and releases more than 65 % and less than 80 % at the end of 12 hours.
DETAILED DESCRIPTION OF THE INVENTION
By the term ’a reduced total daily dose of divalproex or its salt’ as used herein means that the total daily dose of divalproex or its salt is less than that recommended for Depakote™ ER. It means that sustained release pharmaceutical dosage form of the present invention comprises a lesser amount of divalproex or its salt expressed as miligrams of valproic acid as compared to Depakote™ ER, yet it provides a plasma concentration time profile equivalent to that obtained by administering Depakote™ ER. The % reduction in the total daily dose may be at least 15 %, preferably at least 20 %, preferably at least 35 %, most preferably 50 %. More particularly the reduction in total daily dose is in the range of 15 to 25%, still more particularly it is 20%. For example, units of sustained release dosage form of the present invention with divalproex or its salt at a dose of 800 mg of valproic acid may provide a plasma concentration time profile equivalent to that obtained by administering Depakote™ ER units at a dose of 1000 mg. For example, in one embodiment, a single units of the sustained release pharmaceutical dosage form may contain 200 mg, 400 mg, 600, 800 mg of divalproex or its salt, expressed as mg of valproic acid, in contrast to 250 mg or 500 mg of divalproex sodium present in the commercially available product available under the name of Depakote® ER or its equivalent generic products. Table below shows the improvement in .terms of number of tablets the patient needs to ingest:
Dosing with Depakote ER Dosing with present invention
A 250 mg tablet A 200 mg tablet
A 500 mg tablet A 400 mg tablet
A 250 mg tablet and a 500 mg tablet A 600 mg tablet
Two 500 mg tablets A 800 mg tablet
Two 500 mg tablets and a 250 mg tablet A 1000 mg tablet
Three 500 mg tablets A 1200 mg tablet

According to one aspect of the present invention, one or more units of the sustained release pharmaceutical dosage form comprises a reduced total daily dose of divalproex or its salt for treatment of mania, so that the recommended daily dose is at least 15 %, preferably at least 20%, preferably at least 35 %, most preferably at least 20 % reduced than the recommended initial dose is 25 mg/kg/day given once daily for Depakote™ ER for treatment of mania. More particularly the reduction in total daily dose for treatment of mania is in the range of 15 to 25%, still more particularly it is 20%. Further, the maximum recommended dosage is at least 15 % less than 60 mg/kg/day so as to achieve trough plasma concentration between 85 and 125 mcg/mL which provides clinical response for treatment of mania. . More particularly the reduction in total daily dose for treatment of mania is in the range of 15 to 25%, still more particularly it is 20%.

In one embodiment, when the reduced total initial daily dose is for instance, 20 mg/kg/day for treatment of mania, total daily dose to be administered for a 70 kg body weight patient, may be, 1400 mg instead of 1750 mg as indicated in the labelling instructions for Depakote® ER. The sustained release pharmaceutical dosage form contains such reduced amount of divalproex or its salt so as to accommodate 1400 mg either in a single unit or in more than one unit, for eg. 600 mg in one unit and 800 mg in second unit to be administered, instead of administering three units of 500 mg of Depakote® ER and one unit of 250 mg of Depakote® ER.

In one embodiment, when the reduced total daily dose after initial therapy, is for instance, 50 mg/kg/day for treatment of mania, total daily dose to be administered for a 70 kg body weight patient, may be, 3500 mg instead of 4200 mg as indicated in the labelling instructions for Depakote® ER. In one embodiment, the sustained release pharmaceutical dosage form may contain such reduced amount of divalproex®or its salt so as to accommodate about 3500 mg either in a single unit or in more than one unit, for eg. 3 units of 1200 mg to provide 3600 mg; instead of administering eight units of 500 mg of Depakote® ER and one unit of 250 mg of Depakote® ER.

According to one aspect of the present invention, the sustained release pharmaceutical dosage form comprises a reduced total daily dose of divalproex or its salt for treatment of epilepsy, so that the recommended daily dose is at least 15 % reduced than the recommended initial dose is 10 to 15 mg/kg/day given once daily as indicated in the labelling instructions for Depakote® ER. Further, the maximum recommended dosage is at least 15 %, preferably at least 35 %, most preferably at least 50 % lesser than 60 mg/kg/day so as to achieve plasma concentration between 50 to 100 mcg/mL which range is effective in providing clinical response while treating epilepsy such as complex partial seizures, or simple and complex absence seizures. . More particularly the reduction in total daily dose for treatment of epilepsy is in the range of 15 to 25%, still more particularly it is 20%.

A unit of the sustained release pharmaceutical dosage form contains divalproex or its salt, expressed as valproic acid, in amounts of 200 mg, 300 mg, 350 mg, 400 mg, 450 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1100 mg, 1200 mg, 1250 mg, 1300 mg, 1400 mg or 1500 mg per unit dosage form. In one preferred embodiment, it may be 200 mg, 400 mg, 600 mg, 800 mg and 1200 mg. For example, in one embodiment, a single unit of the sustained release pharmaceutical dosage form may contain 200 mg, 400 mg of divalproex or its salt, expressed as mg of valproic acid, in contrast to 250 mg or 500 mg of divalproex sodium present in the commercially available product available under the name of Depakote® ER. In one embodiment, when the reduced total daily dose is for instance, 10 mg/kg/day for treatment of epilepsy, total daily dose to be administered for a 70 kg body weight patient, may be, 700 mg instead of 1050 mg. The sustained release pharmaceutical dosage form contains such reduced amount of divalproex or its salt so as to accommodate 700 mg either in a single unit or in more than one unit, instead of administering two units of 500 mg as indicated in the labelling instructions for Depakote® ER. In another embodiment, when the reduced total daily dose after initial therapy, is for instance, 30 mg/kg/day for treatment of epilepsy, total daily dose to be administered for a 70 kg body weight patient, may be, 2100 mg instead of 4200 mg as indicated in the labelling instructions for Depakote® ER. The sustained release pharmaceutical dosage form contains such reduced amount of divalproex ®or its salt so as to accommodate 2100 mg either in a single unit or in more than one unit, for eg. 1 unit of 1200 mg and 1 unit of 900 mg; instead of administering eight units of 500 mg of Depakote® ER and 1 unit of 250 mg of Depakote® ER.
According to one aspect of the present invention, there are administered one or more units of the sustained release pharmaceutical dosage form such that the total units administered once-daily comprise a reduced total daily dose of divalproex or its salt for treatment of migraine, so that the recommended daily dose is at least 15 %, at least 20 %, preferably at least 35 %, most preferably at least 50 % reduced than the currently recommended initial dose for treatment of migraine. More particularly the reduction in total daily dose for treatment of migraine is in the range of 15 to 25%, still more particularly it is 20%. In such embodiments, when the current total daily dose is for instance 500 mg, a reduced dose a single 400 mg tablet of the present invention may be administered to the patient to give equivalent therapeutic benefit to 1 unit of 500 mg of Depakote® ER or its equivalent generic products. In yet other such embodiment, if the total daily dose is for instance 750 mg, then a single tablet of 600 mg of the present invention will suffice to give equivalent therapeutic efficacy instead of taking one unit of 500 mg and 1 unit of 250 mg of Depakote® ER or its equivalent generic products.

In one embodiment, a unit of sustained release reduced dosage form of divalproex or its salt of the present invention containing a dose of 200 mg of valproic acid may provide a plasma concentration time profile equivalent to that obtained by administering Depakote™ ER containing 250 mg of valproic acid. In another embodiment, a unit of sustained release reduced dosage form of divalproex or its salt of the present invention containing a dose of 400 mg of valproic acid may provide a plasma concentration time profile equivalent to that obtained by administering Depakote™ ER containing 500 mg of valproic acid. In yet another embodiment, a unit of sustained release reduced dosage form of divalproex or its salt of the present invention containing a dose of 600 mg of valproic acid may provide a plasma concentration time profile equivalent to that obtained by administering Depakote™ ER containing 750 mg of valproic acid. In one specific embodiment, a unit of sustained release reduced dosage form of divalproex or its salt of the present invention containing a dose of 800 mg of valproic acid may provide a plasma concentration time profile equivalent to that obtained by administering Depakote™ ER containing 1000 mg of valproic acid. In yet another specific embodiment, a unit of sustained release reduced dosage form comprises a dose of 1200 mg of valproic acid equivalent amount of divalproex sodium which may provide a plasma concentration time profile equivalent to that obtained by administering Depakote™ ER containing 1500 mg of valproic acid.

In another aspect, the present invention provides a sustained release pharmaceutical dosage form suitable for once a day administration, a unit of the dosage form comprises divalproex or its salt in an amount equivalent to from 200 to 1500 mg of valproic acid. Alternatively, it provides sustained release pharmaceutical dosage form suitable for once a day administration, a unit of the dosage form comprises divalproex or its salt in an amount equivalent to from 200 mg of valproic acid. The present invention also provides a sustained release pharmaceutical dosage form suitable for once a day administration, a unit of the dosage form comprises divalproex or its salt in an amount equivalent to from 400 mg of valproic acid. In further embodiments, the present invention provides a sustained release pharmaceutical dosage form suitable for once a day administration, a unit of the dosage form comprises divalproex or its salt in an amount equivalent to from 600 mg of valproic acid. In certain preferred embodiments, the present invention provides a sustained release pharmaceutical dosage form suitable for once a day administration, a unit of the dosage form comprises divalproex or its salt in an amount equivalent to from 800 mg of valproic acid. It also provides a sustained release pharmaceutical dosage form suitable for once a day administration, a unit of the dosage form comprises divalproex or its salt in an amount equivalent to from 1200 mg of valproic acid.

In another aspect, the present invention provides a method of treating disease conditions such as acute manic or mixed episodes associated with bipolar disorders with or without pyschotic features, complex partial seizures and simple and complex absence seizures or migraine, by orally administering once a day a sustained release pharmaceutical dosage for, a unit of the dosage form comprising divalproex or its salt in an amount equivalent to from 200 to 1500 mg of valproic acid. Alternatively, it provides sustained release pharmaceutical dosage form, a unit of the dosage form comprising divalproex or its salt in an amount equivalent to 200 mg of valproic acid. The present invention also a method of treating disease conditions such as acute manic or mixed episodes associated with bipolar disorders with or without pyschotic features, complex partial seizures and simple and complex absence seizures or migraine by orally administering once a day a sustained release pharmaceutical dosage form, a unit of the dosage form comprising divalproex or its salt in an amount equivalent to 400 mg of valproic acid. In further embodiments, the present invention provides a method of treating disease conditions such as acute manic or mixed episodes associated with bipolar disorders with or without pyschotic features, complex partial seizures and simple and complex absence seizures or migraine by orally administering once a day, a sustained release pharmaceutical dosage form, a unit of the dosage form comprising divalproex or its salt in an amount equivalent to 600 mg of valproic acid. In certain preferred embodiments, the present invention a method of treating disease conditions such as acute manic or mixed episodes associated with bipolar disorders with or without pyschotic features, complex partial seizures and simple and complex absence seizures or migraine, by orally administering once a day, a sustained release pharmaceutical dosage form, a unit of the dosage form comprising divalproex or its salt in an amount equivalent to 800 mg of valproic acid. It also provides a method of treating disease conditions such as acute manic or mixed episodes associated with bipolar disorders with or without pyschotic features, complex partial seizures and simple and complex absence seizures or migraine, by orally administering once a day, a sustained release pharmaceutical dosage form, a unit of the dosage form comprising divalproex or its salt in an amount equivalent to 1200 mg of valproic acid.

The rate controlling polymer used in the sustained release pharmaceutical dosage form of the present invention may be hydrophilic or hydrophobic (water insoluble) polymer or mixtures thereof. Depending upon the release rate controlling capacity, the choice and amount of the hydrophilic or hydrophobic (water insoluble) polymer or mixtures thereof, may be made for obtaining the desired degree of control on release. The suitable examples of the hydrophilic polymer include, but are not limited to, of polyacrylic acids, high viscosity grades of cellulose such as as carbomer, high viscosity grades of cellulose such as hydroxypropyl methyl cellulose K4M, K15M, K 100M wherein the K stands for the USP substitution type 2208 corresponding to a methoxy content of 19 to 24% and a hydroxypropoxy content of 4 to 12%. The high viscosity grades of the hydrophilic polymers are preferred having viscosity in the range of 2000 to 1,50,000 cP. Suitable examples of the water insoluble or hydrophobic polymer include, but are not limited to, waxes, water insoluble cellulose derivatives such as ethyl cellulose, cellulose acetate, cellulose butyrate, insoluble grades of polyacrylates such as methacrylates, acrylic acid copolymers, high molecular weight polyvinyl alcohols. In one specific embodiment, where the rate controlling polymer is a mixture of hydrophilic polymer which is a high viscosity grades of hydroxypropyl methyl cellulose K 100M and a polyacrylic acid and the hydrophobic polymer is ethyl cellulose, the amount ranges from 10% to 30 % by weight of the sustained release pharmaceutical dosage form of the present invention.

In one specific embodiment, the pharmaceutical dosage form is a compressed tablet composition, wherein the divalproex or its salt is intimately mixed with a hydrophobic polymer such as ethyl cellulose. In such embodiments, the phase “consists essentially of” divalproex or its pharmaceutically acceptable salts and water insoluble polymer as a sole rate controlling polymer. This means that the phase does not contain other excipients that can interfere in controlling the hygroscopicity of the divalproex or its pharmaceutically acceptable salt and/or increase the bulk of the single unit of the sustained release pharmaceutical dosage form composition. The hydrophobic polymer also has a role as to control the dissolution rate and slows the rate of release of divalproex. Particularly, the hydrophobic polymer is admixed with divalproex or its salt, the amount of hydrophobic polymer ranges from 1 % to 15 % by weight of the tablet, more preferably, in the range of 3 to 12 % by weight of the tablet, most preferably, in the range of 5 % to 10 % by weight of the dosage form which is a compressed tablet.

This phase may be a granular or may be a compressed core, which is then further mixed with other rate controlling polymers such as a hydrophobic polymer or a hydrophilic polymer.

In one preferred embodiment, the divalproex containing phase is a granular phase contains hydrophobic polymer as the sole excipient. This granular phase is surrounded by another phase made up of hydrophilic polymers having high gelling or high viscosity. In this embodiment, the water insoluble polymer is present in the range of 1% to 30% by weight of the granular phase, more preferably in the range of 3 % to 20 % and most preferably in the range of 5 % to 15% by weight of the granular phase. The surrounding phase referred to as, extragranular phase is present in an admixture with the granular phase. In one embodiment, the extragranular phase comprises one or more hydrophilic polymers such as polyacrylic acids such as carbomer, high viscosity grades of cellulose such as HPMC K4M, HPMC K15M, HPMC K 100M CR. The hydrophilic polymer may be present in the range of 50% to 90% by weight of the extragranular phase, more preferably in the range of 60% to 80% by weight of the extragranular phase and most preferably in the range of 65 % to 78% by weight of the extragranular phase. In one specific embodiment, hydrophilic polymer present in the extragranular phase is a mixture of high viscosity hydroxy propylmethyl cellulose and carboxy vinyl polymer. The high viscosity hydroxypropyl methyl cellulose is present in the range of 50% to 85% by weight of the extragranular phase and the carbomer is present in the range of 1% to 10% by weight of the extragranular phase.

According to one embodiment, the present invention provides a sustained release pharmaceutical dosage form comprising divalproex or its salt and rate controlling polymer, wherein when one or more units of the sustained release pharmaceutical dosage form comprising a reduced total daily dose of divalproex or its salt, is/are administered once daily, therapeutically effective levels of divalproex for treating acute manic or mixed episodes associated with bipolar disorders with or without pyschotic features, complex partial seizures and simple and complex absence seizures or migraine are obtained, wherein one unit of the composition comprises a granular phase consisting essentially of divalproex or its pharmaceutically acceptable salts and a water insoluble polymer as a rate controlling polymer, an extragranular phase comprising one or more hydrophilic polymers as a rate controlling polymer, optionally, lubricants, binders and diluents, wherein the two phases are mixed and compressed into a tablet.
The extragranular phase further comprises binders and diluents and lubricants. The binders used in the extragranular phase include but are not limited to polyvinyl alcohol, polyvinyl pyrrolidone, pregelatinised starch, sodium alginate, propylene glycol and mixtures thereof. The binders may be present in the range of 1% to 10% by weight of the extragranular phase, more preferably in the range of 1.5% to 8% and most preferably in the range of 2% to 6% by weight of the extragranular phase. The diluents used include but are not limited to lactose, lactitol, microcrystalline cellulose, calcium phosphate tribasic, dextrins, mannitol, and the like and mixtures thereof. The diluents may be present in a range of 1% to 25% by weight of the extragranular phase, more preferably in the range of 2% to 15% and most preferably in the range of 3% to 10% by weight of the extragranular phase. The lubricants used within the scope of this invention include but are not limited to glyceryl behenate, talcum, waxes, hydrogenated castor oil, colloidal silicon dioxide, stearic acid, magnesium stearate and mixtures thereof. The lubricants may be present in the range of 1 to 15% by weight of the extragranular phase, more preferably in the range of 3 to 12% and most preferably in the range of 5 % to 10% by weight of the extragranular phase.
According to one embodiment, the present invention provides a sustained release pharmaceutical dosage form comprising divalproex or its salt and rate controlling polymer, wherein when one or more units of the sustained release pharmaceutical dosage form comprising a reduced total daily dose of divalproex or its salt, is/are administered once daily, therapeutically effective levels of divalproex for treating acute manic or mixed episodes associated with bipolar disorders with or without pyschotic features, complex partial seizures and simple and complex absence seizures or migraine are obtained, wherein one unit of the composition has a drug to polymer ratio is from 90:10 to 45:55. The sustained release pharmaceutical composition may be prepared any conventional process known in the art.
In one embodiment, the sustained release pharmaceutical dosage form comprising divalproex or its salt and rate controlling polymer, wherein when one or more units of the sustained release pharmaceutical dosage form comprising a reduced total daily dose of divalproex or its salt, such as 200 mg, 400 mg, 600 mg, 800 mg, 1200 mg is/are administered once daily, therapeutically effective levels of divalproex for treating acute manic or mixed episodes associated with bipolar disorders with or without pyschotic features, complex partial seizures and simple and complex absence seizures or migraine are obtained, when administered with or without food. In one preferred embodiment, the present invention provides method of treating disease conditions such as acute manic or mixed episodes associated with bipolar disorders with or without pyschotic features, complex partial seizures and simple and complex absence seizures or migraine, wherein a unit sustained release pharmaceutical dosage form comprises 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1100 mg, 1200 mg, 1300 mg of vaproic acid equivalent amount of divalproex or its pharmaceutically acceptable salt. In yet another preferred embodiment, the present invention provides a method of treating disease conditions such as acute manic or mixed episodes associated with bipolar disorders with or without pyschotic features, complex partial seizures and simple and complex absence seizures or migraine, wherein a unit sustained release pharmaceutical dosage form comprises 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1100 mg, 1200 mg, 1300 mg of vaproic acid equivalent amount of divalproex or its pharmaceutically acceptable salt, the method provides equivalent oral bioavailability when orally administered in fed or fasted state.
The sustained release pharmaceutical dosage form of the present invention provides a desired degree of control on release, particularly, when subjected to in vitro dissolution in 500 ml of 0.1 N hydrochloric acid for 45 minutes followed by 900 ml of pH 5.5 phosphate buffer with sodium lauryl sulphate 75 mM in USP II apparatus at 100 rotations per minute; the dosage form releases divaproex as follows:
a. more than 20 % and less than 40 % at the end of 3 hours and /or
b. more than 55 % and less than 65 % at the end of 9 hours and/or
c. more than 65 % and less than 80 % at the end of 12 hours.

In one aspect, the sustained release pharmaceutical dosage form of the present invention is in the form of compressed tablet, granule filled into hard gelatin capsules, mixture of granules and powder filled into a hard gelatin capsule and the like. In one preferred embodiment, the sustained release pharmaceutical dosage form of the present invention is a compressed tablet. It is prepared by the process of milling both the active agent, i.e divalproex sodium and hydrophobic polymer for eg. a water insoluble polymer separately in a communiting mill and mixing together in a rapid mixer granulator. The mixture is granulated using a non-aqueous solvent and milled to get the appropriate size in a communiting mill and then dried in a fluid bed drier to form the granular phase. The extragranular phase is prepared by mixing the diluent, one or more hydrophilic polymers, and binder together. The granules of granular phase are mixed with the extragranular phase in a mixer granulator. The mixture thus formed is again granulated using a non-aqueous vehicle and the granules thus formed are reduced to appropriate size in a communiting mill. The granules are dried in a fluid bed granulator at a temperature of 55 °C to 65°C. The granules are further blended with hydrophilic polymer and lubricants. The lubricated granules are then compressed into tablets and may further be film coated. The sustained release pharmaceutical dosage form composition of the present invention is illustrated in the example below:

Hereinafter, the invention will be more specifically described with reference to examples. The examples are not intended to limit the scope of the invention and are merely used as illustrations.

EXAMPLE 1
Table 1: composition of the pharmaceutical dosage form
Phases Ingredients % in each phase % by weight of the dosage form
%w/w of granular phase
Granular phase Divalproex sodium 90 67.4
Ethyl cellulose 10 7.6
%w/w of extragranular phase

Extragranular phase Hydroxypropylmethyl cellulose (High viscosity grade) 60-75 13.5
Anhydrous lactose/ Microcrystalline cellulose 3-10 1.8
Polyvinyl pyrrolidone 2-6 1.25
Carbomer 1-2.5 0.4
Talc 1-4 0.75
Magnesium stearate 5-15 2.50
Silicon dioxide 5-15 2.2
Film coating Hydroxypropyl methyl cellulose based coating 2-3 2.91

Procedure:
I. Preparation of granular phase
Divalproex sodium was milled through an appropriately sized screen in a communiting mill. Ethyl cellulose was sifted through # 40 sieve and milled divalproex sodium and sifted ethyl cellulose was mixed in a rapid mixer granulator. The mixture was granulated using isopropyl alcohol methylene chloride by mixing the wet mass and the granules were milled through a 10 mm screen using a commuting mill and then dried in a fluid bed drier. The granules were further air dried. Granules were sifted through #16 sieve.
II. Preparation of extragranular phase
Anhydrous lactose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone and carbomer were sifted through appropriate sieve.
III. Admixture of granular and extragranular phase and preparation of granules
The granules of stage I granular phase were mixed with the extragranular phase of II in a rapid mixer granulator. The material was granulated using a water isopropyl alcohol mixture and the granules thus formed were milled through a 10mm screen using a communiting mill. The granules were dried in a fluid bed granulator at a temperature of 55 to 65° C. The dried granules were sifted through #18 sieve.
IV. Blending, compression and film coating
The granules were further blended with talc, carbomer and magnesium stearate and lubricated with silicon dioxide. The lubricated granules were then compressed into tablets and film coated with a hydroxy propyl methyl cellulose based coating.

The tablets prepared as per example 1 were subjected to in vitro dissolution study and in vivo comparative oral bioavailability study. The in vitro dissolution was carried out in 500 ml of 0.1 N Hydrochloric acid for 45 minutes followed by 900 ml of 0.05 M phosphate buffer with 75 mM of sodium lauryl sulphate in USP apparatus II at a rotating speed of 100 rmp. The result is provided as given below:
Table 2: In vitro dissolution test results
Time in hours % divalproex released
Not Less than Not more than
3 20 30
9 55 65
12 65 75

EXAMPLE 2
Example 1 containing 800 mg of valproic acid equivalent amount of divalproex sodium (860.80 mg) was subjected to pharmacokinetic study in fed and fasted state. It was compared with two tablets of the commercially available product Depakote ER containing 500 mg of valproic acid valproic acid equivalent amount of divalproex sodium (1076 mg). The results are provided as below:
Table 3: Results of the pharmacokinetic data in fed and fasted state
Product Fed State Fasted State
Mean AUC0_t –fed %CV Mean AUC0_t –fasted %CV
Example 1: 800 mg of valproic acid 1721 18.1 1841 27.1
Two tablets of Depakote ER each containing 500 mg valproic acid 1795 28.5 1951.5 34.2

It was surprisingly found that the Example 1 containing 800 mg of valproic acid showed extent of absorption that is the same as the extent of absorption obtained with 500 X 2 tablets of commercially available divalproex ER each containing 500 mg of valproic acid. Further, this result is obtained not only in fasted state but also in fed state.

,CLAIMS:. A sustained release pharmaceutical dosage form comprising divalproex or its salt and rate controlling polymer, wherein when one or more units of the sustained release pharmaceutical dosage form comprising a reduced total daily dose of divalproex or its salt, is/are administered once daily, therapeutically effective levels of divalproex for treating acute manic or mixed episodes associated with bipolar disorders with or without pyschotic features, complex partial seizures and simple and complex absence seizures or migraine are obtained.

2. A sustained release pharmaceutical dosage form as claimed in claim 1, wherein the total daily dose is reduced by 20%.

3. A sustained release pharmaceutical dosage form as claimed in claim 1, a unit of the dosage form comprises divalproex or its salt in an amount equivalent to from 200 to 1500 mg of valproic acid.

4. A sustained release pharmaceutical dosage form as claimed in claim 1, wherein when subjected to in vitro dissolution in 500 ml of 0.1 N hydrochloric acid for 45 minutes followed by 900 ml of pH 5.5 phosphate buffer with sodium lauryl sulphate 75 mM in USP II apparatus at 100 rotations per minute; the dosage form releases divaproex as follows:
a. More than 20 % and less than 40 % at the end of 3 hours and /or
b. More than 55 % and less than 65 % at the end of 9 hours and/or
c. More than 65 % and less than 80 % at the end of 12 hours.

5. A sustained release pharmaceutical dosage form as claimed in claim 1, wherein the rate controlling polymer is a mixture of water insoluble polymer and hydrophilic polymer.

6. A sustained release pharmaceutical dosage form as claimed in claim 5, wherein water insoluble polymer is present in admixture with divalproex or its salt in the form of granular mixture and the hydrophilic polymer is present in another phase surrounding the granular mixture.

7. A sustained release pharmaceutical dosage form as claimed in claim 6, wherein the hydrophilic polymer is a mixture of high viscosity hydropxypropyl methyl cellulose and carboxy vinyl polymer.