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Title:  Process for preparing non-hygroscopic sodium valproate composition

United States Patent:  6,752,997

Issued:  June 22, 2004

Inventors:  Safadi; Mohammed S. (Nazareth, IL); Barder; Maya (Haifa, IL); Golander; Yechiel (Haifa, IL); Yacobi; Avraham (Englewood, NJ); Moros; Daniel A. (Larchmont, NY); Levitt; Barrie (Mamaroneck, NY); Friedman; Michael (Jerusalem, IL)

Assignee:  Taro Pharmaceuticals U.S.A., Inc. (Hawthorne, NY)

Appl. No.:  057155

Filed:  January 24, 2002

Abstract

The invention is directed to non-hygroscopic oral pharmaceutical compositions of a salt of valproic acid, and processes for preparing the compositions. The non-hygroscopic pharmaceutical compositions are prepared by blending a hygroscopic salt of valproic acid, carbomer, and a non-hygroscopic additive.

SUMMARY OF THE INVENTION

This invention is directed to processes for preparing pharmaceutical compositions comprising as an active ingredient a hygroscopic salt of valproic acid in an effective amount comprising the step of intimately mixing (i) said hygroscopic salt; (ii) a carbomer and (iii) a non-hygroscopic additive to form a homogeneous mixture; wherein the amount of said carbomer and said non-hygroscopic additive are sufficient relative to the amount of said hygroscopic salt to produce, said mixture having the following property: when compressed into tablets, said tablets do not absorb more than 5% water by weight after being stored for 3 months at 75% relative humidity.

The invention is also directed to non-hygroscopic oral pharmaceutical compositions comprising a pharmaceutically effective amount of a hygroscopic salt of valproic acid, a carbomer, and a non-hygroscopic additive, wherein the amount of said carbomer and said non-hygroscopic additive are sufficient relative to the amount of said hygroscopic salt to produce, said compositions having the following property: not absorbing more than 5% by weight water after being stored for 3 months at 75% relative humidity.

The invention is further directed to non-hygroscopic oral pharmaceutical compositions comprising a pharmaceutically effective amount of a hygroscopic salt of valproic acid, a carbomer, and a non-hygroscopic additive, wherein the amount of said carbomer and said non-hygroscopic additive are sufficient relative to the amount of said hygroscopic salt to produce, said compositions having the following property: when compressed into tablets, said tablets not absorbing more than 5% by weight water after being stored for 3 months at 75% relative humidity.

The invention also includes a method of treating a medical condition in a human patient, the method comprising the step of orally administering non-hygroscopic highly stable pharmaceutical compositions for release of a salt of valproic acid into the bloodstream at a physiologically effective level, wherein said compositions comprise a pharmaceutically effective amount of a hygroscopic salt of valproic acid, a carrier, a non-hygroscopic additive, and wherein the weight ratio of the carbomer to the hygroscopic salt of valproic acid is from about 1:3 to about 1:10 and the weight ratio of the non-hygroscopic additive to the hygroscopic salt of valproic acid is from about 1:6 to about 1:2.

DETAILED DESCRIPTION OF THE INVENTION

A "hygroscopic" material is a material that readily absorbs water (usually from the atmosphere).

A "non-hygroscopic" composition is intended to mean a composition which absorbs less than 5% moisture and preferably less than 2% of its weight. It is a usual practice to test hygroscopicity at RH 75% by exposing the material to be tested to these RH conditions for three months.

The active ingredient of the present invention is a salt of valproic acid. Although the preferred salt is sodium valproate, any other hygroscopic salt or derivative of valproic acid that is suitable for oral administration, or mixtures of valproic acid salts and derivatives can be used.

The processes for preparing a non-hygroscopic oral pharmaceutical composition of a salt of valproic acid includes the step of intimately mixing the active ingredient, i.e., a hygroscopic salt of valproic acid, a carbomer, and a non-hygroscopic additive to form a homogenous mixture. The amounts of the carbomer and the non-hygroscopic additive are sufficient relative to the amount of the hygroscopic salt so that the composition itself (or tablets made from it) does not absorb more than 5% water after being stored for 3 months at 75% relative humidity. The homogeneity of the mixture is determined by any means known for that purpose, including by testing the uniformity of dissolution of several tablets made from this mixture, or by assaying for the quantity of active ingredient contained in the tablets, or both. Surprisingly, the homogeneous mixture may be prepared in relative humidities of greater than 30 percent. The resulting composition, when compressed into tablets, does not absorb more than 5% water after being stored for 3 months at 75% relative humidity. Alternatively, the mixture can be tested in the same manner as powder or granulate without tableting, and be found to absorb no more than 5% water after being stored for three months.

A "sufficient amount" is that amount needed to obtain the desired result, i.e., a mixture, which itself or when compressed into tablets, is non-hygroscopic.

In one embodiment of the invention, the weight ratio of the carbomer to the hygroscopic salt of valproic acid (C/V) is from about 1:3 to about 1:100, preferably from about 1:3 to about 1:10, and the weight ratio of the non-hygroscopic additive to the hygroscopic salt of valproic acid (A/V) is from about 1:6 to about 1:2.

Sustained release properties are achieved in formulations containing a ratio of carbomer to active ingredient of at least 1:6 and preferably at least 1:10 within the aforementioned broad range.

A preferred embodiment of the process includes an additional step of adding at least one excipient to the mixture containing the hygroscopic salt of valproic acid, carbomer and non-hygroscopic additive.

A further embodiment of the process includes further compressing the ingredients into a solid dosage form after the step of intimately mixing (e.g. by blending) to form a homogenous mixture. The time of mixing depends on several factors, including the ratios of (C/V) and (A/V), and the amount of carbomer. Generally, the present compositions can be mixed into homogeneous mixtures by blending for a few minutes due to the relatively high amount of the active ingredient. If any ingredient is present in a very small amount, the mixing time would be longer in order to assure homogeneity with respect to the low-amount ingredient, since homogeneity with respect to all ingredients is preferred. In any event, the mixing must occur for a period of time which is sufficient to obtain a homogenous mixture. In some embodiments, the time of mixing may be about five minutes or less.

For purposes of this specification and the accompanying claims, the phrase "closed conditions" indicates that the experiment was done in a closed container such as a bottle.

The pharmaceutical composition remains non-hygroscopic under relative humidity of from about 30% to about 75% at 40oC. in closed conditions and more preferably from about 30% to about 60% at 25oC. in closed conditions, when the carbomer is present in an amount such that the weight ratio of carbomer to sodium valproate is in the range of from about 1:3 to about 1:100, preferably about 1:3 to about 1:10 and the weight ratio of non-hygroscopic additive to sodium valproate is in the range of from about 1:6 to about 1:2.

The compositions of the present invention may be prepared as solid dosage forms such as bulk powders, tablets, caplets, pellets, capsules, sachets, granules, and any other dosage form suitable for oral administration. For purposes of this specification and the accompanying claims, the term "tablet" refers equally to a tablet, a caplet or any other solid dosage form which is suitable for oral administration.

Preferably, the solid dosage form contains from about 50 to about 1200 mg of a salt of valproic acid or derivative, and more preferably, from about 100 to about 650 mg.

Preferably, the derivative of valproic acid is present in an amount from about 5% to about 99% of the weight of the final composition, more preferably from about 10% to about 90%, and most preferably from about 40% to about 65% of the weight of the final composition. As long as the composition contains at least 1/100 as much carbomer as the active ingredient, the non-hygroscopic property will be observed provided that the amount of additive is commensurating increased in order to make a composition that does not have a disproportionate amount of active ingredient. For example, if the composition contains 1 gram of carbomer and 100 grams of valproate, it should contain about 90 grams of additive. Preferably, however, the amount of carbomer will not be as low as in this example. See preferred C/V ratio range above.

A carbomer is a synthetic high molecular weight cross-linked polymer of acrylic acid. Carbomers are hydroxylated vinylic polymers referred to as "interpolymers" which are prepared by crosslinking a monoolefinic acrylic acid monomer with a polyalkyl ether of sucrose. Any carbomer which is pharmaceutically acceptable for oral administration may be used. Preferred polymers are lightly crosslinked carboxypolymethylenes available as Carbopol.TM. 971P and Carbopol.TM. 71G from the B.F. Goodrich Chemical Company of Charlotte, N.C.

In contrast to expectations, it is the "three-way" combination of carbomer with a non-hygroscopic additive that prevents the liquefaction of salts of valproic acid due to moisture or water absorption. The combination of carbomer alone with the active ingredient is not enough to prevent the liquefaction of the active ingredient, and furthermore does not form an acceptable composition for compressing into a tablet. However, the three-way combination of carbomer and a non-hygroscopic additive with the active ingredient yields a finished composition that does not absorb significant amounts of water. Without being held to a particular theory, the inventors believe that the non-hygroscopic additive and carbomer synergize to achieve this effect. Additionally, the additive imparts good flow properties to the composition which are necessary for the compression into tablets. No adjustment in pH, by the addition of acids or bases, is necessary to stabilize the composition. It is especially noteworthy that from the point of view of achieving non-hygroscopic properties, a small amount of carbomer is effective, as long as it is used in the three-way combination, as described herein.

Carbomer also serves as a dissolution retarding agent of the composition, thereby enabling the formation of a non-hygroscopic composition of the active ingredient. Carbomer can be mixed with the active ingredient in regulated amounts to attain the desired drug release characteristics.

The term "sustained release" is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, substantially exceeding the half life of the active ingredient if administered in a non-sustained (e.g. instantaneous) release formulation. Preferably, although not necessarily, sustained release administration results in substantially constant blood levels of a drug over an extended time period.

Preferably, a single dose of the solid dosage form contains from about 6 mg to about 400 mg of carbomer and more preferably from about 50 mg to about 250 mg of carbomer.

Preferably, carbomer is present in an amount of from about 0.2% to about 30% of the weight of the final composition and more preferably from about 0.2% to about 20% of the weight of the final composition. The amount of carbomer present in a sustained release form of the composition ranges from about 5 to about 15% of the weight of the final composition, and more preferably from about 6 to about 10% of the weight of the composition. It is to be understood that the "final composition" may include additional optional ingredients. It is also understood that the ratios of the three key ingredients should be within at least the broad ranges of C/V and A/V given above.

Preferably, carbomer is present in an amount such that the weight ratio of carbomer to active ingredient is in the range of from about 1:3 to about 1:100, preferably about 1:3 to about 1:10.

The non-hygroscopic additive is used in the present invention to enhance the non-hygroscopic properties of the composition. The non-hygroscopic additive is any material which assists in preventing the moisture absorption of the salt of valproic acid and retains the non-hygroscopic properties of the composition. It is believed that the non-hygroscopic additive helps delay and prevent water from getting to the active ingredient of the composition while giving the composition optimum flow properties. The preferred ratio of non-hygroscopic additive to active ingredient is within the range of 1:6 to 1:2. The non-hygroscopic additives include, but are not limited to, dibasic calcium phosphate anhydrous, calcium silicate, microcrystalline cellulose or mixtures thereof. Preferably, a single dose of the solid dosage form contains from about 90 mg to about 400 mg of non-hygroscopic additive.

The non-hygroscopic additive is present in an amount of from about 10% to about 40% of the weight of the final composition and more preferably from about 15% to about 35% of the weight of the final composition. Again, the weight ratio ranges given above should be adhered to.

A preferred non-hygroscopic additive is dibasic calcium phosphate anhydrous. Dibasic calcium phosphate anhydrous is a non hygroscopic ingredient which does not pick up significant moisture over a wide range of relative humidities. Dibasic calcium phosphate anhydrous serves also as a direct compression agent when the bulk powder is further processed into compression tablets. Calcium silicate is most preferred. The mixtures according to the invention are highly compressible, thereby resulting in tablets with excellent physical properties.

Preferably, the non-hygroscopic additive is present in an amount such that the weight ratio of the non-hygroscopic additive to the carbomer is in the range of from about 2:1 to about 35:1.

The features of a compressed tablet of the invention include the active ingredient, a carbomer, a non-hygroscopic additive, and optionally at least one additional excipient. The additional excipients include pharmaceutical lubricants, binders, disintegrators, glidants, adsorbents, and mixtures thereof. The excipients give the desired flow of the granules, prevent the adhesion of material to the punches and dies, modify the dissolution profile, improve the non-hygroscopic properties of the tablets and provide the desired compressibility properties of the composition. A moisture barrier coating is preferably included instead of or in addition to any other coatings of the tableted dosage form.

Binders are agents used to impart cohesive qualities to the powdered material. Binders impart a cohesiveness to the tablet formulation which insures the tablet remains intact after compression, and improves the free-flowing qualities by the formulation of granules of desired hardness and size. Suitable binder materials include, but are not limited to, starch (including corn starch and pregelatinzed starch), gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums, e.g., acacia, tragacanth, sodium alginate, celluloses, and Veegum, and synthetic polymers such as polymethacrylates and polyvinylpyrrolidone.

Lubricants have a number of function in tablet manufacture. They prevent adhesion of the tablet material to the surface of the dies and punches, reduce interparticle friction, facilitate the ejection of the tablets from the die cavity and may improve the rate of flow of the tablet granulation. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, talc, sodium lauryl sulfate, sodium stearyl fumarate, polyethylene glycol or mixtures thereof. A preferred lubricant herein is magnesium stearate.

Preferably, the lubricant is present in an amount from about 0.25% to about 5% of the weight of the final composition and more preferably from about 0.5 to about 1.5% of the weight of the final composition.

A disintegrant is a substance, or a mixture of substances, added to a tablet to facilitate its breakup or disintegration after administration. Materials serving as disintegrants have been classified chemically as starches, clay, celluloses, aligns, gums and cross-linked polymers. Examples of suitable disintegrants include, but are not limited to, crosscarmelose sodium, sodium starch glycolate, starch, magnesium aluminum silicate, colloidal silicon dioxide, methylcellulose, agar, bentonite, alginic acid, guar gum, citrus pulp, carboxymethyl cellulose, microcrystalline cellulose, or mixtures thereof. A preferred disintegrant is sodium starch glycolate.

Preferably, the disintegrator is present in an amount from about 0.5% to about 25% of the weight of the final composition and more preferably from about 1% to about 15% of the weight of the final composition.

Glidants are substances which improve the flow characteristics of a powder mixture. Examples of glidants include, but are not limited to colloidal silicon dioxide, talc or mixtures thereof.

Preferably, the glidant is present in an amount of from about 0.1% to about 10% of the weight of the final composition and more preferably from 5 about 0.1% to about 5% of the weight of the final composition.

The adsorbent may be, for example colloidal silicon dioxide, microcrystalline cellulose, calcium silicate or mixtures thereof.

Preferably, the adsorbent is present in an amount from about 0.05% to about 42% of the weight of the final composition and more preferably from about 0.05% to about 37% of the weight of the final composition.

If desired, other ingredients, such as diluents, stabilizers and antiadherants, which are conventionally used for pharmaceutical formulations, may be included in the present formulations.

Optional ingredients include coloring and flavoring agents which are well known in the art.

The present invention further provides a non-hygroscopic orally deliverable pharmaceutical composition containing as an active ingredient a salt of valproic acid or other solid derivative thereof in an effective amount, (i.e., an amount resulting in the release into the bloodstream of effective levels of valproic acid), the composition including a pharmaceutically effective amount of a hygroscopic derivative of valpoic acid, a carbomer, a non-hygroscopic additive, and at least one excipient.

Although the preferred salt is sodium valproate, any other hygroscopic salt or derivative of valproic acid that is suitable for oral administration, or mixtures of valproic acid salts and derivatives can be used.

Any carbomer which is pharmaceutically acceptable for oral administration may be used. A particularly preferred polymer is a lightly crosslinked carboxypolymethylene available as Carbopol.TM. 971P and Carbopol.TM. 71G from the B.F. Goodrich Chemical Company of Charlotte, N.C. Preferably, carbomer is present in an amount from about 0.2% to about 30% of the weight of the final composition and more preferably from about 0.2% to about 20% of the weight of the final composition. The amount of carbomer present in a sustained release form of the composition ranges from about 5 to about 15% of the weight of the final composition, and more preferably from about 6 to about 10% of the weight of the composition.

The non-hygroscopic additive may be, preferably, dibasic calcium phosphate anhydrous, calcium silicate, microcrystalline cellulose or mixtures thereof and more preferably dibasic calcium phosphate anhydrous or calcium silicate. The non-hygroscopic additive is present in an amount ranging from about 10% to about 40% and preferably from about 15% to about 35%.

The present invention further provides a method of treating a medical condition in a human patient, the method including the step of orally administering a non-hygroscopic highly stable pharmaceutical composition for release of a salt of valproic acid into the bloodstream at a physiologically effective level, wherein the composition includes a pharmaceutically effective amount of a hygroscopic salt of valproic acid, a carrier, a non-hygroscopic additive, and at least one excipient.

The terms "effective amount" or "therapeutically effective amount" of an active agent as provided herein is defined as an amount of the agent at least sufficient to provide the desired therapeutic effect. (Preferably, nontoxic levels of the active agent will be employed, if possible.) The exact amount required will vary from subject to subject, depending on age, general condition of the subject, the severity of the condition being treated, and the particular active agent administered, and the like.

The medical condition treated with the present formulation may be, for example, epilepsy, a psychotic disorder or a migraine headache.

The pharmaceutical composition described in the present invention is formulated to release active ingredient in a sustained release or an immediate release manner. The in vitro and in vivo drug release profile depends mainly on the carbomer.

Sustained release compositions can be formulated such that, in vitro, preferably from about 5% to about 40% of the active ingredient is released after 2 hours, preferably from about 10% to about 50% is released after 6 hours, approximately from about 30% to about 90% is released after 8 hours and approximately from about 50% to about 100% is released within 12 to 24 hours.

Immediate release compositions can be formulated such that in vitro approximately 70% of the drug is released in one hour.

Enteric coated compositions are coated with a coating that withstands the low pH conditions of the upper gastric tract but dissolves in the intestines. Enteric coated composition may be released or sustained release compositions (after dissolution of the coating).

The pharmaceutical composition may be, for example, in the form of a tablet, a caplet, a pellet, a capsule, a granule, a tablet which disintegrates into granules, a pill, a powder or a sachet. Preferably the pharmaceutical composition is in the form of a tablet or a caplet, more preferably the caplet is oval shaped. The capsule may contain a powder, a compressed powder or a granule.

The pharmaceutical compositions of the present invention are administered orally.

The pharmaceutical composition may further be coated with a moisture barrier film, to further improve the non-hygroscopic properties of the composition. Suitable moisture barrier coatings comprise aqueous solutions of polyvinyl alcohol. Indeed, it is a tribute to the present composition that it so well protects the active ingredient from absorbing moisture that tablets can be coated with an aqueous solution. Other moisture barrier coatings can also be used, e.g., steatic acid, wax, etc.

The process for preparing non-hygroscopic, highly moisture stable composition of sodium valproate need not be carried in a "dry room" but may be practiced at a relative humidity of from about higher than 30% and up to about 75%. It is, however, preferred that the RH be controlled, but only so that it not exceed about 50%.

The amount of sodium valproate in the formulation varies depending on the desired dose for efficient drug delivery. The actual amount of the used drug is dependent on the patient's age, weight, sex, disease and on any other medical criteria, and is determined according to intended medical use by techniques known in the art. The pharmaceutical dosage forms of the invention may be administered once or more times per day, as determined by the attending physician, and as warranted by the release profile of the composition.

Typically, to treat seizure disorders, sodium valproate is formulated in a tablet or other dosage form in amounts of 10-40 mg/kg body weight per day, preferably 15-30 mg/kg body weight per day. For adults, the daily dose is typically 20 mg/kg body weight per day. For children and infants, the daily dose is typically 25 mg/kg body weight per day.

When a sustained release dosage form is to be administered, the daily dosage of sodium valproate or other solid derivative of valproate acid is formulated in a sustained release composition to be released slowly to maintain therapeutic levels of sodium valproate in patients blood between about 50 to about 100 .mu.g/ml. Above this concentration, patients may experience adverse effects.

The daily dose can be formulated in a single tablet, or more than one tablet, depending on the daily dose of the valproate salt, the final weight of the composition and the number of times the formulation is to be administered.

It is to be understood that the invention is not limited in its application to the details of construction and the arrangement of the components set forth in the following description. The invention includes other embodiments and can be practiced or implemented in various ways. Also it is to be understood that the phraseology and terminology employed herein is for the purpose of description only and should not be regarded as limiting.

Claim 1 of 55 Claims

What is claimed is:

1. A process for preparing a pharmaceutical composition comprising as an active ingredient a hygroscopic salt of valproic acid, comprising the step of intimately mixing (i) said hygroscopic salt; (ii) a carbomer and (iii) a non-hygroscopic additive to form a homogeneous mixture; wherein the amount of said carbomer and said non-hygroscopic additive are sufficient relative to the amount of said hygroscopic salt to produce said mixture having the following property: when compressed into tablets, said tablets do not absorb more than 5% water by weight when tested after being stored for 3 months at 75% relative humidity; wherein said pharmaceutical composition is free of valproic acid; and wherein the weight ratio of carbomer to the hygroscopic salt of valproic acid ranges from about 1:3 to about 1:100.




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