MX2008004774A - Enteric soft capsule comprising valproic acid - Google Patents

Abstract

An enteric valproic acid soft gelatin capsule, in which the enteric polymer is a component of the capsule shell rather than a coating, has been developed. The fill material comprises valproic acid or divalproex sodium and, optionally, one or more pharmaceutically acceptable excipients such as corn oil. The capsule shell is prepared from a mass comprising a film-forming polymer, an acid insoluble polymer, an aqueous solvent, and optionally a plasticizer. Suitable film-forming polymers include gelatin. Suitable acid-insoluble polymers include acrylic-acid/methacrylic acid copolymers. The acid-insoluble polymer is present in an amount from about 8%to about 20%by weight of the wet gel mass. The weight ratio of acid-insoluble polymer to film-forming polymer is from about 25%to about 50%. The aqueous solvent is water or an aqueous solution of alkalis such as ammonia or diethylene amine or hydroalcoholic solutions of the same. Suitable plasticizers include glycerin and triethylcitrate. The enteric soft gelatin capsule does not require an enteric coating and thus is not susceptible to the processing problems associated with enteric coated dosage forms. Enteric valproic acid soft gelatin capsules may be smaller in size and thus easier to swallow than currently available enteric coated tablets due to the presence of fewer ingredients, as well as smaller amounts of ingredients, in the capsule shell.

Description

ENTÉRICA SOFT CAPSULE COMPRISING VALPROIC ACID FIELD OF THE INVENTION This invention is in the field of pharmaceutical compositions, specifically a gelatin capsule formulation of enteric valproic acid. BACKGROUND OF THE INVENTION Valproic acid, or 2-propylpentanoic acid, and its salts and derivatives are used to treat distraction attacks, complex partial seizures, mania, prophylaxis of migraine headache and behavioral dyscontrol. Once in the body, valproic acid and its salts and derivatives are converted to valproate ion, which is responsible for the therapeutic effect. Valproic acid and its salts and derivatives are also known to cause significant side effects including gastrointestinal discomfort (nausea, indigestion, vomiting, diarrhea, and abdominal pain) which may decrease patient compliance. Valproic acid and sodium valproate are difficult to formulate into solid oral dosage forms. Sodium valproate is extremely hygroscopic, frequently liquefies quickly under ambient conditions. Valproic acid is an oily liquid at room temperature and thus is not suitable for manufacturing solid dosage forms, for example tablets for oral administration. Efforts have been made to address the problems associated with the formulation of valproic acid and sodium valproate in solid oral dosage forms. U.S. Patent No. 5,017,613 to Aubert et al. Describes a process for preparing a composition containing valproic acid in combination with sodium valproate. A mixture of valproic acid and ethylcellulose is prepared and the sodium valproate is added to the mixture to form drug granules in the absence of any binder or granulation solvent. Precipitated silica is added to the granules before the granules are compressed into tablets. U.S. Patent Nos. 5,212,326 and 4,988,731 to Meade describe divalproex sodium and its preparation. Divalproex sodium is a stable 1: 1 ionic oligomer in which the valproic acid forms coordinate the sodium bonds with the sodium valproate salt. • Sustained-release forms of divalproex sodium, valproic acid and its salts and derivatives have been developed in an effort to minimize the gastrointestinal side effects associated with these compounds. For example, U.S. Patent No. 5,807,574 to Cheskin et al. Discloses a controlled release dosage form containing divalproex sodium and a process for its preparation. The process involves melting the divalproex sodium and mixing it with a molten wax to form a divalproex sodium-wax compound. The drug-wax mixture is formulated in a capsule. U.S. Patent No. 5,169,642 to Brinker et al. Discloses a sustained release dosage form containing divalproex sodium granules, valproic acid or amides or esters or salts thereof and a polymeric viscosity agent. The drug is coated with a sustained-release compound comprising specified portions of ethylcellulose or a methacrylic methylester, a plasticizer and a detackifying agent. The enteric coated dosage forms are typically produced by a film coating process, wherein a thin film layer of an acid-insoluble (enteric) polymer is applied to the surface of a pre-manufactured dosage form, such as a tablet, and some hard and soft capsules of lesser degree. The enteric coating is sprayed as an aqueous or organic solution or suspension of one or more enteric polymer on the tumbling or movement of the tablets or capsules, followed by drying at elevated temperatures. The enteric dosage forms made by this coating method can suffer from several process related problems that affect performance and / or appearance of the coating. For example, the formation of "orange peel" surface also known as roughness or surface marbling may result. More seriously, coating integrity failure can occur, such as cracking or detachment of the enteric polymer coating. US Pat. No. 5,068,110 to Fawzi et al. Discloses several currently sold delayed release tablets and capsules, including the divalproex sodium delayed-release tablets manufactured by Abbott Laboratories (Depakote® ER). Fa zu states that the stability of enteric coated capsules is increased by applying thicker layers of enteric coating, alone or in combination with hydroxypropyl cellulose or hydroxymethyl cellulose. All coating processes present inherent problems including possible uneven distribution of the coating ingredients, which can occur under multivariate coating processes. These problems are common to all the enteric dosage forms. However, the problems faced during the coating of gelatin or polysaccharide capsules are even more critical due to the delicate and heat-sensitive nature of the soft elastic capsule shell. Both hard and soft capsules can be thermally subjected to agglomeration and induced distortion of the capsule shell. On the other hand, the softness and elasticity of the surface of the capsule makes it difficult to form an enteric coating of intact adhesion, without a sub-coating step to improve the surface of the capsule for coating. On the other hand, enteric coatings cause the loss of the normally bright and clear appearance of gelatin capsules, which is a major reason for the popularity and acceptance of gelatin capsules. WO 2004/030658 of Banner Pharmacaps, Inc. describes a process and resulting enteric capsule where it avoids these problems with most drugs by incorporating the enteric polymer in gelatin, rather than in gelatin. It is therefore an object of the present invention to provide a dosage form of soft gelatin capsule of valproic acid that does not suffer from the processing limitations and efficient stability associated with the additional enteric coated dosage forms. It is another object of the present invention to provide a dosage form of soft gelatin capsule of enteric valproic acid that minimizes the gastrointestinal side effects associated with valproic acid.

It is still another object of the present invention to provide a dosage form of soft gelatin capsule of enteric valproic acid that is smaller, uses fewer ingredients, and is at least easier to ingest, than the dosage forms of valproic acid. conventional enteric It is still another object of the present invention to provide a method for making a dosage form of soft gelatin capsule of enteric valproic acid that is more economical than other methods. BRIEF DESCRIPTION OF THE INVENTION A soft gelatin capsule of enteric valproic acid has been developed, in which the enteric polymer is a component of the capsule shell rather than a coating. The filler material comprises valproic acid or divalproex sodium and, optionally, one or more pharmaceutically acceptable excipients such as corn oil. The capsule shell is prepared from a dough comprising a film-forming polymer, an acid-insoluble polymer, an aqueous solvent, and optionally a plasticizer. Suitable film-forming polymers include gelatin. Suitable acid-insoluble polymers. include copolymers of acrylic acid / methacrylic acid. The acid insoluble polymer is present in an amount of about 8% to about 20% in wet gel mass weight. The weight ratio of the acid insoluble polymer to the film-forming polymer is from about 25% to about 50%. The aqueous solvent is water or an aqueous solution of alkalis such as ammonia or diethyleneamine or hydroalcoholic solutions thereof.

Suitable plasticizers include glycerin and triethyl citrate. The enteric soft gelatin capsule does not require an enteric coating and thus is not susceptible to the processing problems associated with the enteric coated dosage forms. The soft gelatin capsules of enteric valproic acid may be smaller in size and thus easier to ingest than the enteric coated tablets currently available due to the presence of fewer ingredients, as well as smaller amounts of ingredients, in the capsule shell. In addition, the cost of manufacturing due to the fewer stages of processing and ingredients, is significantly less than with other methods. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph of the average serum concentration of valproic acid from 0 to 72 hours after the administration of Soft Gel capsules of 500 mg Enteric Valproic Acid under fasting conditions and not fasting and 500 mg Depakote® Delayed Release Tablets under fasting conditions.

Figure 2 is a graph of the average serum concentration of valproic acid from 0 to 72 hours after dose administration of Soft Gel capsules of 500 mg of Valproic Acid Enteric and 500 mg Depakote® Delayed Release Tablets under non-fasting conditions. Figure 3 is a graph of the estimated steady state time for soft gel capsules of 500 mg Enteric Valproic Acid and 500 mg Tablets Depakote® Delayed Release based on pharmacokinetic data. DETAILED DESCRIPTION OF THE INVENTION I. Composition A. Capsule Filler 1. Valproic acid Valproic acid, or 2-propylpentanoic acid, and its salts and derivatives are compounds that have been used to treat distraction attacks, complex partial seizures, mania, migraine headache prophylaxis and behavior decontrol. Valproic acid (available from Sifa Ltd., Shannon, Ireland, Interchem and Kat ijk Chemie, the Netherlands, and Generichem) is an oily liquid at room temperature. Valproic acid is colorless and has a characteristic odor. It is slightly soluble in water (1.3 mg / mL) and very soluble in organic solvents. Valproic acid can be used pure or as a solution. The The concentration of valproic acid in the filling material is from about 25% to about 100% by weight of the filling material. In the preferred embodiment, divalproex sodium is present in the filler at a concentration of about 40% by weight of the filler. The total dosage per capsule is typically 250 mg, although sizes of 125 mg and 500 mg are also useful. Divalproex sodium can also be used in the formulation of soft enteric gelatin capsules. Divalproex sodium is a 1: 1 molar ratio oligomer of valproic acid and free sodium valproate. Divalproex sodium (available from SST Corp., New Jersey) is a crystalline, white powder, which is soluble in water and alcoholic solvents such as methane and ethanol, as well as organic solvents such as cyclohexane. 2. Excipients Capsule filling can be prepared using a pharmaceutically acceptable carrier composed of materials that are considered safe and effective and can be administered to an individual without causing undesirable biological side effects or unwanted interactions. The carrier consists of all the components present in the pharmaceutical formulation other than the active ingredient or ingredients. As generally used in the present "carrier" includes, but is not limited to, plasticizers, crystallization inhibitors, wetting agents, bulking agents, solubilizers, bioavailability enhancers, solvents, pH adjusting agents and combinations thereof. Suitable excipients include one or more solubilizers such as soybean oil, rapeseed oil, safflower oil, corn oil, olive oil, castor oil, oleic oil, medium chain triglycerides, mono- and diglycerides (available from Abitec Corp. ., Columbus, Ohio, under the tradename Capmul®), medium chain triglyceride esters (available from Abitec Corp., Columbus, Ohio, under the trade name Captex®), medium chain partial triglycerides (available from Sasol under the trade name Imwitor®), maize oil complex-PEG 6 (available from Gattefosse SA, Saint Priest, France under the trade name Labrasol®), propylene glycol monolaurate (lauraglycol), long chain partial glycerides (available from Gattefosse SA, Saint Priest, France under the trade name Maisine®), sorbitan monooleate (available from ICI under the trade name of Span®), polysorbates (available from ICI under the trade name Tween®), ac ethoxylated castor eite (cremophors), beeswax, hydrogenated soybean oil, partially hydrogenated soybean oil, and acetylated triglycerides. In a preferred embodiment, the solubilizer is corn oil. B. Capsule cover The capsule shell is prepared from a mass of gelatin comprising a film-forming polymer, an acid-insoluble polymer that is present in an amount that makes the capsule acid resistant within the stomach, an aqueous solvent, and optionally, one or more plasticizers and / or colorants. Other suitable coating additives that include opacifiers, colorants, humectant, preservatives, flavorings, and regulatory salts and acids. Enteric capsules and a method for making the capsule shell are described in the document • WO 2004/030658 of Banner Pharmacaps, Inc. 1. Film Forming Polymers Exemplary film-forming polymers can be of natural or synthetic origin. Natural film-forming polymers include gelatin and gelatin-like polymers. Other suitable natural film-forming polymers include lacquer, alginates, pectin, and zeins. Synthetic film-forming polymers include hydroxypropylmethyl cellulose, methylcellulose, hydroxypropylmethyl cellulose acetate succinate, hydroxypropylcellulose phthalate, cellulose acetate phthalate, and acrylates such as poly (meth) acrylate. The weight ratio of acid-insoluble polymer to film-forming polymer is from about 15% to about 50%. In one embodiment, the film-forming polymer is gelatin. 2. Acid Insoluble Polymers Acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, alginic acid salts such as sodium or potassium alginate, shellac, pectin, acrylic acid-acid copolymers methacrylic acid (available under the tradename EUDRAGIT® from Rohm America Inc., Piscataway, NJ as a powder or a 30% aqueous dispersion, or under the trade name EASTACRYL®, from Eastman Chemical Co., Kingsport, TN, as a dispersion at 30%). In one embodiment, the acid-insoluble polymer is EUDRAGIT® L100, which is a copolymer of methacrylic acid / methacrylic acid methyl ester. The acid insoluble polymer is present in an amount of about 8% to about 20% by weight of the wet gelatin mass. The weight ratio of the acid-insoluble polymer to film-forming polymer is from about 15% to about 50%. 3. Aqueous Solvent exemplary aqueous solvents include water or aqueous alkali solutions such as ammonia, sodium hydroxide, potassium hydroxide, ethylenediamine, hydroxylamine, tri-ethanolamine, or hydroalcoholic solutions thereof. The alkali can be adjusted such that the final pH of the gelatin mass is less than or equal to 9.0, preferably lower that or equal to 8.5, more preferably less than or equal to 8.0. In one embodiment, the alkali is a volatile alkali such as ammonia or ethylenediamine. 4. Exemplary Plasticizers Plasticizers include glycerol, glycerin, sorbitol, polyethylene glycol, citric acid, citric acid esters such as triethyl citrate, polyalcohols with 3-6 carbons and combinations thereof. The ratio of plasticizer to polymer (film-forming polymer plus acid-insoluble polymer) is from about 10% to about 50% of the weight of the polymer. II. Manufacturing Method A. Capsule Filler Valproic acid or divalproex is dispensed in a suitable container and, optionally, mixed with a diluent carrier such as corn oil. The filling is deaerated prior to encapsulation in a soft gelatin capsule. B. Capsule Coating A method for making the capsule shell is described in WO 2004/030658 of Banner Pharmacaps, Inc. The enteric gelatin mass can be manufactured by preparing an aqueous solution comprising a water soluble polymer, film former. and an acid insoluble polymer and mix the solution with one or more plasticizers appropriate to form a jelly dough. Alternatively, the enteric gelatin mass can be prepared by using an aqueous dispersion already made of the acid-insoluble polymer by adding alkaline materials such as ammonium, sodium, or potassium hydroxides or other alkalis that will cause the acid-insoluble polymer to dissolve. The film-forming polymer, moistened with plasticizer can then be mixed with the acid insoluble polymer solution. The gelatin mass can also be prepared by dissolving the acid-insoluble polymer or polymers in the form of salts of the bases mentioned above or alkalies directly in water and mixing the solution with the film-forming polymer, moistened with plasticizer. The gelatin mass is emptied into films or strips using drums or heat-controlled surfaces. The filling material is encapsulated in a soft gelatin capsule using a rotating mold. The capsules are dried under controlled conditions of temperature and humidity. The final moisture content of the coating composition is from about 2% to about 10% by weight of the capsule shell, preferably from about 4% to about 8% by weight of the capsule shell. III. Method of Use The soft gelatin capsules of valproic acid Enteric agents can be used to administer valproic acid or divalproex sodium to a patient in need thereof. In the preferred embodiment, the capsule contains dose equivalents of 125 mg, 250 mg, or 500 mg. The data in the following examples demonstrate that it is impossible to make soft gelatin capsules or capsules that release valproic acid to produce the following pharmacokinetic profiles: wherein the valproic acid is released after oral administration to an individual on an empty stomach to produce a Cmax between about 37.6 and 72.5 mg of valproic acid / ml of blood with a Tmax between 1 and 4 hours, more preferably wherein the Cmax is between 42.3 and 67.5 mg of valproic acid / ml of blood with a Tmax of between 1.35 and 3 hours; and wherein the valproic acid is released after oral administration to an individual not fasting to produce a Cmax between 27.2 and 58.64 mg valproic acid / ml of blood with a Tmax of between 3 and 9 hours, more preferably where the Cmax it is between 31 and 53.8 mg of valproic acid / ml of blood with a Tmax of between 3 and 9 hours. Although described in the examples with reference to soft gelatin capsules containing specific enteric polymer, those skilled in the art will recognize that other soft gelatin capsules or capsules they can be similarly prepared to achieve equivalent pharmacokinetic drug profiles. Examples Example 1. Enteric Gelatin Mass A gelatin mass was made according to the formula below. Gelatin 28.00% Eudragit® L100 9.00% Glycerin 15.4% Triethylcitrate 0.90% Ammonium hydroxide 0.05% Water 46.65% The acid-insoluble polymer (Eudragit® L 100) was dissolved in an aqueous alkali solution (water and ammonium hydroxide). The film-forming polymer (gelatin), and any of the plasticizers (glycerin), colorants, or other coating additives were added to the acid insoluble polymer solution and the mixture was fired by a heat fusion process. The water content of the gelatin mass was adjusted to the indicated level. The gelatin mass was deaerated and reduced in a receiver. The reduced gelatin mass was maintained in the receivers at a temperature between 43 and 60 ° C (110 and 140 ° F) until encapsulation. Example 2. Enteric Soft Fillers with Acid Filler Valproic Soft enteric capsules were prepared using a conventional rotary mold process. The enteric gelatin mass of Example 1 was emptied as a thin strip. The appropriate filling mass is pumped into each cavity of the mold in order to provide the appropriate filling weight. After the mold cavities were filled, the strip was sealed to form capsules of the desired shape and size. The capsules were initially dried in a tumbling dryer and then dried on trays in a drying tunnel until the desired hardness was achieved. The dried capsules were then inspected, sized, printed, polished and packed. Example 3. Relative Bioavailability Study of Soft Gel Capsules of 500 mg Enteric Valproic Acid Under Fasting Conditions The pharmacokinetic parameters of 500 mg Enteric Valproic Acid Soft Gel capsules were compared to those of a reference compound, Tablets of Depakote® Delayed Release (500 mg). The objective of this three-way, single-dose, randomized crossover study was to compare, under fasting conditions, the relative bioavailability (ratio and degree of absorption) of soft gel 500 mg Enteric Acid Valproic Acid to that of a dose equivalent of Depakote® Delayed Release Tablets when administered to healthy subjects. Materials and Methods Thirty-six healthy adults participated in the comparison between the 500 mg Enteric Valproic Acid Soft Gel and Depakote® Delayed Release Tablets. All 36 subjects completed the study. On the day, after an overnight fast of at least 10 hours, the subjects received an oral, individual dose (1 x 500 mg) of either the 500 mg Enteral Valproic Acid Soft Gel or the Release Tablets. Delay of reference Depakote® with water at room temperature of 240 mL, according to the randomization scheme. During each study period, 21 blood samples (each of 7 mL) of each subject were collected by direct vein puncture using pre-marked vacutainers without anticoagulant. Blood samples were collected within 1 hour prior to the administration of the dose (0 hours) and to 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12 , 16, 24, 36, 48, and 72 hours after the administration of the dose. Approximately 441 mL of blood was collected from each subject for pharmacokinetic samples during the course of the study. At the completion of the clinical study, the serum samples were transferred to the PRACS Institute, Ltd.

Bioanalytical Laboratory for sample analysis. The serum concentration data of all 36 subjects were used in the pharmacokinetic and statistical analysis. The lower limit of the quantification for valproic acid was 2.00 μg / mL. For the statistical analysis, the values of samples subject below the lower limit of quantification (BLQ) were reported as zero. The following pharmacokinetic parameters were calculated for each subject and period: peak plasma concentration (Cmax), time to peak concentration (Tmax), elimination proportion constant (ke), terminal half-life (ty2), area under the concentration-time calculated according to the linear trapezoidal rule (AUCo-t), and area under the zero-time plasma concentration time curve extrapolated to infinity (AUCo-8). A variation analysis (ANOVA) was performed on each of the pharmacokinetic parameters using SAS® software. The factors that contain the ANOVA model for the sequence of products, subjects within the sequence, periods and products were used when comparing the effects between the test and the reference products. The differences were declared statistically significant at the 5% level. A confidence interval of 90% 'about the reaction of the average test value to the reference value average was calculated for all pharmacokinetic parameters for each test product. The calculations for the confidence intervals used the least squares mean (LSMEANS) and the standard error of the estimate, both generated by SAS® software. The geometric mean ratio for the transformed data within and the corresponding 90% confidence intervals were calculated for 'AUC0-t, AUCo-8, and Cmax, as well. The statistical analysis was done using SAS®, Version 8.2 for Windows, using the code based on Chow and Liu pp. 559-562. Results Table 1 shows both untransformed and ln-transformed data for the pharmacokinetic parameters calculated for Depakote® Delayed Release Tablets (Treatment A) and Valproic Acid Enteric Soft Gel capsule (Treatment C). Table 1 also shows the statistical analysis of the untransformed and the ln-transformed data. Confidence intervals of approximately 90% of the ratio of geometric treatment medium A (Fasting of the Test Product) to the geometric medium of Treatment C (Fasting of Reference Product) are within the limits of 80% and 125% for Cmax pharmacokinetic parameters; AUC0-t, and AUCo ^ 8 of the ln-transformed data. Figure 1 shows the average serum concentration of valproic acid from 0 to 72 hours after the administration of the dose for Treatment A (Fasting Test Product) and Treatment C (Fasting Reference Product). The results of this study indicate bioequivalences between the soft gel of 500 mg enteric Valproic Acid Test and Depakote® Delayed Release Tablets 500 mg when administered under fasting conditions.

J o Table 1 . Parameters Ln- and Non-Transformed Pharmacokinetics of Valproic Acid After Oral Administration and Statistical Analysis J Example 4. Study of Relative Bioavailability of Soft Gel Capsules of 500 mg Enteric Valproic Acid Under Feeding Conditions The objective of this three-way crossover study of a randomized dose was to compare the relative bioavailability (proportion and degree of absorption) of Soft Gel of 500 mg Enteric acid of valproic acid under conditions of fasting and not fasting, when administered to healthy subjects. To determine the dietary effects for the Enteric Soft Gel of Valproic Acid, the pharmacokinetic data under fasting conditions was used as a reference. The same 36 subjects of Example 3 were enrolled in the food effect study. Materials and Methods All thirty-six subjects enrolled completed the study. For those subjects who were dosed under non-fasting conditions, a standardized high-fat breakfast was served 30 minutes prior to dose administration, consistent with randomization. Thirty minutes after starting the standardized high-fat breakfast, the subjects received an oral, individual dose (1 x 500 mg) of 500 mg Enteric Valproic Acid Soft Gel with 240 mL of water at room temperature. All subjects fasted at least 4.25 hours after the dosage. There was at least one failure on day seven between the study periods. The blood samples were taken and analyzed as described in Example 3. Table 2 shows both untransformed and ln-transformed data for the pharmacokinetic parameters calculated for the soft-gel capsules of Valproic acid enteric under fasting conditions. (Treatment A) and Soft Enteric Gel capsules of Valproic acid under feeding conditions (not fasting) (Treatment B). Table 2 also shows the statistical analysis of the untransformed and ln-transformed data. Confidence intervals of approximately 90% of the ratio of geometric treatment medium A (Fasting of Test Product) to geometric processing medium C (not Fasting Test Product) are within the limits of 80% and 125% for the pharmacokinetic parameters AUCo-t, and AUCo-8 but not for Cmax, of the ln-transformed data. or Table 2. Ln- and Non-Transformed Pharmacokinetic Parameters of Valproic Acid After Oral Administration and Statistical Analysis Figure 1 shows the average serum concentration of valproic acid from 0 to 72 hours after the administration of the dose for Treatment A (Fasting Test Product) and Treatment B (no Fasting Test Product). The administration of soft gel capsules of 500 mg enteric Valproic acid with food significantly decreased the ln-transformed Cmax (23.44%). However, the food did not decrease significantly in AUCn-t ln-transformed (4.18%) and AUC0-8 (4.12%). Thus, the administration of Soft Gel of 500 mg Enteric Acid Valproic acid under non-fasting conditions did not affect the degree of absorption. Example 5. Relative Bioavailability Study of Soft Gel Capsules of 500 mg Enteric Valproic Acid Under Non-Fasting Conditions An interview by Banner Pharmcaps, Inc. of physicians (N = 24) indicated that a majority of their patients take Depakote © with food. Therefore, a two-way, randomized crossover design was used to compare the relative bioavailability (ratio and degree of absorption) of capsules 500 mg of Valproic acid 500 mg with the reference compound, Depakote 500 mg delayed release tablets ®, under non-fasting conditions. Materials and methods Six healthy subjects were used in this study. An individual oral dose was administered to subjects on two separate occasions under non-fasting conditions with a 7-day failure between doses. The uptake of food and fluids was controlled during each confinement period. The serum concentrations of valproic acid were determined by the bioanalytical laboratory of PRACS Institute, Ltd. Data from all six subjects were used for pharmacokinetic and statistical analysis. The pharmacokinetic parameters that were calculated were the same as for Examples 3 and 4. Current times were used in the calculation of the pharmacokinetic parameters. Results Table 3 shows the ln-transformed data for the calculated pharmacokinetic parameters, Cmax, AUCo-t? and AUCo-8, for the Valproic acid enteric soft gel capsules (test product) and Depakote® delayed release tablets (reference product). Table 3 also shows the statistical analysis of the ln-transformed data. Table 3. For ln-transformed pharmacokinetic methods of valproic acid After Table 4 shows the untransformed data for the calculated pharmacokinetic parameters, Cma ?, AUC0-t, and AUCo-8, for the Valproic Acid Soft Gel Product Capsules (Test Product) and Depakote® Delayed Release Tablets (Reference Product). Table 4 also shows the statistical analysis of the untransformed data. Table 4. Unprocessed Pharmacokinetic Parameters of Valproic Acid After Oral Administration and Acid Statistical Analysis Cmax Ln-AUCo-t Ln-AUC0- «, Transformed Transformed Ln-Valproic Transformed Table 5 shows the untransformed data for the calculated pharmacokinetic parameters, Tma ?, ke, and t? / 2, for the Valproic acid enteric soft gel capsules (Test product) and delayed release tablets of Depakote® (Product of. Reference). Table 5 also shows the statistical analysis of the non-transformed data. Table 5. Pharmacokinetic Parameters Not Transformed Valproic Acid After Oral Administration and Statistical Analysis Figure 2 shows average serum concentrations of valproic acid between subjects at each time point tested from 0 to 72 hours after dose administration of the Valproic Acid Soft Gel Capsules (Enteric Valproic Acid 500 mg) and Depakote® Delayed Release Tablets (Depakote 500 mg). The results of this study indicate almost the equivalence of Valproic acid Enteric Soft Gel Capsules and Depakote® Delayed Release Tablets under non-fasting conditions with respect to Cmax pharmacokinetic parameters, AUC0-tí and AUC0-8- However, the Valproic Acid Soft Gel Capsules induced a negligibly lower Tmax relative to Depakote® Delayed Release Tablets, which indicates a principle faster action under non-fasting conditions. Example 6. Estimated Time Related to the Permanent State of 500 mg capsules of Valproic Acid The time to steady state for the 500 mg Capsules of Valproic Acid and Depakote® Delayed Release Tablets was estimated based on the pharmacokinetic data of Example 5, as shown in Figure 3. This estimate predicts Capsules of 500 mg of Valproic Acid can achieve permanent status in 52 hours, while Depakote® Delayed Release Tablets can achieve permanent status in 72 hours. Thus, the 500 mg Valproic Acid Capsules are predicted to reach permanent status 25% faster than Depakote® Delayed Release Tablets. It is understood that the disclosed invention is not limited to the particular methodology, protocols, and reagents described since these may vary. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the disclosed invention pertains.

Claims (24)

1. CLAIMS 1. A soft enteric valproate gelatin capsule, characterized in that it comprises: (a) a filler material comprising valproic acid or divalproex sodium present in an amount from about 25% to about 100% by weight of the filler; and (b) an enteric capsule shell comprising a film-forming polymer and an acid insoluble polymer, wherein the capsule releases the filling material after passage through the stomach.
2. 2. The capsule according to claim 1, characterized in that the capsule contains a dosage of valproic acid, divalproex sodium or mixtures thereof selected from the group consisting of 125 mg, 250 mg and 500 mg. The capsule according to claim 1, characterized in that the cover comprises additional components selected from the group consisting of plasticizers, coloring agents, opacifiers, humectants, preservatives, flavorings and regulatory salts and acids. . The capsule according to claim 1, characterized in that the filling material further comprises one or more excipients pharmaceutically acceptable The capsule according to claim 4, characterized in that the one or more excipients are selected from the group consisting of crystallization inhibitors, wetting agents, bulking agents, solubilizers, bioavailability enhancers, solvents, pH adjusting agents , dyes, preservatives, solvents, surfactants and combinations thereof. The capsule according to claim 5, characterized in that the excipient is a solubilizer selected from the group consisting of soybean oil, rapeseed oil, safflower oil, corn oil, olive oil, castor oil, oleic acid , medium chain triglycerides, mono- and diglycerides, medium chain triglyceride esters, medium chain partial triglycerides, corn oil complex-PEG 6, propylene glycol monolaurate, long chain partial glycerides, sorbitan monooleate, polysorbates, ethoxylated castor oil, beeswax, hydrogenated soybean oil, partially hydrogenated soybean oil and acetylated triglycerides. 7. The capsule according to claim 6, characterized in that the solubilizer is corn oil. 8. The capsule in accordance with claim 1, characterized in that the film-forming polymer is of natural origin. The capsule according to claim 8, characterized in that the film-forming polymer is a natural film-forming material selected from the group consisting of gelatin, shellac, alginates, pectin and zeins. The capsule according to claim 9, characterized in that the natural film-forming polymer is gelatin. The capsule according to claim 1, characterized in that the film-forming polymer is of synthetic origin. The capsule according to claim 11, characterized in that the film-forming polymer is selected from the group consisting of hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate and acetate acetate phthalate. cellulose. The capsule according to claim 1, characterized in that the acid-insoluble polymer is selected from the group consisting of cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, salts of alginic acid such as sodium or potassium alginate, shellac, copolymers of acrylic acid-methylacrylic acid. The capsule according to claim 13, characterized in that the acid insoluble polymer is a copolymer of acrylic acid-methacrylic acid. The capsule according to claim 1, characterized in that the acid-insoluble polymer is present in an amount of about 8 to about 20% by weight of the wet gelatin mass. 16. The capsule according to claim 15, characterized in that the acid-insoluble polymer is present in an amount of about 12% by weight of the wet gelatin mass. 17. The capsule according to claim 1, characterized in that the weight ratio of the acid-insoluble polymer to the film-forming polymer is from about 15% to about 50%. The capsule according to claim 1, characterized in that the capsule shell contains a plasticizer and the ratio of plasticizer to polymer is from about 10% to about 50% of the weight of the polymer. 19. The capsule according to claim 1, characterized in that the content of final moisture of the capsule is from about 2% to about 10% by weight of the capsule. 20. The capsule according to claim 19, characterized in that the final moisture content of the capsule is from about 4% to about 8% by weight of the capsule. 21. The capsule according to claim 1, characterized in that the valproic acid is released after oral administration to a fasted individual to produce a Cmax between about 37.6 and 72.5 mg of valproic acid / ml of blood with a Tmax between 1 and 4 hours. 22. The capsule according to claim 1, characterized in that valproic acid is released after oral administration to an individual not fasting to produce a Cmax between 27.2 and 58.64 mg valproic acid / ml of blood with a Tmax of between 3 and 9 hours. 23. The capsule according to claim 21, characterized in that the Cmax is between 42.3 and 67.5 mg of valproic acid / ml of blood with a Tmax of between 1.35 and 3 hours in a fasted individual. 24. The capsule according to claim 22, characterized in that the Cmax is between 31 and 53.8 mg of valproic acid / ml of blood with a Tmax of between 3 and 9 hours. SUMMARY OF THE INVENTION A soft enteric valproic acid gelatin capsule has been developed in which the enteric polymer is a component of the capsule shell before a coating.The filler material comprises valproic acid or divalproex sodium and optionally , one or more pharmaceutically acceptable excipients such as corn oil The capsule shell is prepared from a dough comprising a film-forming polymer, an acid-insoluble polymer, an aqueous solvent and optionally a plasticizer. include gelatin Suitable acid-insoluble polymers include copolymers of acrylic acid / methacrylic acid The acid insoluble polymer is present in an amount of about 8% to about 20% by weight of the wet gel mass. by weight of the acid-insoluble polymer to the film-forming polymer is about 25 % to about 50% The aqueous solvent is water or an aqueous solution of alkalis such as ammonia or diethylene amine or hydroalcoholic solutions thereof. Suitable plasticizers include glycerin and triethyl citrate. The enteric soft gelatin capsule does not require an enteric coating and thus is not susceptible to the processing problems associated with the enteric coated dosage forms. The gelatin capsules Soft of enteric valproic acid may be smaller in size and thus easier to ingest than the enteric coated tablets currently available due to the presence of fewer ingredients, as well as smaller amounts of ingredients, in the capsule shell.