MXPA01007814A - Ph independent extended release pharmaceutical formulation - Google Patents

Abstract

Pharmaceutical formulations of acidic pharmacologic agents which demonstrate improved uniformity of release over the wide range of pH values encountered between the stomach and intestinal tract comprise an acidic pharmacologic agent dissolved or dispersed in a matrix comprising about 10 weight percent to about 40 weight percent of a neutral water-swellable hydrophilic polymer and 20 weight percent to about 50 weight percent of an acid-soluble polymer which swells in water at pH values above about 5. A particularly preferred formulation comprises divalproex sodium. Also disclosed are pre-tablet granulations and process for preparing both the pre-tablet granulation and the tablet unit dosage form.

Description

PHARMACEUTICAL FORMULATION OF PROLONGED RELEASE INDEPENDENT TO THE PH Technical Field This invention relates to pharmaceutical formulations. More particularly, the present invention relates to prolonged release pharmaceutical formulations containing an acidic pharmacological agent, which formulations have reduced dependence on the rate of release of the pH.

BACKGROUND OF THE INVENTION The normal pH of gastric juices is about pH 1, while the pH in the intestinal tract averages about pH 7. This fact has been used to take advantage for years in the pharmaceutical formulations so-called "enteric coatings" . These formulations are generally in the form of tablets coated with a substance that is insoluble or partially soluble in acidic solutions, but which dissolve rapidly at a higher pH. Such enteric coating formulations allow oral administration of drugs that would present problems if released into the stomach, such as irritation of the stomach lining. In addition, enteric layer tablets also allow the extension of a drug release over time. For example, a tablet can be formulated by compressing granules containing the drug, some of those granules are enterically coated and some of those are not covered. As the tablet disintegrates, the granules without enteric coating dissolve in the stomach, immediately releasing the drug, while the enteric coated granules pass into the intestine before the solution releases the drug. In this way the release of the drug can be prolonged for as long as the drug resides both in the stomach and in the intestine. Such a sustained release system is crude, essentially releasing the drug in a bi-modal manner. It is generally desirable to release a drug more evenly for as long as it can be performed by a partially enteric coating formulation of the type described above. In the effort to achieve a controllable, uniform release of the acidic pharmacological agents, several systems have been envisaged. These fall into one of three general classes: osmotic systems, dissolution systems and diffusion systems. An example of an osmotic system is a tablet consisting of a drug core surrounded by a semipermeable membrane containing a small hole. When the tablet is exposed to an aqueous body fluid, the water flows into the tablet through the semipermeable membrane due to the difference in osmotic pressure. The drug is then pumped out of the tablet through the orifice at a constant rate controlled by the parameters of the drug concentration, the diameter of the orifice, the osmotic pressure difference, etc. , until the concentration of the drug inside the tablet falls below saturation. The dissolution systems take advantage of the inherent dissolution rate of the drug itself or of a particular derivative or salt. Alternatively, the drug can be covered with a slow dissolution coating or by incorporation of the drug in a slow dissolving vehicle. Diffusion systems include both container devices, in which a drug core is surrounded by a polymer membrane and matrix devices in which the dissolved or dispersed drug is evenly distributed through an inert polymer matrix. The release of the drug from a container system involves the flow of the drug through the membrane and is controlled by Fick's first law of diffusion. Depending on the shape of the tablet the equation describing the release will vary. In matrix systems, the mechanism of drug release is assumed to involve the dissolution of the drug from the surface layer of the first device, followed by dissolution of the underlying layer and diffusion through the drug-poor cover layer, etc. The design of a prolonged or sustained release formulation of drugs that are acidic presents particular problems for the pharmaceutical formulator. The solubility of such drugs in gastric juices is typically low as a result of the repression of acid ionization by low pH in the stomach. On the other hand, such acidic drugs dissolve rapidly in the intestine, sometimes more quickly than desired. The various systems described above easily lead to the formulation of prolonged-release formulations of drugs that are not affected by pH, as they pass through the alimentary canal, but do not provide adequate formulations where the drug has release rates dependent on a pH widely variant between the stomach and intestinal tract. One such acidic pharmacological agent is 2-propylpentanoic acid, more commonly known as valproic acid (VPA), which is effective in the treatment of epileptic access or as an antipsychotic agent. The U.S. Patent No. 4,988,731 discloses an oligomer having a 1: 1 molar ratio of sodium valproate and valproic acid containing four units and US Pat. No. 5,212,326 to Meade discloses a solid, non-hygroscopic, stable form of valproic acid, comprising an oligomer having a molar ratio of 1: 1 of sodium valproate and valproic acid and containing from four to six units. The sodium of divalproex (sodium hydrogen divaproate), a complex formed between one mole of 2-propylpentanoic acid and its sodium salt, is one of the most widely accepted antiepileptic agents currently available. However, despite its efficacy in the treatment of epilepsy, valproic acid is sparingly soluble in the stomach and has been shown to exhibit a half-life elimination that is shorter than commonly used antiepileptic agents. Half-lives of the drug have been reported in six and seventeen hours in adults and between four and fourteen hours in children. This leads to substantial fluctuations in the plasma concentration of the drug, especially in chronic administration. To maintain stable, reasonable plasma concentrations, it is necessary to resort to frequent dosing and the resulting inconvenience to the patient often results in decreased compliance of the prescribed dosage regimen. In addition, widely fluctuating plasma concentrations of the drug can result in the administration of lower therapeutic amounts of the drug in a conservative dosing regimen or in amounts too large for the particular patient in an aggressive dosing regimen. To overcome these disadvantages, a concerted effort has been devoted to the discovery of formulations that will maintain more constant plasma levels of acidic drugs in general and valproic acid in particular, after administration. The ultimate purpose of these studies has been the discovery of a formulation that produces stable plasma levels in a once-a-day dosing regimen for such drugs. These efforts fall generally into one of two categories: (a) finding a form of the active ingredient that is metabolically more uniformly released in the body, and (b) finding a formulation that delivers the drug either through a controlled release mechanism or synchronized release. With respect to valproic acid, the U.S. Patent. 4,369, 172 by Schor, et al., Describes, for example, a sustained release therapeutic composition based on mixtures of hydroxypropyl methyl cellulose, ethyl cellulose and / or sodium carboxylmethyl cellulose. The patents provide a long list of therapeutic agents that suggest they can be incorporated into the formulation including sodium valproate.

The U.S. Patent 4,913,906 to Friedman, et al. , discloses a controlled release dosage form of valproic acid, its amide, or one of its salts or esters in combination with a synthetic or natural polymer, compounded in a tablet under elevated pressure. The U.S. Patent 5,009,897 from Brinker, e al. , exposes suitable granules to be compressed into tablets, the granules comprising a sodium core of divalproex and a coating of a mixture of a polymer and microcrystalline cellulose. The U.S. Patent 5, 019,398 of Daste, exposes a prolonged release sodium tablet of divalproex in a cellulose matrix of hydroxypropylmethyl and hydrated silica. The U.S. Patent 5,055,306 from Barry,? T al. , exposes a formula of prolonged release, granular, dispersible in water, suitable for use with a vapedad of therapeutic agents. The granules comprise a core comprising the active ingredient and at least one excipient and a water-swellable, water-insoluble shell comprising a copolymer of ethyl acrylate and methyl methacrylate and a hydroxylated cellulose derivative, soluble in water. The patentans suggest a list of therapeutic agents that can be used in the formulation of the invention, including sodium valproate. U.S. Patent 5,169,642 to Brinker, et al. , discloses a sustained release dosage form comprising divalproex sodium granules or valproic acid amides or esters coated with a sustained release composition comprising ethyl cellulose or a methacrylic methyl ester, a plasticizer, a separating agent and an agent of slow-release polymeric viscosity. The U.S. Patent 5, 185, 159 of Aubert,? T al., Discloses a formulation of valproic acid and sodium valproate, which is prepared without the use of a binder or a granulation solvent. The formulation optionally contains precipitated silica as an anti-adhesion or separation agent. The U.S. Patent 5,589, 191 from Exigua, et al., Discloses a slow-release sodium valproate tablet formulation, in which the tablets are covered with ethyl cellulose containing silicic acid anhydride. The published PCT Application WO 94/27587 of Yesterday, et al. , discloses a method for controlling epilepsy by providing a therapeutic composition of valproic acid or a derivative in combination with a polyalkylene oxide. Bailer, et al., "Metabolism of Antiepileptic Drugs", pp. 143-151, R.H. Levy, Ed. Raven Press, New York 1984; Int.J. Pharmaceutics. 20: 53-63 (1984); and Biopharmaceutics and Drug Disposition, 6: 401-41 1 (1985); and Israel J. Med. Sci. 20: 46-49 (1995), report the pharmacokinetic evaluation of several prolonged-release formulations of valproic acid. However, despite these efforts, the need remains for formulations of acidic pharmacological agents (in general) and valproic acid (in particular), which demonstrate less dependence on the rate of release and dissolution after variation in pH in the alimentary canal.

BRIEF DESCRIPTION OF THE INVENTION In accordance with the present invention, prolonged-release pharmaceutical formulations of acidic pharmacological agents that have decreased dependence on the rate of release to pH and gastric residence time (GRT), comprise a therapeutically effective amount of the agent pharmacological acid dissolved or dispersed in a polymer matrix comprising (a) from about 10 weight percent to about 40 weight percent of a hydrophilic polymer, water expandable, neutral, pharmaceutically acceptable, and (b) from about 20 percent by weight up to about 50 weight percent of a pharmaceutically acceptable acid-soluble polymer, which is extensible in water above about pH 5, all percentages by weight based on the total weight of the formulation. The formulations provide an improved release rate of the acidic pharmacological agent in the stomach, where the pH of the gastric juices is low, and the rate of release of the acidic pharmacological agent decreases to a slightly alkaline or neutral pH in the intestinal tract. The result is a more uniform release of the pharmacological agent as the agent moves from the acidic environment of the stomach into the slightly alkaline or neutral environment of the upper and lower intestinal tracts. In addition, the release of the agent is less dependent on the time in which the agent resides in the acidic environment of the stomach.

In an alternative embodiment, the present invention comprises a pharmaceutical formulation comprising a therapeutically effective amount of divalproex sodium dissolved or dispersed in a matrix comprising from about 10 weight percent to about 40 weight percent of a hydrophilic, expandable polymer. in water, neutral and from about 20 weight percent to about 50 weight percent of an acid soluble polymer, which is extensible in water at pH values above about 5, all percentages by weight based on total weight of the granular composition. In another embodiment, the present invention provides a dry granular composition suitable for being compressed into a tablet dosage form, the granular composition comprising particles containing an acidic pharmacological agent dissolved or dispersed in a matrix comprising from about 10 weight percent to about 40 weight percent of a hydrophilic, water-expandable, neutral polymer and from about 20 weight percent to about 50 weight percent of an acid-soluble polymer that is extensible in water at pH values above about 5, all percentages by weight based on the total weight of the granular composition. In a further embodiment, the present invention provides a process for preparing a granular pharmaceutical composition suitable for tabletting, comprising the steps of (a) dry blending a mixture of from about 5 weight percent to about 50 weight percent. weight of an acidic pharmacological agent, from about 20 weight percent to about 40 weight percent of a hydrophilic polymer, water swellable, neutral, from about 20 weight percent to about 50 weight percent of a soluble polymer in acid, which is extensible in water at pH values above about 5 to form a uniform mixture; (b) wet granulating the dry uniform mixture of step (a); and (c) drying and sizing the wet granules of step (b), wherein all percentages are based on the total weight of the granulation. In yet another embodiment, the present invention provides a method for preparing a controlled release tablet dosage form of an acidic pharmacological agent comprising the steps of (a) dry blending a mixture of from about 5 weight percent to about 50 weight percent of an acidic pharmacological agent, from about 20 weight percent to about 40 weight percent of a hydrophilic polymer, water expandable, neutral, from about 20 weight percent to about 50 weight percent of an acid-soluble polymer, which is extensible in water at pH values above about 5 to form a uniform mixture; (b) wet granulating the dry uniform mixture of step (a); (c) drying and sizing the wet granules of step (b); and (d) compressing the mixed granules of step (c) under a force ranging from about 2000 Ibf (about 8.9 x 103 Nes) to about 10,000 Ibf (about 4.45 x 10 Nes).

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graphical representation of data showing the percentage release of drugs over time at various pH values, from a pharmaceutical control formulation comprising a prolonged release formulation of polymer matrix, but which It lacks any ingredient proposed to moderate the effect of pH. Figure 2 is a graphical representation of data showing the percentage release of drugs over time at various pH values, of a formulation comprising a prolonged release formulation of polymer matrix and also containing anhydrous dibasic calcium phosphate. Figure 3 is a graphical representation of data showing the percentage release of drugs over time at various pH values, of a formulation comprising a prolonged release formulation of polymer matrix and also containing amorphous magnesium aluminometasilicate. Figure 4 is a graphical representation of data showing the rate of drug release over time at various pH values, for the preferred formulation of the present invention. Figure 5 is a graphical representation of data showing the effect of gastric residence time in vitro on the release of valproic acid from a hydroxypropyl methylcellulose matrix formulation of the prior art.

Figure 6 is a graphical representation of data showing the effect of gastric residence time in vitro on the release of valproic acid from a formulation according to the present invention.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES As used throughout this specification and the appended claims, the terms "sustained or extended release", "prolonged release" and "controlled release", as applied to drug formulations, have the meaning assigned to them in "Remington's Pharmaceutical Sciences", 18th Ed., p. 1677, Mack Pub. Co., Easton, PA (1990). Sustained or extended release drug systems include any drug delivery system that achieves slow release of the drug over a prolonged period of time and includes both prolonged and controlled release systems. If such a sustained release system is effective in maintaining substantially constant levels of drugs in the target blood or tissue, it is considered a controlled release drug delivery system. However, if a drug delivery system is not successful in achieving substantially constant drug levels in the blood or tissue, but nonetheless prolongs the duration of action of a drug over that achieved by conventional delivery, Consider a prolonged release system. The formulations of the present invention provide an extended or prolonged release formulation for acidic pharmacological agents. By the term "acidic pharmacological agent" is meant any compound having therapeutic activity and exhibiting a kPa value of less than about 6.0. Although not supported by any theory to the exclusion of others, it is believed that the formulations of the present invention normalize or regulate the rate of release of the acidic pharmacological agents over a wide range of pH values by the interaction of the effects on the release of the two polymer components of the matrix in which the pharmacological agent is dissolved or dispersed. At low pH values in the stomach, it is believed that the acid-soluble polymer has the greatest effect on the release of the pharmacological agent. In this environment, where the pharmacological agent is typically of low solubility, the acid-soluble or ionisable polymer is protonated and begins to dissolve from the formulation matrix. This aids in the release of the pharmacological agent in the regions of the matrix where the agent dissolves or disperses in this component of the polymer matrix in either or both of two ways. First, the dissolution of the acid-soluble polymer component of the matrix physically aids in the release of the pharmacological agent and second, the protonation of the acid-soluble polymer by the acidic gastric juices raises the pH in the local environment of the formulation matrix to levels where the acidic pharmacological agent is more soluble. At neutral or alkaline pH values found in the intestine, the acid soluble polymer is dilated, together with the second water-expanding component, neutral, from the formulation polymer matrix, thus presenting a more tortuous route the acidic pharmacological agent should migrate to get rid of the formulation matrix. In this way, the release rate of the pharmacological agent is both accelerated to a low pH and decreased at a higher pH to provide a more uniform or regulated release rate over a wide pH range. Furthermore, since the release of the acidic pharmacological agent in the acidic environment of the stomach and the neutral or alkaline pH of the intestine is moderated by the polymer matrix of the formulation, the total release of the pharmacological agent is less dependent on the time that the agent resides in. stomach. Table 1 Size of the dose Status GRT (min.) 1 mm Fasting 60-150 3 mm Fasting 15-240 14 mm Fasting 15-210 1 mm Fed 101 +53 3.2 mm Fed 152 + 40 9 mm Fed 105 > 600 14 mm Powered 180 > 780 Table 1, reproduced from Dressman, e al. , Pharm Res., 15: 1 (1998) shows the gastric residence time (GRT) of drug formulations of various dose sizes in patients in both states, fed and fasted.

In a preferred embodiment, the invention provides an oral dose form of valproic acid that has decreased dependence on the rate of release to pH. The term "valproic acid" is understood to encompass the 2-propylpentanoic acid compound per se and salts thereof which include the complex formed between one mole of 2-propylpentanoic acid and its sodium salt, commonly referred to as divalproex sodium. Sodium of divalproex is disclosed in U.S. Patent Nos. 4,988,731 and 5,212,326 to Meade and may be represented by the following formula, where m varies from two to about six: Na Na1 m divavalproex sodium is a typical acidic pharmacological agent, which has a pKa of 4.8 and, as shown in Table 2, has a widely varying solubility over the pH range between pH 1.0 and pH 6.7, i.e., over the range of the difference in pH between the stomach and the intestinal tract. Accordingly, it is a good example of an acidic pharmacological agent to illustrate the formulations of the present invention.

Table 2 Solubility of Divalproex Sodium at Various pH Values Upon reaching the present invention, various systems were contemplated to obtain a formulation that would improve the solubility / release of an acidic pharmacological agent at a low pH and retard its release at a higher pH. In this way, the release of the agent would be regulated as it passed from the stomach to the intestinal tract. The divalproex sodium was selected as a representative example of an acidic pharmacological agent. One approach involved the inclusion of the drug in a polymer matrix together with a basic excipient (alkaline) that had the desired compression capacity for the tablet formation, which was compatible with the other ingredients of the formulation and which improved the solubility / release in the acidic environment of the stomach by raising the pH in the local environment of the matrix and by rapid filtration. In this way, the acidic drug was expected to be released more rapidly by improved solubility / release of the excipient than from a similar polymer matrix lacking such an excipient. On the other hand, it was expected that the normally rapid dissolution / release of the acidic pharmacological agent at the higher pH values found in the intestinal tract would be diminished to some extent by the drug's need to diffuse through the polymer matrix and through the undissolved excipient remaining in the formulation that becomes insoluble in the intestine. Through the use of this approach two formulations were examined. In a first formulation (Formulation 3 below), an anhydrous dibasic calcium phosphate that is soluble in acidic pH, but soluble in neutral pH, and has superior compression and disintegration capacity, was mixed together with the drug, hydroxypropylmethyl cellulose (Methocel® grade K4MP CR, Dow Chemical) and lactose and compressed into tablets. The anhydrous dibasic calcium phosphate used is deciphered in US Patent 5,486,365 and is available as Fujicalin® from Fuji Chemical Industries, Inc. In a second formulation (Formulation 4 below), an amorphous, finely powdered magnesium aluminosilicate, which also it is basic and has superior compression and dispersion capacity, it was substituted for dibasic calcium phosphate. This material is available as Neusilin®, also from Fuji Chemical Industries, Inc. For comparative purposes, a prolonged-release formulation (Formulation 2) of divalproex sodium based on a polymer matrix system was used as a comparative control., but lacking any of the two excipients described above. As shown by the data compiled in the accompanying figures, none of the approaches used in Formulation 3 or Formulation 4 resulted in the desired regulation of drug release over a wide pH range, nor the typical matrix formulation that comprises a water-expandable, neutral polymer, as in Formulation 2. Only the preferred formulation of the invention (Formulation 1), comprising a matrix of a water-swellable, neutral polymer and a polymer that was both acid-soluble and extensible in water at a higher pH, produced the desired results. Figure 1 shows the percentage release of drug over time from the control formulation (Formulation 2). Formulation 2 was a prolonged-release formulation of active drug matrix, but lacking any proposed ingredient to moderate the effect of pH. Three curves are shown, illustrating the release of the drug at pH 1.0, pH 4.5 and pH 6.8. The graph clearly shows a slower release of the drug at pH 1.0 than at higher pH values as would be expected from an acidic pharmacological agent. In addition, there is an undesirable range, after eight hours, in the total drug released. Figure 2 illustrates the percentage release of drug over time of the formulation containing anhydrous dibasic calcium phosphate (Formulation 3) at pH 1.0 and pH 6.8. In this case, the total drug released after eight hours is the same in both pH values, but there is still a difference before that point in the rate of release of the drug in the different pH values.

Figure 3 shows fa percentage release over time of the formulation containing amorphous magnesium aluminometasilicate (Formulation 4) at pH 1.0 and pH 6.8. The result is clearly unacceptable as a solution to the problem of alleviating pH dependence on the rate of drug release. The speeds at the two pH values vary widely and the total amount of drug released at the lower pH after eight hours is unacceptably low. Figure 4 illustrates the drug time percentage release of the preferred formulation of the present invention (Formulation 1) at pH 1.0, 4.5 and 6.8. As can be seen from the figure, the three curves that illustrate the percentage release of the drug track each other comparatively closely. The dependence of valproic acid release on the gastric residence time of two formulations was also examined. One formulation was a typical formulation of the prior art in which the drug was dispersed in a hydroxypropyl methylcellulose matrix and the other was a formulation according to the present invention in which the drug was in a matrix comprising a mixture of a polymer of neutral hydroxypropyl methylcellulose and an acid-soluble dimethylaminoethyl methacrylate polymer. The drug formulations were exposed to 0.1 M HCl solution in vitro to stimulate gastric conditions and at pH 6.8 regulator (tribasic phosphate) to stimulate intestinal conditions in a USP Apparatus II shaking apparatus and the amount of drug released was measured by Fluorescent polarization immunoassay as described below. The zero-hour gastric residence time data represent data from experiments in which the release rate of the formulations was followed from the start in the tribasic phosphate buffer at pH 6.8. The two and four hour gastric residence time data are data from experiments in which the drug formulations were initially exposed for 2 or 4 hours, respectively, to 0.1 M HCl and, for the rest of the experiments, a tribasic regulator of pH 6.8. The latter experiments thus stimulate the exposure of the drug to the acidic environment of the stomach for a pre-determined period, followed by exposure to the intestinal environment slightly alkaline or neutral for the remaining time of the experiment. The results are illustrated in Figures 5 and 6. In Figure 5, the release rate of the prior art formulation shows a marked increase in the rate of release (slope of the curve) after the change in pH (lines dotted at 2 hours and 4 hours) as would be expected when the acidic drug "moves" from the acidic environment of the stomach to the higher pH of the intestine where it is more soluble. In addition, with the formulation of the prior art of Figure 5, there is a longer interval between the curves for gastric residence times at 2 hours and 4 hours. However, the data curves in Figure 6 track each other much more closely where the drug is in a formulation of the present invention. The change in the rate of release after 2 hours of gastric residence time is considerably less and in the case of the gastric residence time of 4 hours is not remarkable. These data indicate that the formulations of the present invention demonstrate reduced dependence of release with respect to gastric residence time in addition to their reduced dependence on pH. EXAMPLES Formulation 1 (Present invention) 400 milligram tablets containing 60 mg of divalproex sodium, 140 mg of a copolymer of a methacrylate modified with dimethylaminoethyl and neutral methacrylates of weight average molecular weight of approximately 150,000 Daltons ("Eudragit E-100", Róhm America), 100 mg of hydroxypropylmethyl cellulose (Methocel®, grade K4MP CR, Dow Chemical) and 100 mg lactose. This formulation represented a drug load of 15% by weight. The crude drug was ground before use. The crude comminuted drug was mixed dry with polymer and excipients. Tablets of 400 mg weight were compressed in a Model C Carver Press tablet forming machine by using a round die (diameter = 0.95 cm) at a compression force of approximately 2000 Ibf (approximately 8.9 x 103 Newtons). Formulation 2 - (Control Example) The tablets were prepared by the same method and having the same composition as described in Formulation 1 above, but lacking the dimethylaminomethyl modified methacryate polymer. The drug was dispersed in a hydroxypropylmethyl cellulose matrix (HPMC).

Test Formulation 3 - (Comparative Example) Tablets were prepared by the same method and having the same composition as described in Formulation 1 above, containing 140 mg of anhydrous dicalcium phosphate ("Fujicalin", Fuji Chemicals, Inc.) instead of the methacrylate polymer modified with dimethylaminomethyl. Formulation 4 - (Comparative Example) The tablets were prepared by the same method and having the same composition as described in Formulation 1 above, but containing 140 mg of magnesium aluminometasilicate ("Neusilin", Fuji Chemical Industries, Inc.) in place of the methacrylate polymer modified with dimethylaminomethyl. In vitro dissolution tests in aqueous solutions at various pH values were conducted with each of the formulations described above by the use of Apparatus II and the detailed method in the United States Pharmacopeia XXI / National Formulary XVI. The speed of the stirring blade of the apparatus was 100 rpm and the temperature of the medium was maintained at 37 ° C. The dissolution of each of the formulations was observed and measured at two or more of three pH values: pH 1 (0.1 M HCl), pH 4.5 (0.05 M phosphate buffer) and pH 6.8 (0.05 M regulator of tribasic phosphate). Aliquots of 1.5 ml sample were separated from the shaken samples at 0, 1, 2, 3, 4, 6 and 8 hours and filtered through a filter. 0. 45 μm. The aliquot samples were assayed for drug by fluorescence polarization immunoassay using the TDX® analyzer (Abbott Laboratories). After separation of each sample, an equal volume of medium was added to the test mixture to maintain a constant volume. The results of the test are shown in Figures 1-4. Preferred Formulations of the Invention Due to its superiority in the control and regulation of the release of an acidic pharmacological agent (e.g., divalproex sodium) over a wide pH range, the compositions corresponding to Formulation 1 above, comprising a polymer Water-expandable, neutral, in combination with a polymer that is both soluble in acidic pH and extensible in water at an alkaline or neutral pH, is the preferred formulation of the present invention. The formulation comprises a therapeutically effective amount of an acidic pharmacological agent dissolved or dispersed in a polymer matrix comprising from about 10 weight percent to about 40 weight percent, preferably from about 15 weight percent to about 30 percent by weight, of a hydrophilic, water-expanding, neutral, pharmaceutically acceptable polymer, in combination with from about 20 weight percent to about 50 weight percent, preferably from about 25 weight percent to about 40 weight percent of a pharmaceutically acceptable acid soluble polymer, which is extensible in water above pH 5, all percentages by weight based on the total weight of the formulation. The remainder of the formulation comprises pharmaceutically acceptable excipients such as diluents, binders, lubricants, glidants, disintegrating agents and / or dyes and flavoring agents of the type generally known in the art of formulations and the following detailed. The hydrophilic, water-expandable, neutral polymers suitable for use in the formulations of this invention include methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose and hydroxypropyl methylcellulose and copolymers thereof. The neutral, water-expandable modified cellulose polymers which can be used in the formulations of the present invention include, for example, Methocel®, E10MP CR, E4MP, K100V, K4MP, K15MP and K100MP grades (available from Dow Chemical); Klucel® HXF hydroxypropyl cellulose (available from Hercules, Inc.); Keltona®, LVCR grades and HVCR alginates (available from Kelco Co.), Poiyox®, polyethylene oxide polymer (available from Union Carbide Co.), Keltrol®, xanthan gum (available from Kelco Co.) and Carbopol®, grades 934P, 971 P and 974P (available from BF Goodrich Specialty Chemicals). A water-dispersible, neutral polymer preferred for the formulations of the present invention is Methocel® K4MP, a cellulose ether comprising about 19-24% methoxy substitution and about 7-12% hydroxypropyl substitution having a hydroxypropyl substitution. % of nominal aqueous viscosity of approximately 4000 centipoise (4 pascals-seconds). Polymers suitable for use in formulations of the present invention which are soluble in acid and which dilate in water at higher pH values are copolymers of methacrylic acid / methacrylic ester, which have been modified by the incorporation of a basic functional group such as amino-, alkylamino-, dialkylamino- or dialkylaminoalkyl-group. These materials are soluble in acidic pH values due to the protonation at the sites of basic nitrogen atoms contained within the polymer to form ionized ammonium groups. Therefore, these materials are also referred to as "acid-ionisable" or "salt-forming" methacrylic acid / methacrylic acid copolymers. Acid-soluble modified methacrylate polymers, which swell in water at alkaline or neutral pH values, which can be used in the formulations of the present invention include Eudragit® E100, which is a cationic copolymer based on methacrylate dimethylaminoethyl and neutral methacrylates, which have a molecular weight of approximately 150,000 Daltons (available from Róhm America, Inc.). Excipients In addition to the active pharmacological agent and the polymer matrix, the pre-compressed or compressed formulations of the present invention may contain additives or excipients that act in one or more capacities as diluents, binders, lubricants, glidants, disintegrating agents, dyes or excipients. flavoring agents. In those situations where the amount of active pharmacological agent in a tablet is small, one or more inert diluents are added to increase the volume of the tablet. Diluents used for this purpose include dicalcium phosphate, calcium sulfate, dextrose, amylose, lactose, microcrystalline cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar. The binders impart cohesiveness to the tablet formulation, ensuring that the tablet remains intact after compression, as well as improving the free-flow characteristics and the desired hardness of the granulations prior to tableting. The materials commonly used as binders include starch, gelatin and sugars such as sucrose, glucose, dextrose, molasses and lactose. Natural and synthetic gums such as acacia, sodium alginate, Irish moss extract, panwar gum, ghatti gum, carboxymethyl cellulose, methyl cellulose and polyvinyl pyrrolidone can also be used as binders. Lubricants serve a number of functions in the tablet formulation that include preventing the adhesion of the compressed tablet to the surface of nozzles and voids, facilitating the release of the tablet from the nozzle and improving the speed of flow of the granulations prior to the formation of tablets. Commonly used lubricants include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils and poly (ethylene glycol). The amount of lubricants used in the tablet formulation can range from a low of about 0.1 weight percent to as high as about 5 weight percent. Slippers improve the flow characteristics of dry powder mixes. Colloidal silicon dioxide is the most commonly used as a slider, although asbestos-free talcum powder is also sometimes used. When the skimmer is used, it typically constitutes about 1 weight percent or less of the formulation. The disintegrating agents, either as single substances or as mixtures, are added to tablet formulations to facilitate rupture or disintegration of the tablet after administration. Corn and potato starch, which have been dried and pulverized very well, are the most commonly used tablet disintegrating agents. The amount of starch added to the formulation varies, depending on the desired disintegration rate and ranges from about 5 weight percent to about 10 to 15 weight percent. Dilative disintegrating agents, such as croscarmellose, crospovidone, and sodium starch glycolate, respectively, represent examples of degraded cellulose, degraded polymer, and degraded starch agents that may also be used. These materials are typically used in amounts ranging from about 2 to 4 weight percent in the tablet formulation. Dyestuffs can be added to the tablet formulation or to a polymeric material used as a tablet coating. Suitable coloring agents include those approved for use by the United States Food and Drug Administration (FDA) and are well known to those in the art of formulations.

Tableting Conformation Processes Tablets are generally prepared by one of three methods well known to those skilled in the art: wet granulation, dry granulation, or direct compression. Any of the three methods can be used to formulate tablets according to the present invention. Although it has been shown and described what are believed to be the preferred embodiments of the present invention, it will be apparent to those of ordinary skill in the pharmaceutical formulation art that various modifications may be made to the formulations and processes described herein without departing from the scope of the invention. the invention as defined by the appended claims.

Claims (10)

1. CLAIMS 1. A pharmaceutical composition comprising a therapeutically effective amount of an acidic pharmacological agent dissolved or dispersed in a polymer matrix, characterized in that it comprises a) from about 10 weight percent to about 40 weight percent of a hydrophilic, water swellable polymer , neutral, pharmaceutically acceptable, and b) from about 15 weight percent to about 50 weight percent of a pharmaceutically acceptable acid soluble polymer, which is extensible in water above about pH 5, all percentages based on to the total weight of the formulation.
2. 2. The pharmaceutical composition according to claim 1, characterized in that said polymer matrix comprises from about 20 weight percent to about 30 weight percent of said hydrophilic, water expandable, neutral, pharmaceutically acceptable polymer.
3. 3. The pharmaceutical composition according to claim 1, characterized in that said polymer matrix comprises from about 20 weight percent to about 40 weight percent of said pharmaceutically acceptable acid-soluble polymer, which is expandable in water over and above approximately pH 5.
4. 4. The pharmaceutical composition according to claim 1, characterized in that said hydrophilic polymer, water expandable, neutral, comprises a polymer selected from the group consisting of methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose and copolymers thereof, poly (ethylene oxide) polymer, degraded homopolymers and copolymers of acrylic acid, xanthan gum and alginate.
5. 5. The pharmaceutical composition according to claim 1, characterized in that said acid-soluble polymer, which is extensible in water above about pH 5, comprises a methacrylate polymer modified with a basic functional group.
6. 6. The pharmaceutical composition according to claim 5, characterized in that said acid-soluble polymer, which is extensible in water above about pH 5, comprises a dialkylaminoalkyl-modified methacrylate polymer. A pharmaceutical composition comprising a therapeutically effective amount of an acidic drug agent dissolved or dispersed in a matrix comprising from about 10 weight percent to about 40 weight percent of a cellulosic polymer, water expandable, neutral, pharmaceutically acceptable, and from about 15 weight percent to about 50 weight percent of an acid soluble polymer comprising a dialkylaminoalkyl modified methacrylate polymer, which is extensible in water above about pH 5, all percentages in based on the total weight of the composition. The composition according to claim 7, characterized in that said acidic pharmacological agent is a compound having a pKa value below about 6. 9. The pharmaceutical composition according to claim 8, characterized in that said cellulosic polymer, expandable in water, Neutral, pharmaceutically acceptable, is present in an amount ranging from about 20 weight percent to about 30 weight percent, based on the total weight of the composition. The pharmaceutical composition according to claim 8, characterized in that said pharmaceutically acceptable acid-soluble polymer, which is extensible in water above pH 5, is present in an amount ranging from about 20 weight percent to about 40 weight percent. percent by weight, based on the total weight of the composition. eleven . The pharmaceutical composition according to claims 8, 9 or 10, characterized in that the acidic pharmacological agent is divalproex sodium. 12. A pharmaceutical composition comprising a therapeutically effective amount of an acidic pharmaceutically dissolved or dispersed agent in a matrix comprising from about 10 weight percent to about 40 weight percent of a cellulosic polymer, expandable in water, neutral, and from about 15 weight percent to about 50 weight percent of an acid-soluble dialkylaminoalkyl methacrylate polymer, which expands in water above about pH 5, all the percentages based on the total weight of the composition. The pharmaceutical composition according to claim 12, characterized in that said hydrophilic polymer, water expandable, neutral, comprises a polymer selected from the group consisting of methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose and hydroxypropyl methylcellulose and copolymers of the same. 14. The pharmaceutical composition according to claim 12, characterized in that said acid-soluble dialkylaminoalkyl methacrylate polymer is a methacrylate polymer modified with dimethylaminoethyl. 15. The pharmaceutical composition according to claim 12, characterized in that said acidic pharmacological agent is divalproex sodium. 16. A pharmaceutical dosage form comprising a therapeutically effective amount of divalproex sodium dissolved or dispersed in a matrix comprising from about 10 weight percent to about 40 weight percent of a water-expanding, neutral, cellulosic polymer. and from about 20 weight percent to about 50 weight percent of an acid-soluble dialkylaminoalkyl methacrylate polymer, which expands in water at pH values above about 5, all percentages based on total weight of the dosage form. 1
7. 7. A dry granular composition, suitable for compressing into a tablet dosage form, characterized in that it comprises particles containing an acidic pharmaceutically dissolved or dispersed agent in a matrix comprising from about 10 weight percent to about 40 weight percent of a hydrophilic polymer, water expandable, neutral and from about 20 weight percent to about 50 weight percent of an acid soluble polymer, which is extensible in water at pH values above about 5, all of which percentages by weight based on the total weight of the granular composition. The granular composition according to claim 1, characterized in that said matrix comprises from about 20 weight percent to about 30 weight percent of said hydrophilic, water expandable, neutral polymer. The granular composition according to claim 17, characterized in that said matrix comprises from about 20 weight percent to about 40 weight percent of said acid soluble polymer, which is extensible in water at pH values above 5. 20. The granular composition according to claim 17, characterized in that said pharmacological agent is divalproex sodium. twenty-one . The granular composition according to claim 17, characterized in that said hydrophilic polymer, water expandable, neutral, is selected from the group consisting of methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose and hydroxypropyl methylcellulose and copolymers thereof. 22. The granular composition according to claim 17, characterized in that said acid soluble polymer, which is extensible in water at pH values above about 5, comprises a dialkylaminoalkyl modified methacrylate polymer. 23. A process for preparing a granular pharmaceutical composition suitable for tabletting, characterized in that it comprises the steps of a) dry blending a mixture of from about 5 weight percent to about 50 weight percent of an acidic pharmacological agent, from about 20 weight percent to about 40 weight percent of a hydrophilic polymer, expandable in water, neutral, and from about 20 weight percent to about 50 weight percent of an acid soluble polymer, which is extensible in water at pH values above about 5, to form a uniform mixture; b) wet granulating the dry uniform mixture of step a); and c) drying and sizing the wet granules of step b), wherein all the percentages are based on the total weight of the granulation. 24. The process according to claim 23, characterized in that said hydrophilic, water expandable, neutral polymer comprises hydroxypropyl methyl cellulose. 25. The process according to claim 23, characterized in that said acid soluble polymer, which is extensible in water, at pH values above about 5, is a dialkylaminoalkyl modified methacrylate polymer. 26. The process according to claim 23, characterized in that said acidic pharmacological agent is divalproex sodium. 27. A method for preparing a controlled-release tablet dosage form of an acidic pharmacological agent, characterized in that it comprises the steps of a) dry blending a mixture of from about 5 weight percent to about 50 weight percent of an acidic therapeutic agent, from about 20 weight percent to about 40 weight percent hydrophilic polymer, water expandable, neutral, and from about 20 weight percent to about 50 weight percent of a soluble polymer acid, which is extensible in water at pH values above about 5, to form a uniform mixture; b) wet granulating the dry uniform mixture of step a); c) drying and sizing the wet granules of step b), and d) compressing the mixed granules of step c) under a force ranging from about 2000 Ibf (about
8. 8.9 x 103 Newtons) to about 10,000 Ibf (about 4.45 x 104) Newtons). 28. The process according to claim 27, characterized in that said hydrophilic, water expandable, neutral polymer comprises hydroxypropyl methyl cellulose. 2
9. 9. The process according to claim 27, characterized in that said acid-soluble polymer, which is extensible in water, at pH values above about 5, is a dialkisminoalkyl modified methacrylic polymer. 30. The process according to claim 27, characterized in that said acidic pharmacological agent is divalproex sodium.