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 advantage for years in so-called "enteric coated" pharmaceutical formulations. These formulations are generally in the form of tablets coated with a substance which is insoluble or sparingly soluble in acidic solutions, but which dissolves rapidly at higher pH. Such enteric coated formulations permit the oral administration of drugs which would present problems if released in the stomach, such as irritation of the stomach lining. Moreover, enteric-coated tablets also permit extending the release of a drug over time. For example, a tablet can be formulated by compressing granules containing the drug, some of which granules are enteric coated and some of which are not. As the tablet disintegrates, the non-enteric coated granules dissolve in the stomach, immediately releasing the drug, while the enteric coated granules pass to the intestine before dissolving to release the drug. In this way, release of the drug can be extended over the time the drug is resident in both the stomach and intestine. Such an extended release system is crude, essentially releasing the drug in a bi-modal manner. It is generally desirable to release a drug more smoothly over time than can be done by a partially enteric coated formulation of the type just described.
In the effort to achieve smooth, controllable release of acidic pharmacologic agents, several systems have been devised. 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 core of drug surrounded by a semi-permeable membrane containing a small orifice. When the tablet is exposed to an aqueous body fluid, water flows into the tablet through the semi-permeable membrane due to the osmotic pressure difference. The drug is then pumped out of the tablet through the orifice at a constant rate controlled by the parameters of drug concentration, orifice diameter, osmotic pressure difference, etc., until the drug concentration inside the tablet falls below saturation.
Dissolution systems take advantage of the inherent dissolution rate of the drug itself, or of a particular salt or derivative. Alternatively, the drug can be coated with a slowly dissolving coating, or by incorporating the drug into a slowly dissolving carrier.
Diffusion systems include both reservoir devices, in which a core of drug is surrounded by a polymeric membrane, and matrix devices in which dissolved or dispersed drug is distributed uniformly throughout an inert polymer matrix. The release of drug from a reservoir system involves the flow of drug through the membrane, and is controlled by Fick's first law of diffusion. Depending upon the shape of the tablet, the equation describing the release will vary.
In matrix systems, the mechanism of drug release is assumed to involve dissolution of the drug from the surface layer of the device first, followed by dissolution from the underlying layer and diffusion through the overlying drug-depleted layer, etc.
The design of a sustained or extended release formulation for drugs which are acidic present particular problems for the pharmaceutical formulator. The solubility of such drugs in gastric juices is typically low as a result of the repression of ionization of the acid by the low pH in the stomach. On the other hand, such acidic drugs dissolve rapidly in the intestine, sometimes more rapidly than desired. The various systems described above lend themselves readily to the formulation of extended release formulations of drugs which are unaffected by pH as they traverse the alimentary canal, but do not provide adequate formulations where the drug has widely varying pH-dependent release rates between the stomach and intestinal tract.
One such acidic pharmacologic agent is 2-propylpentanoic acid, more commonly known as valproic acid (VPA), which is effective in the treatment of epileptic seizures or as an antipsychotic agent. U.S. Pat. No. 4,988,731 to Meade discloses an oligomer having a 1:1 molar ratio of sodium valproate and valproic acid containing 4 units, and U.S. Pat. No. 5,212,326 to Meade discloses a stable, non-hygroscopic solid form of valproic acid which comprises an oligomer having 1:1 molar ratio of sodium valproate and valproic acid and containing four to six units. Divalproex sodium (sodium hydrogen divalproate), a comple 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 poorly soluble in the stomach and has also been shown to exhibit an elimination half-life which is shorter than other commonly used anti-epileptic agents. Half-lives for the drug of between six and seventeen hours in adults and between four and fourteen hours in children have been reported. This leads to substantial fluctuations in the plasma concentration of the drug, especially in chronic administration. To maintain reasonable stable plasma concentrations, it is necessary to resort to frequent dosing, and the resulting inconvenience to the patient often results in lowered compliance with the prescribed dosing regimen. Moreover, widely fluctuating plasma concentrations of the drug may result in administration of less than therapeutic amounts of the drug in a conservative dosing regimen, or to 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 which will maintain more constant plasma levels of acidic drugs in general, and valproic acid in particular, following administration. The ultimate goal of these studies has been the discovery of a formulation which affords stable plasma levels in a once-a-day dosing regimens for such drugs. These efforts fall generally into one of two categories: (a) finding a form of the active ingredient which is more uniformly released to the body metabolically, and (b) finding a formulation which delivers the drug by either a timed- or controlled-release mechanism.
With regard to valproic acid, U.S. Pat. No. 4,369,172 to Schor, et al. describes, for example, a prolonged release therapeutic composition based on mixtures of hydroxypropylmethyl cellulose, ethyl cellulose and/or sodium carboxymethyl cellulose. The patentees provide a long list of therapeutic agents which they suggest can be incorporated into the formulation including sodium valproate.
U.S. Pat. No. 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 natural or synthetic polymer, pressed into a tablet under high pressure.
U.S. Pat. No. 5,009,897 to Brinker, et al. discloses granules, suitable for pressing into tablets, the granules comprising a core of divalproex sodium and a coating of a mixture of a polymer and microcrystalline cellulose.
U.S. Pat. No. 5,019,398 to Daste discloses a sustained-release tablet of divalproex sodium in a matrix of hydroxypropylmethyl cellulose and hydrated silica.
U.S. Pat. No. 5,055,306 to Barry, et al. discloses an effervescent or water-dispersible granular sustained release formulation suitable for use with a variety of therapeutic agents. The granules comprise a core comprising the active ingredient and at least one excipient, and a water insoluble, water-swellable coating comprising a copolymer of ethyl acrylate and methyl methacrylate and a water soluble hydroxylated cellulose derivative. The patentees suggest a list of therapeutic agents which may be used in the formulation of the invention, including sodium valproate.
U.S. Pat. No. 5,169,642 to Brinker, et al. disclose a sustained release dosage form comprising granules of divalproex sodium or amides or esters of valproic acid coated with a sustained release composition comprising ethyl cellulose or a methacrylic methyl ester, a plasticizer, a detackifying agent, and a slow-release polymeric viscosity agent.
U.S. Pat. No. 5,185,159 to Aubert, et al. disclose a formulation of valproic acid and sodium valproate which is prepared without the use of either a binder or a granulating solvent. The formulation optionally contains precipitated silica as an anti-sticking or detackifying agent.
U.S. Pat. No. 5,589,191 to Exigua, et al. discloses a slow release sodium valproate tablet formulation in which the tablets are coated with ethyl cellulose containing silicic acid anhydride.
Published PCT application WO 94/27587 to Ayer, et al. discloses a method for control of epilepsy by delivering 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: 401-411 (1985); and Israel J. Med. Sci., 20: 46-49 (1995) report the pharmacokinetic evaluation of several sustained release formulations of valproic acid.
Despite these efforts, however, there remains a need for formulations of acidic pharmacologic agents (in general), and valproic acid (in particular) which demonstrate less dependence in dissolution and release rate upon variation in pH in the alimentary canal.