JP2009525953A - Sustained release formulation of divalproic acid and its derivatives - Google Patents

Abstract

The present invention provides: a) a valproic acid compound in an amount of from about 40% to about 80% by weight, such as divalproex sodium, and b) each of at least two, preferably in an amount up to about 20% of the weight of the tablet. Provides a sustained release formulation comprising a hydrophilic polymer.
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Description

  The present invention relates to pharmaceutical formulations. More particularly, the invention relates to a formulation comprising valproic acid, a pharmaceutically acceptable salt, ester or amide thereof, or divaproex sodium in a sustained release tablet formulation.

  2-Propylpentanoic acid (more commercially known as valproic acid (VPA)), its amide, valpromide (VPO), and certain salts and esters of the acid are useful in the treatment of epileptic seizures or as antipsychotics Useful as. Meade, US Pat. No. 4,988,731 describes an oligomer containing 4 units and having a 1: 1 molar ratio of sodium valproate to valproic acid, and Meade, US Pat. No. 5,212,326 is one of sodium valproate and valproic acid. A stable non-hygroscopic solid of valproic acid having a molar ratio of: 1 and comprising an oligomer comprising 4 to 6 units is described. Divalproex sodium (sodium divalproate) is useful in preventing migraine in adults and can be used to treat or prevent stroke.

  However, despite its effectiveness in the treatment of epilepsy, valproic acid has been known to exhibit a significantly shorter elimination half-life than other commercially used antiepileptic agents. The half-life of the drug is reported to be 6-17 hours in adults and 4-14 hours in children. This can lead to substantial fluctuations in the plasma concentration of the drug, especially in chronic administration. In order to maintain a sufficiently stable plasma concentration, it will likely need to be administered frequently, and the resulting inconvenience to the patient often results in reduced compliance with the prescribed dosing schedule. Furthermore, widely varying drug plasma concentrations result in the administration of sub-therapeutic drugs in a conservative regimen, or in excess for certain patients in an aggressive regimen.

  To overcome this disadvantage, valproic acid formulations have been developed that maintain a more stable plasma level of the drug after administration. The ultimate goal is the development of formulations that provide stable plasma levels in a once daily dosing regimen. Efforts to achieve this goal generally involve two categories: (a) discovering forms of active ingredients that are metabolically slowly released by the body, and (b) either sustained release or sustained release mechanisms. This is one of the discovery of a formulation that delivers a drug.

  US Pat. No. 4,369,172 (Schor et al.) Discloses sustained release therapeutic compositions based on, for example, a mixture of hydroxypropyl methylcellulose, ethylcellulose and / or sodium carboxymethylcellulose. Schor et al. Provide a long list of therapeutic agents that they suggest can be incorporated into formulations containing sodium valproate.

  US Pat. No. 4,913,906 (Friedman et al.) Describes sustained release formulations of valproic acid, its amides, or salts or esters thereof in combination with natural or synthetic polymers molded into tablets at elevated pressure. It seems.

  US Pat. No. 5,009,897 (Blinker et al.) Describes a granule comprising a granule suitable for molding into a tablet, a core of divaproex sodium, and a coating of a mixture of polymer and crystalline cellulose.

  US Pat. No. 5,019,398 (Daste) describes sustained release tablets of divalproex sodium in a matrix of hydroxypropyl methylcellulose and silicic acid.

  US Pat. No. 5,055,306 (Barry et al.) Describes effervescent or water dispersible granule sustained release formulations suitable for use with a variety of therapeutic agents. The granule comprises an active ingredient and at least one excipient and a core comprising a water insoluble, water swellable coating comprising a copolymer of ethyl acrylate and methyl methacrylate and a water soluble hydroxylated cellulose derivative. Become. These patent holders suggest a list of therapeutic agents that can be used in the formulations of the invention containing sodium valproate.

  U.S. Pat.No. 5,169,642 (Brinkler et al.) Describes divalproex sodium or coated with a sustained release composition comprising ethyl cellulose or methyl methacrylate, a plasticizer, a detackifier, and a sustained release polymer viscosity agent. It appears to describe a sustained release formulation comprising granules of an amide or ester of valproic acid.

  US Pat. No. 5,185,159 (Aubert et al.) Describes formulations of valproic acid and sodium valproate that are apparently prepared without the use of any binders or granulating solvents.

  US Pat. No. 5,589,191 (Exigua et al.) Describes sustained release sodium valproate tablet formulations coated with ethylcellulose containing anhydrous silicic acid.

  Published PCT application WO 94/27587 (Ayer et al.) Describes a method for the control of sputum by delivering a therapeutic composition of valproic acid or a derivative thereof in combination with a poly (alkylene oxide).

  Bialer, et al., "Metabolism of Antiepileptic Drugs," pp. 143-151, RH Levy, Ed., Raven Press, New York, 1984; Int. J. Pharmaceutics, 20: 53-63 (1984); and Biopharmaceutics and Drug Disposition, 6: 401-411 (1985); and Israel J. Med. ScL, 20: 46-49 (1995) report the pharmacokinetic evaluation of several sustained release formulations of valproic acid.

  US Pat. No. 6,419,953 (Qiu et al.) Discloses hydrophilicity suitable for once daily administration of a valproic acid compound with hydroxypropylmethylcellulose, such as divalproex sodium, in an amount of about 20% to about 40% by weight. It appears to describe matrix tablets.

  US Pat. No. 6,528,090 (Qiu et al.) Is suitable for once daily administration of a valproic acid compound with a pharmaceutically acceptable hydrophilic polymer in an amount of about 20% to about 50% by weight of the formulation. Oral sustained-release preparations are described.

  However, there is still a need for a sustained release formulation of valproic acid that can effectively maintain the plasma concentration of the drug at a more constant level.

  a) a valproic acid compound in an amount of from about 40% to about 80% by weight, such as divalproex sodium, and b) at least two preferably hydrophilic polymers, each in an amount of about 20% or less of the weight of the tablet. A sustained release tablet formulation comprising: Preferably the sustained release formulation comprises 2 to 4 polymers, more preferably 2 polymers. Preferably, the sustained release formulation comprises about 45 to about 55% valproic acid compound. Further, the polymer is preferably selected from the group consisting of hypromellose (hydroxypropyl methylcellulose, HPMC), hydroxyethylcellulose, and polyethylene oxide.

In another aspect, the invention is also a sustained release tablet formulation comprising a valproic acid compound and at least two preferably hydrophilic polymers, each in an amount of about 20% or less of the tablet weight, In an aqueous buffer at 37 ° C. and pH 5.5,
a) About 30% or less of the total valproic acid compound is released within 3 hours or less as measured in the device;
b) About 35 to about 70% of the total valproic acid compound is released within 9 hours or less as measured in the device;
c) About 50 to about 95% of the total valproic acid compound is released within 12 hours or less in the measurement in the device; and d) At least about 75% of the total valproic acid compound is 18 in the measurement in the device. A formulation is provided that has a dissolution profile of being released in time or less.

Further, a method for preparing a granular composition suitable for filling into a capsule or molding into a sustained release tablet, comprising:
a) Valproic acid compounds such as divalproex sodium, at least 2, preferably 2-4, and more preferably 2, preferably hydrophilic polymers, preferably hypromellose, and hydroxyethylcellulose, and a binder, Preferably dry-mixing a mixture comprising pregelatinized starch;
b) wet granulation with an aqueous alcohol solution (mixture of alcohol and water) to form a homogeneous mixture;
c) drying and sizing the wet granules;
d) surface coating the dried granules with a dispersant with purified water containing a hydrophilic polymer, preferably hypromellose and talc;
e) drying the coated granules;
f) adding a glidant, preferably silicon dioxide, and sieving the coated granules;
g) dry mixing the coated granules with a filler, preferably crystalline cellulose, and a lubricant, preferably stearic acid;
h) compressing the granules into tablets; and i) coating the tablets with a cosmetic coat;
Is provided.

  In the embodiment where the granules are filled into capsules, this may be done after step e), so steps f) and g) above are optional, and steps h) and i) are not relevant.

  In another aspect, the present invention is a method for treating a patient suffering from a condition, comprising about 40 to about 80% valproic acid compound, and an amount of about 20% or less of the weight of each tablet. A sustained release formulation of a valproate compound comprising administering a therapeutically effective amount of the valproate compound once a day in a sustained release tablet formulation comprising at least two preferably hydrophilic polymers in Provide a method to be treated with.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the terms “sustained release”, “sustained release”, and “sustained release” applied in pharmaceuticals are described in “Remington's Pharmaceutical Sciences,” 18th Ed. , p. 1677, Mack Pub. Co., Easton, Pa. (1990). Sustained release drug systems include any drug delivery system that achieves drug release over an extended period of time and includes both sustained release and sustained release. Such sustained release systems are effective in maintaining a substantially constant drug level in the blood or target tissue, which is considered as a sustained release drug delivery system. However, if the drug delivery system extends the duration of drug action achieved by conventional delivery, it does not take into account whether this is successful in achieving a substantially constant blood or tissue drug level. Considered as a sustained release system.

  The formulation of the present invention provides a sustained release formulation for valproic acid compounds. The term “valproic acid” refers to the 2-propylpentanoic acid compound itself, pharmaceutically acceptable salts thereof, and compounds that are readily metabolized to produce valproic acid in vivo, such as valproic acid amide (valpromide). , And other pharmaceutically acceptable amides and esters of the acid. A particularly preferred form of valproic acid for the composition of the present invention is a complex formed between 2-propylpentanoic acid and its sodium salt (2: 1), commonly referred to as “divalproex sodium”. Is the body.

Divalproex sodium can be represented by the following structure, where m is an integer from 2 to 6:

  A method for synthesizing valproic acid is described in Oberreit, Ber. 29, 1998 (1896) and Keil, Z. Physiol. Chem. 282, 137 (1947). Its activity as an antidepressant compound is described in the Physician Desk Reference, 52nd Edition, page 421 (1998). Upon ingestion into the gastrointestinal tract, the acid moiety dissociates to form a carboxylic acid moiety (ie, valproate ion). The sodium salt of valproic acid is also known in the art as an antidepressant. It is also known as sodium valproate and is described in detail in The Merck Index, 12th Edition, page 1691 (1996). Further descriptions can be found in the Physician Desk Reference, 52nd Edition, page 417 (1998).

  Divalproex sodium is effective as an antidepressant and is also used for migraine and depolarization disorders. Methods for its preparation can be found in US Pat. Nos. 4,988,731 and 5,212,326, the contents of which are incorporated herein by reference. Like valproate, it also clearly dissociates in the gastrointestinal tract to form valproate ions.

In addition, as used herein:
a) Any reference to “valproic acid compound” refers to dissociation in the gastrointestinal tract or in vitro dissolution media and valproate ion, eg, without limitation, valproic acid, sodium salt of valproic acid, divalpro It should be construed to include compounds that produce exsodium, various salts of any of the above valproic acids, and prodrugs of any of the above valproic acids. Divalproex sodium is the most preferred valproic acid compound of the present invention.

b) “C _max ” means the maximum plasma concentration of valproate ion produced by ingestion of the composition of the present invention.

  c) “AUC” as used herein means the area under the plasma concentration-time curve calculated by the trapezoidal formula over the complete 24-hour interval for all formulations.

  d) “Pharmaceutically acceptable” as used herein is within the scope of appropriate medical judgment, and includes human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc. Means those salts, polymers and excipients that are suitable for use in contact with, maintain a reasonable benefit / risk ratio and are effective for their intended use in the treatment and prevention of various disorders To do.

  Moreover, in vitro dissolution properties are also often used in the manufacture of drugs. They serve as quality control devices to ensure that different batches have the same dissolution characteristics and produce comparable biological responses.

  The novel valproic acid compound formulation has significant advantages over prior art sustained release formulations. These formulations provide a substantially zero (0) order release of valproic acid, minimizing variability between the valproic acid peak and trough plasma levels. All formulations of the present invention each comprise a matrix system comprising at least two preferably hydrophilic polymers in an amount of 20% or less of the weight of the tablet, and further comprises a particulate matrix surface coating. It's okay.

  In a matrix system, the drug or pharmaceutically active ingredient is uniformly dispersed in the polymer associated with the conventional excipient. This mixture can be compressed under pressure to produce tablets. The drug is released from the tablet by diffusion and erosion. Matrix systems are described in (1) Handbook of pharmaceutical controlled release technology, Ed.DL Wise, Marcel Dekker, Inc. New York, NY (2000), and (2) Treatise on controlled drug delivery, fundamentals, optimization, applications, Ed. A. Kydonieus, Marcel Dekker, Inc. New York, NY (1992), which are both incorporated herein by reference.

Enhanced pharmacokinetic properties, described in more detail below, can be obtained by administration of a matrix formulation of valproic acid compounds comprising at least two, preferably hydrophilic polymers. In one embodiment, the sustained release formulation according to the present invention is:
a) a valproic acid compound present in an amount sufficient to provide the required daily dose of valproic acid, and b) at least two, preferably 2-4, and more preferably two, preferably hydrophilic Polymers, wherein each polymer is in an amount of no more than about 20% by weight of the tablet, preferably no more than about 16% by weight of the tablet,
Comprising.

In another aspect of the invention,
a) a valproic acid compound present in an amount sufficient to provide the required daily dose of valproic acid;
b) at least two, preferably 2-4, and more preferably two, preferably hydrophilic polymers, and c) a polymer, preferably a hydrophilic polymer, wherein each type of polymer in the formulation A granule surface coating of a pharmaceutical matrix grain comprising an amount of about 20% or less of the composition, preferably about 16% or less of the tablet),
A sustained release formulation comprising is provided.

  In a preferred embodiment, the surface-coated grains are formed into a tablet core, which may be optionally coated, preferably with a cosmetic coat.

  Preferably, the valproic acid compound is divalproex sodium. The amount of valproic acid compound sufficient to provide the daily required dose of valproic acid is from about 40% to about 80% by weight of the formulation. More preferably, the sustained release formulation of the present invention comprises from about 45% to about 60% by weight valproic acid compound, most preferably from about 45% to 55% valproic acid compound.

  Suitable preferred hydrophilic polymers for use in the sustained release formulation include hypromellose (HPMC, eg Methocel K100, Methocel E15, and Pharmacoat 606), hydroxyethylcellulose (HEC, eg Natrosol® 250M), Polyethylene oxide, polyvinylpyrrolidine, hydroxypropylcellulose, methylcellulose, vinyl acetate copolymer (eg Kollicoat SR30, aqueous dispersion of polyvinyl acetate stabilized with polyvinylpyrrolidone and lauryl sulfate), polysaccharides (eg alginate, xanthan gum) Etc.), methacrylic acid copolymer, maleic anhydride / methyl vinyl ether copolymer and derivatives thereof. Preferably, the hydrophilic polymer is selected from hypromellose, hydroxyethyl cellulose, polyethylene oxide, and coricoat. Most preferably, the hydrophilic polymer is hypromellose and hydroxyethyl cellulose. Preferred hypromellose compounds are commercially available Methocel K100, Methocel E15, and Pharmacoat 606. A preferred commercially available hydroxyethyl cellulose is Natrosol® 250M.

  The amount of each polymer in the formulations of the present invention is no more than about 20% by weight of the composition. Preferably, the amount of each polymer is no more than about 16% by weight of the composition. More preferably, the amount of each polymer is from about 10% to about 16% by weight of the formulation. Most preferably, the amount of each polymer is from about 12% to about 16% by weight of the formulation.

  The sustained release tablet formulation of the present invention may further comprise a hydrophobic polymer, such as ethyl cellulose. Preferred commercially available ethylcellulose includes 7 cps etose premium and 100 cps etose premium.

  The compositions of the present invention also typically include a pharmaceutically acceptable excipient. As is well known to those skilled in the art, pharmaceutical excipients are conventionally incorporated into solid dosage forms. This is done to facilitate the manufacturing process as well as to improve the performance of the formulation. Common excipients include diluents, binders, extenders, lubricants, binders and the like. Such excipients are conventionally used in the formulations of the present invention.

  Diluents or fillers are added to increase the individual volume to a size suitable for tableting. Suitable diluents include powdered sugar, calcium phosphate, calcium sulfate, crystalline cellulose, lactose, mannitol, kaolin, sodium chloride, dried starch, sorbitol and the like.

  Lubricants are incorporated into formulations for a variety of reasons. These reduce the friction between the granules and the die wall during pressing and extrusion. This prevents the tablet punch and granules from sticking to the die and facilitates its extrusion from the tablet punch. Examples of suitable lubricants include talc, sodium lauryl sulfate, stearic acid, vegetable oil, calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate and the like.

  Glidants are also typically incorporated into the formulation. Glidants improve the flow characteristics of the granules. Examples of suitable glidants include talc, silicon dioxide, and corn starch.

  A binder can be incorporated into the formulation. A binder is utilized when a granulation process is used in the production of the dosage form. Examples of suitable binders include povidone, polyvinylpyrrolidone, xanthan gum, cellulose gum, such as carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxycellulose, gelatin, starch, and pregelatinized starch. Also, the binder is often the same polymer that is used to control the release of the active ingredient from the formulation.

  Other excipients that can be incorporated into the formulation include preservatives, antioxidants, or any other excipient commonly used in the pharmaceutical industry. The optional tablet coat is preferably cosmetic, for example commercially available for coating suspensions based on either hypromellose or polyvinyl alcohol together with polyethylene glycol and colorants etc. It can be prepared from possible powders.

  In other embodiments of the invention, from about 47 to about 50% by weight valproic acid compound; from about 13 to about 16% by weight hypromellose; from about 13 to about 15% by weight hydroxyethyl cellulose; from about 8 to about 9% by weight alpha A sustained release tablet core formulation comprising: about 4 to about 10% by weight crystalline cellulose; about 3 to about 4% by weight silicon dioxide; and about 1 to about 2% by weight stearic acid is provided. . All weight percentages are based on the total weight of the tablet formulation.

Particularly preferred sustained release formulations of the present invention are listed in Table 1 below. Here all weight percentages are based on the total weight of the formulation.

In another embodiment of the present invention, a sustained release tablet formulation comprising at least 2, preferably 2-4, and more preferably 2, preferably hydrophilic polymers, wherein the formulation comprises: a ) About 30% or less of the total valproic acid compound is released in 3 hours or less;
b) About 35% to about 70% of the total valproic acid compound is released within 9 hours or less; c) About 55% to about 95% of the total valproic acid compound is released within 12 hours or less And d) a formulation is provided having a dissolution profile that at least about 75% of the total valproic acid compound is released within 18 hours or less. The dissolution profile of the sustained release tablet formulation of the present invention is the base of 900 ml 0.05 M phosphate buffer with an acid step of 500 ml 0.1 N HCl for 45 minutes followed by 75 mM sodium ralyl sulfate (SLS) pH 5.5. USP type II apparatus at 100 rpm, 37 ° C., in stages.

In yet another aspect of the present invention, there is provided a sustained release tablet formulation comprising a valproic acid compound and at least 2, preferably 2 to 4, and more preferably 2 and preferably hydrophilic polymers. Compared to the pharmacokinetic properties of Depaquat ER (commercially available sustained release divalproex sodium formulation), a) average AUC values in the range of about 85% to about 120%, where , sets the AUC values observed for Depakote ER 100%), and b) C _max values in the range of from about 90% to about 160% (where the C _max values observed for Depakote ER to 100% There is provided a sustained release tablet formulation characterized in that the controlled release tablet formulation is administered to a non-fasting mammal. Further, in fasting mammals, the AUC value is from about 90 to about 130, and the C _max value is from about 100 to about 160. In the pharmacokinetic properties, the parameters for AUC and C _max are expressed as 100 times the ratio of the value observed for the formulation of the invention to the value observed for Depacoat ER. Preferably, the values for the pharmacokinetic parameters of the formulations of the present invention satisfy Depacoat ER and an equivalent criterion of 0.80 to 1.25. Thus, the formulations of the present invention comprising a valproic acid compound and no more than 20%, preferably no more than 16%, preferably a hydrophilic polymer, have pharmacokinetics comparable to commercially available depacoat ER formulations. And preferably bioequivalence.

  The sustained release formulations are generally prepared using standard techniques well known in the art. Typically, these are preferably dry blended with hydrophilic polymers, fillers, valproic acid compounds, and other excipients, followed by aqueous alcohol solution (alcohol and water until suitable granules are obtained). Prepared by granulating the mixture using a mixture. The granulation is performed by methods known in the art. The wet granules can be dried in a fluid bed dryer, sieved and powdered to the appropriate size and then surface coated with a dispersant containing a hydrophilic polymer. Fillers and lubricants are mixed with the dried granules to obtain the final formulation.

More specifically, sustained release tablet formulations comprising a valproic acid compound and at least two preferably hydrophilic polymers can be prepared according to the following examples. A method for preparing a granular composition suitable for molding into a sustained release tablet formulation includes:
1) Valproic acid compounds, such as divalproex sodium, and at least 2, preferably 2-4, and more preferably 2, hydrophilic polymers, preferably hypromellose and hydroxyethylcellulose, and binders, preferably Dry blending a mixture of polymers comprising pregelatinized starch;
2) wet granulation with a hydroalcoholic solution (a mixture of alcohol and water) to form a homogeneous mixture;
3) drying and sizing the wet granules;
4) surface coating the dried granules with a dispersant containing purified water with diluent and polymer, preferably hydrophilic polymer, more preferably hypromellose, and talc;
5) drying the coated granules;
6) adding a glidant, preferably silicon dioxide, and sieving the coated granules;
7) Dry mixing the coated granules with a filler, preferably crystalline cellulose and a lubricant, preferably stearic acid;
8) molding the mixed granules into a tablet; and 9) optionally coating the tablet with a cosmetic coat;
Comprising.

  The composition of the present invention can be administered orally in the form of tablets, pills, or the granules can be packed into capsules. Tablets can be prepared by techniques known to those skilled in the art and contain a therapeutically useful amount of a valproic acid compound and the excipients necessary to form a tablet by such techniques. Tablets and pills can be further prepared with enteric coatings and other sustained release coatings for the purpose of facilitating acid protection, swallowing ability. The coating can be colored with a pharmaceutically acceptable dye. It is believed that the amount of dye and other excipients in the coating fluid can be varied and does not affect the performance of the sustained release tablet. The coating fluid generally comprises a film-forming polymer, such as hydroxypropylcellulose, polyvinyl alcohol, hydroxypropylmethylcellulose, cellulose ester or ether, such as cellulose acetate or ethylcellulose, an acrylic polymer or polymer mixture. The coating solution generally comprises an aqueous solution or further comprising a plasticizer such as polyethylene glycol, propylene glycol, sorbitan monooleate, sorbic acid, a colorant such as titanium dioxide, a pharmaceutically acceptable dye or lacquer. Organic solution.

  In another aspect of the invention, a method of treating a patient suffering from a condition that is treated with a sustained release formulation of a valproic acid compound, comprising about 40% to about 80% valproic acid compound, and each of the tablets Sustained release tablet formulation comprising at least 2, preferably 2 to 4, and more preferably 2 and preferably hydrophilic polymers in an amount of about 20% or less by weight, more preferably 16% or less Wherein a method comprising administering a therapeutically effective amount of a valproic acid compound once a day is provided. The sustained release tablet formulation of the present invention provides an effective delivery system for once daily administration of a valproic acid compound (divalproex sodium) to a patient in need of treatment. The formulations of the present invention provide sufficient plasma levels of valproic acid within the therapeutic range of the drug in a period that allows for once daily administration.

  The following examples are provided to further illustrate the present invention. These examples should not be constructed in any manner that would limit the invention.

Example 1: Divalproex Sodium Formulation Tablets containing 538 mg divalproex sodium, starch, and tablet cores of various polymers were prepared. The tablet composition is shown in Table 2.

Example 2: Preparation of divalproex sodium sustained release formulation This example illustrates the preparation of a preferred dosage form of the present invention on a 2500 tablet scale.
Divalproex sodium was milled through a Quadro comill equipped with a 0.187 inch aperture screen. 2.691 kg of milled drug was placed directly into the mixer and mixed with 230 g starch NF, 225 g Methocel K-100M (hypromellose NF) and 375 g Natrosol® 250M (hydroxyethyl cellulose NF) for 4 minutes. This mixture was granulated with 150 g of 95% alcohol USP for 1 minute, and a mixture of 25 g of purified water and 25 g of 95% alcohol was mixed for an additional 30 seconds and then dried. The dried granules were milled through a 1 mm aperture screen. The granules were then granule coated in a fluid bed dryer using a suspension prepared from 1350 g purified water, 280 g Methocel E-15 (hypromellose 15 cps NF) and 140 g talc. The coated granules were mixed with 100 g silicon dioxide (Syloid 244) and 125 g microcrystalline cellulose (Avicel PH 102) for 10 minutes in a mixer. 50 g of stearic acid was added and mixed for an additional 5 minutes. The mixed mixture was molded into a 100 gram tablet core.

Example 3: Dissolution test with divalproex sodium sustained-release tablet A dissolution test was conducted with a sustained-release divalproex sodium tablet formulation. These in vitro dissolution tests were performed using apparatus II described in US Pharmacopeia XXI / National Medicine Collection XVI. The comparative dissolution test in the release medium was performed under the following conditions. The divalproex sodium ER tablets were added in a 500 ml 0.1 N HCl acid step for 45 minutes followed by a 900 ml 0.05 M phosphate buffer base step with 75 mM sodium lauryl sulfate (SLS) pH 5.5. Dissolved in a USP Type II apparatus at 100 rpm at a temperature of ° C. Sampling times at the base stage were 3, 9, 12 and 18 hours. The results of this dissolution test are shown in Table 3.

  Based on these dissolution experiments, ie, the results shown in Table 3 above, the following conclusions were drawn: a) Less than about 30% of the total valproic acid released in 3 hours or less as measured by the instrument B) about 35 to about 70% of the total valproic acid is released in 9 hours or less in the measurement with the device; c) about 55 to about 55% of the total valproic acid is measured in the device. About 95% is released in 12 hours or less; and d) At least 75% of the total valproic acid is released in 18 hours or less as measured by the device.

Example 4: In vivo pharmacokinetic experiments In three in vivo in vivo experiments, the pharmacokinetics of the preferred formulation and the control drug were compared. Biological versus time profile from oral sustained release tablet formulations of divalproex sodium (K-34999, K-35002, and K-35689 described in Table 2) measured under fasting and non-fasting conditions Availability and plasma concentrations were determined in healthy subjects (15 subjects in non-fasting, 13 subjects in fasting experiments), commercially available sustained release divalproex sodium tablet formulation (depacoat) under the same conditions ER).

Pharmacokinetic parameters were obtained for C _max and AUC _{0-24 in} both fasting and non-fasting (feeding) biological experiments. Analysis of variance (ANOVA) was similarly obtained for these parameters. The pharmacokinetic results for each formulation in comparison with the control formulation are summarized in Table 5.

The 90% confidence interval for the AUC value for the test formulation administered under fasting and non-fasting conditions relative to the fasting and non-fasting controls is in the range of 0.80 to 1.25 times the control value. Meet the criteria for bioequivalence. In addition, the 90% confidence interval for the ratio of median C _max for test formulations under fasting and non-fasting administration is also satisfied by the same _{bioequivalence} criteria.

The sustained release tablet formulation functions well. The controlled release regimen is equivalent to the control regimen or biologically equivalent with respect to the extent of absorption, as characterized by AUC. The two study regimens were not statistically significantly different from the control regimen in terms of the _{Cmax of the} sustained release regimen compared to the control regimen. This suggests that the sustained release tablet formulation provides controlled release of valproic acid in vivo under fasting and non-fasting conditions.

  Furthermore, the results demonstrate these similarities in the sustained release characteristics of the test formulation and AUC based bioavailability when compared to the control formulation.

Claims (53)

a) a valproic acid compound in an amount of about 40% to about 80% by weight of the formulation, and b) at least two polymers, each in an amount up to about 20% of the weight of the tablet,
A sustained-release preparation comprising:   The sustained release formulation according to claim 1, wherein the valproic acid compound is selected from the group consisting of valproic acid, a pharmaceutically acceptable salt, ester or amide thereof, and divalproex sodium.   The sustained-release preparation according to claim 1, wherein the preparation is a tablet.   The sustained-release preparation according to claim 1, wherein at least one of the polymers is a hydrophilic polymer.   The sustained release formulation according to claim 1, wherein the valproic acid compound is in an amount of about 45% to about 60%.   6. The sustained release formulation of claim 5, wherein the valproic acid compound is in an amount of about 45% to about 55%.   The sustained-release preparation according to claim 1, wherein the valproic acid compound is divalproex sodium.   The sustained release formulation according to claim 1, wherein the amount of each polymer is about 16% or less of the weight of the tablet.   The sustained release formulation of claim 1, wherein the amount of each polymer is from about 10% to about 16% of the weight of the tablet.   The sustained release formulation of claim 1, wherein the amount of each polymer is from about 12% to about 16% of the weight of the tablet.   The polymer is hypromellose (HPMC), hydroxyethyl cellulose (HEC), polyethylene oxide (polyox), polyvinyl pyrrolidine, hydroxypropyl cellulose, methyl cellulose, vinyl acetate copolymer, polysaccharide, methacrylic acid copolymer, maleic anhydride / methyl vinyl ether. The sustained release formulation according to claim 1, selected from the group consisting of copolymers and derivatives thereof.   The sustained release formulation according to claim 1, wherein the polymer is selected from the group consisting of hypromellose (hydroxypropylmethylcellulose, HPMC), hydroxyethylcellulose, polyethylene oxide, and Kollicoat 30SR.   The sustained release formulation according to claim 1, wherein the polymer is selected from the group consisting of hypromellose K100 (Methocel K100), hypromellose E15 (Methocel E15), and hydroxyethylcellulose 250 (Natrosol® 250M).   5. The sustained release formulation according to claim 4, further comprising at least one additional polymer that is hydrophobic.   15. The sustained release formulation according to claim 14, wherein the at least one hydrophobic polymer is ethyl cellulose.   The sustained release formulation according to claim 1, wherein the polymer is hydrophilic and comprises at least one hydrophobic polymer.   The sustained release formulation according to claim 16, wherein the at least one hydrophobic polymer is ethyl cellulose. The formulation is in the form of a coating core,
a) a compressed surface-coated matrix grain, and b) a coating on the compressed core,
The sustained-release preparation according to claim 1, comprising:   The coated core of claim 18, wherein the surface coated matrix grain comprises a valproic acid compound and at least two hydrophilic polymers.   The hydrophilic polymer is hypromellose (HPMC), hydroxyethyl cellulose (HEC), polyethylene oxide, polyvinyl pyrrolidine, hydroxypropyl cellulose, methyl cellulose, vinyl acetate copolymer, polysaccharide, polyethylene oxide, methacrylic acid copolymer, maleic anhydride / methyl 20. A coating core according to claim 19 selected from the group consisting of vinyl ether copolymers and derivatives thereof.   20. The coating core of claim 19, wherein the hydrophilic polymer is selected from the group consisting of hypromellose (hydroxypropylmethylcellulose, HPMC), hydroxyethylcellulose, polyethylene oxide, and Kollicoat 30SR.   The coating core of claim 19, wherein the hydrophilic polymer is selected from the group consisting of hypromellose K100 (Methocel K100), hypromellose E15 (Methocel E15), and hydroxyethylcellulose 250 (Natrosol® 250M).   20. The coating core of claim 19, wherein the surface coating of the surface coated matrix grain comprises a hydrophilic polymer.   24. The coating core of claim 23, wherein the hydrophilic polymer is selected from the group consisting of hypromellose (Pharmacacoat 606), hypromellose E15 (Methocel E15), and Kollicoat 30SR.   The coating core according to claim 21, wherein the hydrophilic polymer is hypromellose E15 (Methocel E15). The formulation is
a) about 47-50% by weight of a valproic acid compound;
b) about 13-16% by weight of hypromellose;
c) about 13-15% by weight of hydroxyethylcellulose;
d) about 8-9% by weight pregelatinized starch;
e) about 4-10% by weight of crystalline cellulose;
f) about 3-4% by weight of silicon dioxide; and g) about 1-2% by weight of stearic acid,
The sustained-release preparation according to claim 1, comprising:   27. The sustained-release preparation according to claim 26, wherein the valproic acid compound is divaproex sodium. In an aqueous buffer at 37 ° C. and pH 5.5,
a) about 30% or less of the total valproic acid compound is released in 3 hours or less;
b) About 40 to about 70% of the total valproic acid compound is released in 9 hours or less;
c) about 50 to about 95% of the total valproic acid compound is released within 12 hours or less; and d) at least about 75% of the total valproic acid compound is released within 18 hours or less.
The sustained-release preparation according to claim 1, which has a dissolution characteristic as described above. Compared to the pharmacokinetic properties of commercially available divalproex sodium ER 500 mg tablets (Depacoat ER) when administered to mammals a) Average AUC values in the range of about 90% to about 130%, where setting the observed mean AUC value for the Depakote ER 100%), and b) the mean C _max value in the range of from about 100% to about 160% (where the average C _max values observed for Depakote ER 100 %)
A sustained release formulation according to claim 1 having the following comparative pharmacokinetic properties, wherein the sustained release formulation is administered to a fasting mammal.   30. The sustained release formulation of claim 29, wherein the mammal is a human. Compared to the pharmacokinetic properties of commercially available divalproex sodium ER 500 mg tablets (Depacoat ER) in mammals a) Average AUC values in the range of about 85% to about 120% (where observed for Depacoat ER) setting the by mean AUC value of 100%), and b) the mean C _max value in the range of from about 90% to about 160% (where setting the average C _max values observed for Depakote ER to 100% )
A sustained release formulation according to claim 1 having the following comparative pharmacokinetic properties, wherein the sustained release formulation is administered to a non-fasting mammal.   32. The sustained release formulation according to claim 31, wherein the mammal is a human. A method for preparing a granular composition suitable for molding into sustained release tablets or filling into capsules, comprising:
a) dry mixing a mixture comprising a valproic acid compound, at least two hydrophilic polymers, and a binder;
b) wet granulation with an aqueous alcohol solution (mixture of alcohol and water) to form a homogeneous mixture;
c) drying and sizing the wet granules;
d) surface-coating the dried granules with a dispersant containing hydrophilic polymer with purified water and talc;
e) drying the coated granules;
And optionally,
f) adding a glidant and sieving the coated granules;
g) dry mixing the coated granules with filler and lubricant;
Wherein each hydrophilic polymer in steps a) and d) is in an amount up to about 20% of the composition.   34. The method of claim 33, wherein each hydrophilic polymer is no more than about 16% of the composition.   The valproic acid compound is divalproex sodium, at least two hydrophilic polymers are at least hypromellose and hydroxyethylcellulose, the binder is pregelatinized starch, and the hydrophilic polymer for surface coating is hypromellose Item 34. The method according to Item 33. further,
f) optionally adding a glidant and sieving the coated granules;
g) optionally, dry mixing the coated granules with filler and lubricant;
h) compressing the granules into tablets; and i) optionally coating the tablets with a cosmetic coat;
34. A granulate for molding into a sustained release tablet formulation according to claim 33, wherein each hydrophilic polymer in steps a) and d) is in an amount of about 20% or less of the composition. A method for preparing a composition.   The valproic acid compound is divalproex sodium, at least two hydrophilic polymers are at least hypromellose and hydroxyethylcellulose, the binder is pregelatinized starch, the hydrophilic polymer for surface coating is hypromellose, flowable 37. The method of claim 36, wherein the accelerator is silicon dioxide, the filler is crystalline cellulose, and the lubricant is stearic acid. A sustained release capsule formulation comprising a granular composition comprising:
a) a valproic acid compound in an amount of about 40% to about 80% by weight of the formulation, and b) at least two polymers, each in an amount of about 20% or less of the weight of the capsule,
A formulation comprising   39. The sustained release capsule formulation of claim 38, wherein at least one of the polymers is a hydrophilic polymer.   39. The sustained release capsule formulation according to claim 38, wherein the valproic acid compound is divalproex sodium.   40. The sustained release capsule formulation of claim 38, wherein the amount of each polymer is about 16% or less of the capsule weight.   40. The sustained release capsule formulation of claim 38, wherein the amount of each polymer is from about 10% to about 16% of the weight of the capsule.   40. The sustained release capsule formulation of claim 38, wherein the amount of each polymer is from about 12% to about 16% of the weight of the capsule.   The polymer is hypromellose (HPMC), hydroxyethyl cellulose (HEC), polyethylene oxide (polyox), polyvinyl pyrrolidine, hydroxypropyl cellulose, methyl cellulose, vinyl acetate copolymer, polysaccharide, methacrylic acid copolymer, maleic anhydride / methyl vinyl ether. The sustained release capsule formulation of claim 38, selected from the group consisting of copolymers and derivatives thereof.   39. The sustained release capsule formulation of claim 38, wherein the polymer is selected from the group consisting of hypromellose (hydroxypropylmethylcellulose, HPMC), hydroxyethylcellulose, polyethylene oxide, and Kollicoat 30SR.   40. The sustained release capsule formulation of claim 38, further comprising an additional hydrophobic polymer.   40. The sustained release capsule formulation of claim 38, wherein the formulation is in a form comprising capsules containing pharmaceutical surface coated matrix granules.   48. The sustained release capsule formulation of claim 47, wherein the pharmaceutical surface coated matrix granule comprises a valproic acid compound and at least two hydrophilic polymers.   A therapeutically effective amount of valproic acid in a sustained release formulation comprising about 40% to about 80% valproic acid compound, and at least two hydrophilic polymers, each in an amount up to about 20% of the weight of the formulation A method for treating a patient comprising administering the compound once a day.   50. The method of claim 49, wherein the sustained release formulation is a sustained release tablet formulation.   51. The method of treating a patient according to claim 50, wherein each hydrophilic polymer is about 16% or less of the weight of the tablet.   50. The method of claim 49, wherein the sustained release formulation is a sustained release capsule formulation.   53. The method of treating a patient according to claim 52, wherein each of the hydrophilic polymers is about 16% or less of the weight of the capsule contents.