MXPA01000205A - Sustained release pharmaceutical preparation - Google Patents

Abstract

The present invention pertains to a sustained release drug delivery system which comprises a core of active ingredient, an enteric coating, a second coating of active ingredient and lastly a readily gastric-soluble protective coating. In another embodiment, the sustained release drug delivery system comprises a core of active ingredient, an enteric coating;a second coating of active ingredient;a second enteric coating and a third coating of active ingredient. The sustained release dosage form of this invention is useful for pharmaceutically active ingredients that have limited aqueous solubility, especially phenytoin sodium, and other pH dependent soluble drugs.

Description

PHARMACEUTICAL PREPARATION FOR SUSTAINED OR PROLONGED RELEASE FIELD OF THE INVENTION This invention describes sustained release pharmaceutical preparations and a method for making them. The new drug release system contains a core comprising the active pharmaceutical, an enteric coating on the core comprising a water soluble polymer that is pH dependent, a second active pharmaceutical coating, and then a coating which is soluble in gastric juices. The invention in another aspect comprises an active pharmaceutical core, an enteric coating on its core comprising a water soluble polymer, which is pH dependent and which breaks in the colon and / or the large intestine, a second coating of the active pharmaceutical, a second enteric coating that dissolves primarily in the small intestine, a third active pharmaceutical layer, and a protective coating that is soluble in gastric juices. The ref. No. 126594 - - The drug delivery system of the invention can be used with a wide variety of pharmaceutically active agents which have pH dependent solubilities to prepare the sustained release compositions. This invention also discloses a new method for preparing these drug delivery systems and sustained release compositions manufactured therewith.

BACKGROUND OF THE INVENTION A prolonged release dosage form can be defined as a preparation which releases a drug, in vi ve, at a considerably lower rate than in the case of an equivalent dose of a dosage form (not prolonged release). ) conventional. The objective of employing a prolonged release product is to obtain a satisfactory response to the drug while at the same time reducing the frequency of administration. An example of a medication, which is commonly used in the extended-release form is maleate de - - chlorpheniramine. In a conventional manner, the medicament may be administered in doses of 4 mg every four (4) hours or in a prolonged release form in a dose of 12 mg every twelve (12) hours. Prolonged-release compositions for the sequential or stopped release of medicaments are well known in the art. Generally, such compositions contain drug particles, normally administered in divided doses two (2) or three (3) times daily, mixed with covered by a coating material which is resistant to degradation or disintegration in the stomach and / or in the intestine for a selected period of time. The release of the drug can occur by detachment, erosion, rupture, diffusion or similar actions that depend on the nature and thickness of the coating material. It is known that different pharmaceutical preparations of the same active ingredient will result in different biodi sponsibilities of the active ingredient for the mammal. Bioavailability or biological availability can . ? i **? - "*" "" * - • •• "• - • - * • • * * '' A & -» a * < - to be defined as the percentage of the drug released from the dosage form administered that becomes available in the body for the biological effect. The different formulations of the same drug may vary in bioavailability to a clinically relevant extent and the variation that may occur between batches of the same product due to useful variations in manufacturing procedures. Many medications that are usually administered in the form of tablets or capsules have a low solubility in biological fluids. For many low solubility drugs, there is considerable evidence that the dissolution rate partially or completely controls the rate of absorption. Bioavailability can be affected by a number of factors such as the amounts and types of auxiliaries used, the granulation process, the compressive forces (in the manufacture of the tablets), the surface area available for dissolution, and environmental factors such as like the agitation in the stomach and the presence of food. Because # ** s * - - ** $ ^^^^^ »* these numerous factors specific formulations play an important role in the preparation of long-acting solid dosage forms. Epilepsy is an ancient disease which affects about 1% of the global population. Disregarding the progress made in the antiepileptic therapy of the drug, there are still patients who continue to suffer from uncontrollable attacks and toxicity of the medication. Currently, only four (4) of the main anti-epileptic medications are in use; phenobarbit al, phenytoin sodium, carbamazapine and valporic acid. The pharmacological activity, in general, and the antiepileptic activity in particular, correlate better in a concentration of the drug in the blood (or in some other biophase) than with the administered dose. This phenomenon is due, in part, to the variability in drug absorption and disposition between and within individuals, particularly when the drug is supplied orally. Optimizing r, »i * MSkdttSh, - the direction of drug therapy in achieving and maintaining safe and therapeutic drug concentrations in the patient's plasma. Therefore, it may be advantageous if the patient receives a dosing regimen once or twice per day. Phenytoin is 5,5-diphenyl-2,4-imide zol idinedione. This is a well-known pharmaceutical agent that has anti-convulsant and anti-epileptic activity. Due to the poor solubility in water of phenytoin, phenytoin sodium, of the empirical formula C15H1? Na02, which is much more soluble, is used in the preparation of injectable solutions of the drug and in solid unit dosage forms. While phenytoin is the antiepileptic drug of choice for most types of epileptic seizures, except for the small malignancy, monitoring of the therapeutic drug is required because of the difficulty in maintaining an effective therapeutic plasma level of between 10 and 20 μg / ml. In addition to the problems of narrow therapeutic plasma levels, the - Phenytoin exhibits large variations in bioavailability by following oral administration to patients due to its poor solubility. With the new approaches to the release of phenytoin (ie, Parke-Davi's Dilantin® Kapseals® which are 100 mg phenytoin sodium capsules), it is still necessary for patients to take the drug several times in One day to maintain an effective therapeutic plasma level without side effects. While many encapsulation techniques have been tried, none has been satisfactory. Karasa et al., Bi or l. Ph a rm. B u l l. , 17 (3) 432-436 (1994) in the article entitled "Sustained Rilease of Phenytoin Following the Oral Ad inistration of Phenytoin sodium / Ethylcellulose My crocaps ul es in Human Subjects and Rabbits", studies the release patterns of phenytoin as the sodium salt in combination with ethylcellulose. Phenotoin sodium microcapsules are prepared by mixing 80% by weight of phenytoin sodium in a 10% (w / v) ethylcellulose solution in ethyl acetate. The suspension is stirred and n-pentane drop is added to - - drop until the separation of the phase occurs and the microcapsules are obtained. The microcapsules are collected on a filter paper, dried and stored. Karakasa et al. notes that by following oral sodium administration of phenytoin, salt can be easily transferred into free phenytoin in the acidic fluids of the stomach. As free phenytoin is practically insoluble in water, its absorption may be incomplete in the gastrointestinal tract. On the other hand, as it passes through the stomach, the volume of water that penetrates the microcapsules of ethylcellulose may be minimal. In this way, most of the sodium of phenytoin in the microcapsules can not be converted to free phenothione. This reference fails to suggest a dosage form in which the portion of the active ingredient is released into the stomach and the remaining portion is released into the intestines. A review article by Boxenbaum in Drug Devel opm in t & Indu s t ri a l Ph a rma cy, 1982, 8 (V), 1-25, entitled "Physiological and Pharmacokinet ic Factors Affecting Performance of Sustained Relase - - Dosage Forms "currently suggests that prolonged-release formulations for medications such as phenytoin are unnecessary." Boxenbaum points out that the schedule of doses once a day against three times a day produces similar plasma curves. in slow absorption, drug disposition and low solubility One position of the inventors is that it is a desirable objective that phenytoin be slow release, delayed release, prolonged release or sustained release. with long half-lives, such as phenotoin, have previously been neglected by prolonged-release formulations since they produce a small change in blood concentration after administering multiple doses.The existence of such products may, however, be justified , on the basis of its ability to minimize toxicity and occur reaction to the patient and in this way, a better compliance of the patient.

- Bialer in his article entitled "Pharmacokmet ic Evaluation of Relaying Formulations of Antiepileptic Drugs ... Clinical implications" in Cl ini ca l Ph a rm a cok ineti cs 22 (1): 11-21, 1992, also suggests that the Phenytoin is not a suitable candidate for sustained release formulations. In what Bialer and Boxenbaum failed is that through the new use of the physical properties of phenytoin sodium and medications Similar to phenytoin sodium, one can prepare a sustained release formulation that is beneficial to the patient.

The dosage form according to this invention has an essentially unprotected layer of an active ingredient that is released immediately from the gastric juices of the stomach and a second, and optionally to the third layer of the active ingredient that is protected by a coating. enteric. The second portion of the dose is subsequently made available to pass into the duodenum. The third portion is made subsequently available to pass through the - - large intestine, more preferably the colon. The drug delivery system according to the present invention provides an unusually stable drug concentration profile in the plasma. In addition, patients benefit from this formulation since many drugs similar to fenotoin have limited therapeutic windows which require multiple daily dosages (3 or more). In addition, Irvin et al., In an article in Ph a rma ce uti ca l Res ea rch, Vol. 8, No 2, 1991, entitled "Computer-Aided Dosage Form Design III, Feasibility Assessment for an Oral Prolonged-Release Phenytoin Product "also emphasizes that phenytoin is not an acceptable candidate for prolonged release dosage forms. It is noted that dosage forms which pass through the stomach tend to be expelled before the release of phenytoin is complete. These theories fail again to realize a new dosage form, which has protected and unprotected components, can be effectively used to prepare a formula of ugly ^ H ^^^. - - prolonged release for medications with pH-dependent solubilities. Deasy, Critical Reviews in Therapeutic Drug Carrier Systems, 8 (1): 39-89 (1991) in an article entitled "Microencapsulation of Drugs by Pan and Air Suspension Techniques" states that drugs such as phenytoin with a half-life greater than six ( 6) hours, tend to have inherent prolonged release properties and benefit from prolonged release preparations. The article by Deasy comments that medications such as phenytoin, with narrow ranges of therapeutic plasma levels, present special problems when formulated as prolonged-release preparations. This reference also provides a good general discussion of the microencapsulation dosage forms prepared by the air suspension and evaporation methodologies. A paper by Bourgeois entitled "Important Pharmacokinetics of Antiepi lept ic Drugs" in Epilepsy, Vol.36 (Supp.5) 1995, discusses pharmacokinetic properties - - important antiepileptic drugs. The author states that the profile of the absorption rate of the drug is described by its absorption constant (Kabs). • A high absorption constant results in high peak and rapid onset serum concentrations. A high value (Kabs) also results in large fluctuations in drug levels compared to stable concentrations resulting from low values (Kabs). A low absorption constant can sometimes be produced by formulating a drug quickly absorbed in another way in a slow release preparation. However, the enteric coated preparations do not alter a value (Kabs) of the medicament; they merely retard absorption. Enteric coatings are designed to prevent absorption in the acidic environment of the stomach. Considering for example, a patient who has received a single dose of the enteric coated preparation. For the first few hours after dosing, serum measurements will fail to detect any medication in the blood. Until no - - When the alkaline environment reaches the duodenum, the concentration of the serum rapidly increases, finally carrying out a profile similar to that of an uncoated preparation of valproate. Therefore, the enteric cover merely changes the profile of the concentration time to the correct one. In a publication in Cl i n i ca l Ph a rma cy, Vol. 3, Nov-Dec. 1984; Titrated "Absorption characteristics of three phenytoin sodium products after administration of oral loading doses" by Goff et al., the absorption characteristics of the three (3) phenytoin sodium products are evaluated after loading the oral dose. Goffet al., Suggests that the intravenous administration of phenytoin will be associated with serious adverse effects, including cardiac arrhythmias and hypotension. The reported study is conducted to determine the effect of different sodium preparations of phenytoin on the speed and extent of absorption followed by the administration of oral phenytoin loading doses. Goff et al. Reports that the absorption - - followed by oral administration of the phenytoin sodium solution is found to be erratic and highly variable among individuals. In the acid medium of the stomach, the sodium of phenytoin 5 rapidly changes to the phenytoin acid with subsequent precipitation. The authors of this reference suggest that following the administration of the phenytoin sodium solution, the solubility agents are rapidly absorbed from the stomach and this can result in the precipitation of phenytoin acid very little soluble in the stomach. A similar mechanism is proposed for the poor absorption of phenytoin following intramuscular administration. 15 In an article by Yazici et al., Entitled "Phenytoin Sodium microcapsules: Bench Scale Formula, Process Characterization and Relay Kinetics" in Ph a rm a ce u t i ca l Devel opm en t a n d Te chn o l or gy, 1 (2), 175-183 (1996), the Preparation of phenytoin sodium microcapsules using ethylcellulose and methyl acrylic acid copolymers (Eudragit® S-100 and L-100) as coating materials. The microcapsules of - - Phenytoin sodium are formulated by an organic phase separation and granule coating method. The optimum ratio of sodium of phenytoin to ethyl cellulose of 1: 2: 3 is reported. The authors report that phenytoin sodium is a problem material until the absorption of the drug is of interest as the stage of determining the proportion of phenytoin absorption is the release of dosage forms. Optimized experimental dose forms are evaluated against the release action, commercially available capsules and are found to provide superimposable release characteristics. The authors fail to suggest that the sodium dose of phenytoin, in the form of microcapsules, are divided between the enteric coatings. Neither the microcapsules nor the production method Yazici et al., Are entirely similar for the presently claimed dosage forms wherein the core comprises 25-75% of an effective amount of a therapeutic agent and one or two re-separations separating one. or two additional layers of the therapeutic agent (second and third portions), and finally a coating of a soluble protective coating at low pH. The U.S. Patent No. 4,968,508 for Oren et al. describes a matrix composition for the prolonged release of the drug which comprises an active agent, a hydrophilic polymer and an enteric polymer. The enteric polymer is impermeable to gastric fluids and helps slow the release of the drug in the areas of low pH, in this way allows low levels of the hydrophilic polymer to be employed. Oren et al., Suggests that this approach is useful in maintaining the release of numerous active agents whose solubility declines with increasing pH, "a characteristic of strongly basic drugs." The extended-release matrix of Oren et al., Is prepared using conventional hydrogel technology.This patent does not suggest or describe the division of a given dose of an active agent by one or more enteric coatings. The enteric coating releases a portion of the active substance after entering - - the duodenum and a portion after entering the large intestine. US Patent No. 4,994,260 to Allstrand et al., Discloses a pharmaceutical preparation for the controlled release of a pharmaceutically active substance prepared by mixing, in an aqueous carrier, a pharmaceutically active substance encapsulated in a shell and 60-99% by weight of a substance that controls the release selected from the group consisting of polysaccharides, oligosaccharides, disaccharides, monosaccharides, polyhydroxyalcohols and mixtures thereof. The patent describes the use of Eudragit® E 100 and sucrose to perform the dosage form. EudragitTE 100 is a polymer soluble in an acid. U.S. Patent No. 5,188,836 to Muhammad et al., Describes a semi-enteric prolonged-release pharmaceutical consisting of a biologically active composition of layers in an inert core and an inert outer shell, consisting of a methacrylic acid polymer. . &. & , i;. • -. . *, t insoluble in water, a water soluble cane alcohol, a food grade acid and a plasticizer characterized by a solubility profile formed by two rows in the human digestive tract. The dosage forms of this reference initially dissolve in the stomach and then completely dissolve and are absorbed in the intestine. This patent describes the use of Eudragi t®L3 OD as the constituent of the main cover. In this reference, the release characteristics of the Eudragit® L30D polymer are modified so that the semi-enteric formulation is created. The dissolution characteristics of Eudragi t®L3 OD are modified through the inclusion of a water-soluble bulking agent such as cane alcohol. The U.S. Patent No. 5,102,668 to Eichel et al., Discloses a pharmaceutical preparation containing multiple units of microparticles comprising a granular medicament that is less soluble at a low pH and more soluble at a high pH. The granular medicament is mixed with or surrounded by - - a pH controlled material which is formed of at least one polymer that is hydrophilic at a low pH and hydrophobic at a high pH. The pH controlled material is in a proportion to the granular medicament so that the resulting prolonged release pharmaceutical preparation is dependent on the ambient pH. Eudragi t® 00 is described as a polymer which is useful in the invention since the pH is controlled. The U.S. Patent No. 5,229,131 to Amidon et al., Discloses a system for releasing the medicament for administering a medicament at controlled pulse dose in an aqueous environment for a predetermined period of time of dose. A unitary body contains a plurality of subunits. Each of the subunits has a portion of the nucleus that contains a single dose of the medication. The core is surrounded by a portion of the associated coating respectively which is formed of the selected first and second polymer materials. Permeable polymers are described as including - - acetate cellulose, Eudragit® RS and Eudragit® R30D. The drug release system of the patent x131 describes being useful with antiepileptic drugs and beta adrenergic blockers 5 such as phenytoin. The U.S. Patent No. 5,238,686 to Eichel et al., Discloses a double fortified coated medicament having a substance in the water soluble core, a microencapsular wall coating interior and an enteric coating of exterior wall. When enterically coating the microcapsules, the release of the drug from the nucleus into the stomach is greatly impeded and the release of the medicament is substantially delayed until the coated microcapsules reach the intestine. The double fortified drug of the '686 patent is claimed to release less than 10% per hour of said drug while in the stomach, it is slowly released said medication in the intestines to provide adequate levels for eight (8) or more hours without resulting in excessively high levels of medication at any time.

- - From a review of the above techniques, it is evident that a need continues for a prolonged release system for drugs with pH-dependent solubilities, such as phenytoin sodium, which provides initial therapeutic levels of the drug, retards the release of the drug. another fraction of the medicament for removing excess concentrations for about 1-5 hours and then maintaining the release of that delayed fraction to provide adequate plasma blood drug levels for 12 or more hours. BRIEF DESCRIPTION OF THE INVENTION The present invention fills the unsatisfied needs of the pharmaceutical industry to provide a medicament having a given proportion of a required dose separated by enteric coatings. In one aspect of the invention, the required dose of the therapeutic agent is separated by two (2) enteric coatings, the second coating provides release of the active after passing through the small intestines and the first coating . »» »« W ». ~ - * • - * A- ~ -» »» - '* agaiSte - - Enteric (known as nucleus) provides release after passing through the large intestine and colon. The microcapsules according to the invention immediately release a portion of the medicament in the stomach while leaving a portion of the medicament to pass into the duodenum where it dissolves the enteric coat and in this way the medicament is slowly absorbed by the intestines. The unprotected portion of the microcapsule quickly dissolves in the stomach and this portion of the medication dose quickly enters the bloodstream. The enteric-coated portion of the drug begins to dissolve in the small intestine where the substantial increase in pH occurs to then controllably release the remainder of the active. In the dosage form of the improved two (2) enteric coating, the first dose is released in the stomach, as described above, the second dose in the small intestines and the third in the large intestine or colon. This is possible due to the presence of an extra layer of enteric coating. In the - - Thin intestines, the enteric coating or membrane dissolves or disperses the intestinal fluid. In a similar manner, the enteric coating dissolves or disperses in the fluids of the large intestine and the colon. Depending on the relative pH solubility of the active ingredient, the percentage of total intemal and external activity of the enteric coatings can be adjusted so that the excess drug concentrations in the plasma are minimized and the release for a long period stable. of the medication is maximized. Thus, a release form in oral dosage adapted to release a pH-dependent water-soluble therapeutic agent comprising: (a) a core comprising said therapeutic agent in an amount sufficient to release 25-75% is described. of an effective amount of said therapeutic agent over the proposed release time; (b) an enteric polymeric coating on said core; (c) a coating of said therapeutic agent on said enteric polymeric coating in an amount sufficient to release a second portion of an effective amount of said therapeutic agent over the proposed release time; and (d) a soluble protective coating of low pH on the coating of the therapeutic agent.

The first and second portions of the therapeutic agent may each be in the range of 25 to 75% of an effective amount of the therapeutic agent. In this way, if the first portion is 25%, the second portion is 75%.

In an alternative aspect, the release form of the inventive oral dosage may omit the low pH protective coating. The protective coating does not impact under the release properties for a long period of the invention and is used primarily to reduce or eliminate damage to the outer shell of the therapeutic agent. In an additional aspect, the j i, i i i - - The inventive oral release form further comprises an edible acid in the enteric polymeric reagent. It has been determined that the inclusion is from about 5 to about 40% by weight 5 of edible acid, such as fumaric acid, in the enteric coating will make the coating resistant to dissolution in the relative alkaline environment of the small intestine. The inclusion of the acid in the enteric coating will also retard the release of the drug with a pH-dependent solubility, thus makes the inventive dosage form capable of being released in a time of 24 hours. In a further aspect, a description is Oral dosage release form adapted to deliver a pH-dependent water-soluble therapeutic agent comprising: (a) a core comprising said therapeutic agent in an amount sufficient to release The first portion of an effective amount of said therapeutic agent over the proposed release time; «Grt ^^^^? ßfiÉ ^? Aí? & ^^^^^^^^ jg ^^^^ '" ... -AA .AA. - (b) an enteric polymer coating over said core; c) a second coating of said therapeutic agent in an amount sufficient to release a second portion of an effective amount of said therapeutic agent over the proposed release time, and (d) a second enteric polymeric coating over said second coating of the therapeutic agent. and (e) a third coating of said therapeutic agent on the second enteric polymeric coating in an amount sufficient to release a third portion of an effective amount of said therapeutic agent over the proposed release time.

The first, second and third portions of the therapeutic agent can each be independently in the range of 25 to 75% of an effective amount of the therapeutic agent over the proposed release time. Thus, for example, the kernel (first portion) can contain 25% - - From the dose for the large intestine / colon release, the second portion may contain 50% for release in the small intestine and the third portion may contain 25% for release into the stomach.

The core is typically formed around a biologically inert sphere such as a non-similar one. An unlike one, as is known to those skilled in the art, is a sugar particle that is frequently used in the pharmaceutical industry. The core of the therapeutically active agent may also contain other ingredients such as adhesives, anti-adhesive agents, disintegrants, anti-foaming agents and lubricants. Especially preferred for use with sodium for phenytoin is sodium lauryl sulfate. The presence of sodium lauryl sulfate increases the solubility of this compound. This is especially true in gastric fluids. The solution of the enteric polymeric coating may also contain components such as plasticizers and anti-adhesive agents. The final protective coating must be a material that quickly dissolves or disperses in the gastric juices. This is required to complete the administration of 25-75% of the dose in the stomach. Thus, an oral dosage release form comprising: (a) a core comprising phenytoin sodium, sodium lauryl sulfate and a disintegrant, said core containing 25-75% by weight of an amount is more specifically described herein. effective sodium phenytoin over a proposed release time; (b) an enteric coating on the core, the enteric shell comprises a copolymer of ethylacrylate methacrylic acid and a plasticizer; (c) a coating on the enteric coating comprising phenytoin sodium, sodium lauryl sulfate and a disintegrant, - - coating contains 25-75% by weight of an effective amount of sodium of phenytoin over the proposed release time; Y (d) a low pH soluble protective coating on the coating comprising phenytoin sodium.

The present invention also describes a novel process for the preparation of a sustained release pharmaceutical dosage form. The method of the invention comprises the steps of: (a) preparing an aqueous suspension of the therapeutic agent wherein said solubility of the agent is pH dependent; (b) preparing an aqueous solution of the enteric coating comprising a material that does not dissolve or disperse in the gastric juices; - - (c) loading a coating machine by air suspension with biologically inert spherical pills; (d) spraying 25-75% by weight of the suspension of the therapeutic agent while the air suspension coating machine is in operation with the inert coating pills; after (e) spraying the aqueous solution of the enteric coating to cover the pills of step (d); and then optionally: (f) spraying the remaining suspension of the therapeutic agent to coat the pills of step (e).

The work of the inventors in the field of drug preparation through the use of a fluidized bed or air suspension coating machines that leads the results discovered in the oral dosage forms .J inventives and methods for their production. As a dosage form by itself is uniquely bound to its production method, the claims directed to the dosage form per se and its production method are appropriate. As mentioned above, the nucleus of the inventive release form can be formed around an inert seed, such as unlike (non-parei 1 s), with a mesh of 10 to 100. The core can also contain process auxiliaries and disintegrants. As used herein and in the claims, the phrase "enteric polymeric coating" means any coating that does not "dissolve" in the acidic environment of the stomach, but dissolves at a pH of 5.0 or more. Representative enteric polymer coatings may be selected from the group consisting of ethylcellulose, hydroxypropylcellulose and carboxymethylcellulose.The ethylcellulose is a common microencapsular shell which will not dissolve or disperse rapidly in the stomach.

C -j üt ^ 'i- 8- > < H - - Solvents or aqueous can be used since they do not dissolve or disperse quickly in the gastric juices of the stomach but they dissolve or disperse in the intestinal fluid. Mixtures of various enteric polymers can also be used. For example, acrylic resins, lacquers, waxes or other film-forming materials which will dissolve or disperse in the intestine but remain intact in the stomach, as possible alternatives. More preferably, the enteric polymeric coating comprises a water-based emulsion polymer. A useful enteric coating is a copolymer of ethylacrylate methacrylic acid sold under the trade name Eudragit® by Rhom GmbH of Domstadt, Germany. A preferred enteric polymeric coating is Eudragit® L30D which has a molecular weight of about 250,000 and is generally applied as a 25-75% aqueous solution. The most preferred polymeric enteric coating is Eudragit® L30D-55 and is applied as an aqueous solution of 45-55% by weight. May - - Other Eudragits® covers, such as HP50, HP 55 and L100, will also be useful. In the aspect of the present invention, where there are two (2) coatings the enteric polymer separating three (3) doses of the active, the first coating (closest to the core) is preferably an enteric coating that will survive until the dosage form reach the large intestine / colon. A coating Preferred enteric is a series of anionic methacrylic acid copolymers known as Eudragit®S, manufactured by Rohm Pharma GmbH of Darmstadt, Germany. The Eudragit S films are colorless, transparent and fragile. These are insoluble in pure water, in buffer solutions below pH 6.0 and also in artificial and natural gastric juices. They are also slightly soluble in the region of the digestive tract where the juices are neutral to strongly alkaline (ie, the large intestine and colon) and in buffer solutions above a pH of 7.0. Mixtures of these enteric polymers named above can be i ,,, -. .. j * W_ * MSí & m KR * * i, > s - * ~ j > - - t v * _. - * . . . - - to be used in the present invention. In addition, the use of plasticizers is preferred in the enteric polymer coatings useful herein. The enteric coatings can also be modified through the inclusion of a weak acid to delay the dissolution of the coating in the intestines. Any weak acid can be used. Representative weak acids include acetic acid, benzoic acid, fumaric acid, sorbic acid, propionic acid, hydrochloric acid, citric acid, malic acid, tartaric acid, isocitric acid, oxalic acid, acid lactic acid, phosphoric acids and mixtures thereof. Especially preferred are fumaric acid and malic acid. The weight percent of the weak acid in the enteric coating solution (polymer, plasticizer, anti-adhesive agents, water and the like) can be from about 5 to about 40%, with 10 to 30% being the most preferred and from 10 to 25% even the most preferred. For those with experience in the art they will quickly be able to determine the exact amount of weak acid - - to include it in the solution of the cover, depending on the pKa of the particular weak acid and the desired delay in the dissolution of the enteric coating. After application of the enteric coating solution, as further described below, the percent of the weak acid in the coating will be from about 10 to about 80% by weight of the coating; more preferably from 20 to 60% and even more preferably from 25 to 50%. The coating of the therapeutic agent on the enteric coating may be identical to the core composition, except for the inert seed, or may vary to some extent. The therapeutic agent will, however, be the disintegrant (s), lubricant (s), antiadhesive agent (s), dividing agent (s), process aid (s), and the like may vary. Soluble protective coatings at a low pH can be any material that rapidly dissolves in stomach fluids (at a pH of about 1.5 to 3.0) and provides protection for the fundamental coatings of the agent. therapeutic. At least, the protective coating prevents abrasion of the therapeutic agent coating, reduces water absorption and reduces adhesion between the individual dosage forms. Representative useful materials for protective coatings include Methocel® and other cellulosics and sugars that are soluble. in water As mentioned above, the soluble protective coating at a low pH can be omitted from the inventive dosage form, however, the preferred dosage form does not include the protective coating.

In one aspect of the present invention it discloses the discovery of water-dependent pH-soluble water-soluble agents, such as phenytoin sodium, which can be placed in the dose-release form according to this invention, to produce plasma concentrations of Prolonged blood of therapeutic agents. More specifically, the present invention provides 25 to 75% of the therapeutic agent is present - - in the core of the release form of the dosage and that the remainder of the therapeutic agent is present in a coating on the reattachment of the enteric polymer or divided between the second and third layer of the therapeutic agent. It has been found that the therapeutic agents which have solubilities that vary according to pH, of the present invention is effective in exceeding the concentrations of variable blood plasma that these therapeutic agents typically exhibit. More specifically, by phenytoin sodium, it has been discovered that about 50% by weight of a given dose should be in the nucleus and about 50% should be in the coating on the coating of the enteric polymer. More preferably, the core contains about 48% by weight of the sodium of phenytoin and about 52% by weight of the sodium of phenytoin should be in the coating on the enteric coating. It will be understood by those skilled in the art that the effective amounts are about a time of release - - proposed and for a desired blood plasma concentration. The pharmaceutically active compounds that will benefit from the dosage form according to the invention include the typical salts of organic nitrogen compounds such as chlorides, fluorides, maleates, succinates, tartatos, carbamates, acetates, sulfates, phosphates, lactates, citrates. and the similar. Alkali metal earth salts and the alkali metal of organic nitrogen compounds which have pH dependent solubilities will also benefit from the oral dosage form of this invention. Representative salts of the pharmaceutically active compounds undergo a change in water solubility as the ambient pH at which the changes reside (ie, the stomach against the intestinal tract). Those skilled in the art will appreciate that oral administration followed by a medication, the rate of dissolution is of paramount importance in determining eventual levels reached in the blood and tissues.

If the drug is very insoluble in the environment "of the gastrointestinal tract to dissolve at an appreciable rate, it can not diffuse into the gastrointestinal wall and be absorbed.These factors describe the" prolonged action "of the dosage form. the present invention takes advantage of the main variations in the acidity in the body of an animal by various body components, the high acidity (a pH of about 1) of the stomach, the relatively neutral environment of the lumen (about 6.6); the plasma (about 7.4), the large intestine and the colon (about 7.0), and more body tissues and organs (brain, spinal fluid, pH 7.4) .The majority of the drugs are weak acids or bases, and the degree of its ionization, as determined by the dissociation constant (pKa) of the drug and the pH of the environment, the influence of its solubilities The dissociation constant (pKa) is the negative logarithm of the acid dissociation constant and the preferred expression for both acids and bases. An acid with a small pKa - - (ie about 1.0) placed in an environment with a pH of 7 can be almost completely ionized and can be classified as a strong acid. In contrast, when a weak base passes from the strong acidic environment of the stomach into the less acidic intestinal lumen, the extent of ionization decreases. The concentration of the non-ionized species for a base with a pKa of about 4.0 is about 10 times that of the ionized species and because the neutral molecule diffuses freely through the intestinal mucosa, the medium is well absorbed. or The division of the internal or external active agent of the enteric coating, in part, can be related to the reduction in the excess absorption of the intestine by the acids with a pKa of less than about 2.5 and for the bases with a pKa of more than about 8.5. With these and other factors in mind, a dosage form according to the present invention can be prepared which achieves relatively consistent levels of an active in the blood serum.

M ^ ^ q ^. . i. . * * *! *. avfo-a. . - - ~ < - '- • "~ M *« * - »* - > - >" • -,.

In this manner, pharmaceutically representative active salts will benefit the dosage form of the present invention include: di-feriramine hydrochloride (Benadryl®), dimenhydrinate (Dramamine®, bromodi-phenylamine hydrochloride (Ambodryl®, doxylamine succinate (Decapryn®), phenyl toloxamine dihydrogen citrate (Bri s ta in®), carbinoxylamine maleate (Clistin®), feni ramin chlorhexid maleate, promethazine hydrochloride (Phenergan®), cyclizine hydrochloride (Marezine®), diltiazam hydrochloride (Cardizem®) , Di Isopyramide phosphate (Norpace®), Iodihipurate sodium (Hippuran®, Phenylpropanolamine hydrochloride, Propane hydrochloride I-1 (Inderal®), Thiopental sodium, mepensin carbamate, Hydroxyzine hydrochloride, Benaacizine hydrochloride, hydrochloride of methamphetamine, phenylpropanolamine hydrochloride, epdrine sulfate and iproniaz phosphate ida.

While there are many and varied agents that can beneficially use the form of - - dosage of the present invention, it is important to consider each of the reactions of the active agents for the intestinal and gastric environments. These considerations will dictate the current manufacturing procedure. The division of the given dosage between the enteric coatings can be controlled through the manufacturing process. Those skilled in the art will be able to adjust the air suspension of the fluidized bed, a rotor (rotating disk), or the uster column device to achieve the desired result. The speed of spraying through the appropriate nozzle is also known to those skilled in the business. The invention will be better understood by the following Examples which are only representative of the invention as shown in the claims. ^^^^ u * - - EXAMPLE 1 Preparation of beads according to the invention The following compositions are prepared using conventional techniques and equipment: Therapeutic suspensions - - Enteric coating Top coating Those skilled in the art will understand that Matocelo solutions must be left to hydrate completely for at least twelve (12) hours before use. The equipment used to prepare the prolonged release dosage form according to the invention is a laboratory-scale fluidized bed or an air suspension coating machine (Vector Model FLM 15 with a 7-inch bottom-drawer sprayer Co ., Cambery, NJ, and an alternative machine can be % », ^. ~ - - a GPCG-5 Model from Glatt® Air Techniques Inc., Ramsey, New Jersey). The coating by air suspension is a process widely used by the pharmaceutical industry for the microencapsulation of medicines. It is often referred to as a Wurster machine. The process uses biological inert nuclei such as spherical sucrose pills, also known as unlike USPs. In this example, 3.0 Kg of unlike 25/30 mesh is loaded onto a Wurster machine to be used as a core for the preparation of the dosage form. The unlike ones useful in this invention may vary in diameter from 0.5 mm to above about 1.25 mm in diameter with 0.5 to about 0.6 mm being preferred.

The parameters of the machine are the following: Nozzle orifice size - 1.2 mm straight slots Partition height - 30 mm to 2.5 cm Atomizing pressure - 3.0 bar Spray style - GPCG or FLM 15 Sifting - about 60 meshes .. ^ a », k 4". d - - Plate bottom Wuster - 9 'plate B or plate GP The machine is reheated with a temperature reference point higher than 55 ° C. The operating parameters are as follows: Upper temperature - 40-100 ° C Product temperature -35 - 55CC Spray air pressure - 2.5 - 4.0 bar 10 Spray speed - 10 - 100 g / min Air volume - 100 - 450 cfm After the machine is adequately warmed, it is returned and loaded with 3.0 Kg of 25/30 mesh not similar. The machine is restarted and the fluidization is started with a temperature reference point higher than 55 ° C, an air volume of 120 cfm and a humidity point higher than the average of 12 ° C. Spraying the Therapeutic Suspension starts when the temperature of the product reaches 40 ° C. The spray speed starts at 10 g / min and increases to 10 g / min for 15 minutes until the spray speed reaches 80 g / min. The temperature of the product is maintained between 38 and - - 50 ° C by modulation of the upper temperature. After about 6 Kg of the Therapeutic Suspension is sprayed, a sample is removed from the processing unit. The nozzle of the machine is flushed with 100 g of water, while the non-similar phenytoin coating is allowed to dry for 5 minutes. The enteric coating solution is then charged to the spray pump and the dew starts at 2.5 bar and 20 g / min then the upper temperature is lowered to 45 ° C. The spray speed is increased to 10 g / min for 15 minutes until 70 g / min is reached. The upper temperature is modulated to maintain a product temperature of about 25-50 ° C. After the enteric coating solution is finished, a sample of the beads is removed from the machine. The nozzle is then flushed with 100 gms of water while it is cured of the place where it was taken. enteric coating. The curing takes place through the increase of the upper temperature of 60 ° C and by keeping it close to 30 minutes. After the curing is completed, the ^ =? ^^^^^ fej ^^ íi ^; _ ^ _ ¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡! - Higher temperature is increased to 70 ° C and the portion leaving the Therapeutic Suspension is then sprayed at a rate of 50 g / min, while the temperature of the product is maintained at. about 35-45 ° C. A sample of the beads is removed from the machine and the top coat solution is then loaded into the machine. The temperature above 65 ° C is adjusted and the top coating solution is sprayed while the product temperature is maintained at 40-44 ° C. At the spray end of the topcoat, the batch is allowed to cool for 2 minutes with the upper temperature set at 0 ° C. The pearls are discharged from the machine. The beads contain about 33 mg of phenytoin sodium per 100 mg of beads.

EXAMPLE II Study of bioavailability In this experiment, a single comparative dose, 3 crossover pathways, the study of bioavailability is conducted from the dosage form prepared in Example 1 (EXP) and two commercially available dosage forms of sodium phenytoin. The study is used on twelve (12) healthy adult male volunteers after pointing out the appropriate rejected ones.

The two commercially available reference products are: 1) Parke-Davis (a division of Warner-Lambert Co.) Dilantin® Kapseals®, mixed phenytoin sodium capsules of 100 mg, USP Lot No. 05017F, Expiry date: Dec ., 1998, (CON I); and 2) Parke Davis (Dilatin -125®) phenytoin oral suspension of 125 mg phenytoin / phenytoin suspension 5 ml Lot. - ~ No. 31517L, Expiration Date: December 1998 (CON II). The beads prepared in Example I are placed in a gelatin capsule as well as 100 mg of sodium phenytoin in each capsule (about 303-309 mg of beads per capsule). Dosage regimens A and B consist of the administration to a subject of one capsule (100 mg of active per capsule) with 240 ml of water. The dosage regimen C consists of a single dose of 5 ml (125 mg of active) administered with 240 ml of water. Subjects fasted overnight before the dose and for at least 4 hours afterwards. Blood samples are collected from each subject before the dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 12, 16, 24, 36, 48, 72 and 96 hours after the dose. They are given dard food about 4 to 9 hours after dosing and at appropriate times afterwards. The period of uselessness between the doses of the route is 21 days and the determined analysis is of phenytoin in the plasma. The analytical method used is HPLC with UV detection within a limit of quantification by phenytoin in plasma at 20 ng / ml. The pharmacokinetic parameters for phenytoin plasma are calculated as follows: AUC 0-t: the concentration of the plasma under the area against the time curve, from time 0 to the lowest measurable concentration, as calculated by the linear trapezoidal method. . t i t AUCinf: the concentration of the plasma under the area against the time curve from time 0 to infinity. AUCinf is calculated as the sum of the AUC 0-t plus the velocity of the lowest measurable plasma concentration at the elimination rate constant.

AUC / AUCinf: the velocity of AUC 0-t to AUCinf.

Cmax: maximum plasma concentration measured over the specified duration time.

Tmax: time of the maximum plasma concentration measured. If the maximum value occurs at more than one time point, tmax is defined as the first time point with this value.

Kel: Apparent first order elimination or calculated terminal velocity constant of a semi log design of the plasma concentration against the time curve. The parameter will be calculated by linear least square regression analysis when using at least three (or more) non-zero plasma concentrations. t 1/2 the terminal half-life or elimination will be calculated as 0.693 / Kel.

The values of Kel or AUCinf are not reported for cases that do not exhibit a terminal log-linear phase in concentration against the time profile. The date where the dose is normalized for phenytoin.

Statistical analysis Statistical analyzes, which include the following, are developed for the date of phenytoin. The date of all the subjects who complete the study is analyzed.

Analysis of the variance The analysis of the variance is developed in the pharmacokinetic parameters listed above, with the exception of the proportion of AUC 0-t to AUCinf. Additionally, the log-trans date formed is used for the analysis of AUC 0-t, AUCinf and Cmax. ^^^^ _ ^ _ ¿_ * _ »_ ^ The analysis of the variance model includes subjects, period, remnant of first order and drug formulation as factors. A level of significance of 5% is used. Each analysis of variance 5 includes a calculation by means of least squares, the adjusted differences between formula means and the standard error associated with these differences. The above statistical analyzes are conducted using the SAS® GLM procedure.

Ratio analysis The proportions of the means are calculated by using the LMS for both AUC 0-t untransformed and 15 transformed log, AUCinf and Cmax. The values of the geometric mean are reported for the transformed log parameters. The speeds of the means are expressed as a percentage. The comparisons of interest are XEP vs CON I and EXP vs 20 CON II.

,. .. »,. ,.,,,. ", J, -? * i «I * á £ á Power tests Power (ie, the probability of detecting a 20% difference relative to the LMS reference formulation at the 5% significance level when using a t test under the null hypothesis of the zero difference) is calculated for unprocessed AUC 0-t and transformed log parameters, AUCinf and Cmax. Table I presents the results of this clinical study.

TABLE I Summary of results - Phenytoin pharmacokinetics parameters in plasma * is reported for the parameters Ln transformed, the antilog of the mean (ie the geometric mean).

Results and Discussion The individual time-concentration profiles and the pharmacokinetic parameters for plasma phenytoin are not reported here. The results for the pharmacokinetic parameters Ln transformed AUC 0-t, AUCinf, Cmax and the untransformed parameters tmax, half-life and kel are presented in Table 1. The results for the parameters AUC 0-t, AUCinf and Cmax after the Adjustments for the measured drug content can be found in Table 2.

EXP vs. WITH I The speeds of the mean least squares for the parameters Ln transformed AUC 0-t, AUCinf and Cmax are 88.5%, 89.2% and 69.1% respectively. The mean tmax for the delayed-release capsule EXP is 7,417 hours, compared to 2,833 hours for the CON I. After correcting the drug content measured for the transformed Ln parameters, the velocities of the least squares means for the parameters Ln transformed power corrections AUC 0-t, AUCinf and Cmax are 87.8%, 88.6% and 68.6% respectively.

EXP vs. CON II The speeds of the means of the least squares for the parameters AUC 0-t, AUCinf and Cmax are 82.7%, 84.4% and 69.3%, respectively. The mean tmax for the delayed-release capsule EXP is 7,417 hours compared to 4,958 hours for the CON II.

Conclusion Based on the velocities of least squares means for AUC 0-t and AUCinf, the delayed release capsules EXP according to the invention, CON I and CON II comparable bioavailability under certain conditions.

TABLE 2 Calculations of Power Corrections-Speeds Adjusted means of the pharmacokinetic parameters Ln AUC 0-t, Ln AUCinf and Ln Cmax TABLE 3 Active -% of claimed label * yü ^ EXAMPLE III Preparation of the beads 48/52 according to the invention Using a therapeutic suspension, an enteric coating and an upper coating, as described in Example I, a second batch of sodium of phenytoin is prepared in the dosage form according to the invention. The main difference is that about 48% by weight of the active is inside the enteric coating and about 52% is outside the enteric coating. The establishment of the equipment and the operation thereof are similar to that discussed in Example I except that the release levels for the first and second coatings of the therapeutic suspension are adjusted to perform fraction 48/52 of the active. The pearls of the final product contain about 33 mgs of phenytoin sodium per 100 mgs of pearls. The pearls are uniform size, free flowing, stable to atmospheric conditions and white pearl color.

EXAMPLE IV Bioavailability Study The study set forth in Example II is repeated except that the six (6) subjects are evaluated for a period of 24 hours. The results (not available at the time of registration of this application) will that the formulation 48/52 will have a ter Tmax, a Cmax and a higher AUC than the formulation prepared in Example I.

EXAMPLE V Preparation of the beads according to the invention with a edible acid in the enteric coating The process and ingredients set forth in Example I are used in this Example, except that the Enteric coating solution additionally contains 2 Kg of fumaric acid, for a total of 8.0 Kg of the Enteric coating solution. Therapeutic Suspension, the Enteric coating and the top coating solution are used as described in Example I. EXAMPLE VI Preparation of the beads according to the invention Without a protective coating The process and ingredients set forth in Example I are used in this Example, except that the application of the Superior coating solution is omitted. The final beads contain about 34 mgs of phenytoin sodium per 100 mgs of the beads.

EXAMPLE VII Preparation of the beads according to the invention with two layers of enteric coating The compositions set forth in Example I are used, except that a Second Enteric Layer is prepared.

- - SECOND ENTREME COATING The equipment set forth in Example I is used, however, the procedure for placing the second enteric coating on the core of the therapeutic agent is modified. The Therapeutic Suspension is divided to obtain 25% by weight in the core, 50% by weight in the second layer and the 25% by weight in the third layer. The pearls contain about 25.5 mgs of phenytoin per 100 mgs of the beads.

Industrial Applicability 15 While many drugs are conventionally dosed using the technology of the ítßUÍS & i? A? Ki? i t, tk A »* Afea.,. prolonged release or conventional delayed release, certain pharmaceutics whose solubility is highly dependent on pH presents special problems. Pharmacists such as sodium phenytoin which have half-lives extended and whose therapeutically effective plasma concentrations are preferably narrow present especially problems of difficulty. The present inventors have, through extensive research, determined that a nucleus of the therapeutic agent surrounded by an enteric coating which is then surrounded by an additional active ingredient, can be manipulated to utilize the solubility of the variable pH of the drug for the benefit of the patient. The application of this technology for a certain class of pharmacists who present a substantial advance in the state of the art. Having thus described the present invention in detail, it will be obvious to those skilled in the art that various modifications or changes may be made without departing from the scope of the invention defined in the appended claims and disclosures in the specification.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property: fifteen twenty ^^^ Égájs¿jg ^^

Claims (17)

RE IVINDICATIONS

1. An oral dosage release form adapted to deliver a water-soluble, pH-dependent therapeutic agent, characterized in that it comprises: (a) a core comprising said therapeutic agent in an amount sufficient to release 25-75% of an effective amount of said therapeutic agent over the proposed release time; (b) an enteric polymeric coating on said core; (c) a coating of said therapeutic agent on said enteric polymeric coating in an amount sufficient to release 25-75% of an effective amount of said therapeutic agent over the proposed release time; and (d) a soluble, low pH protective coating on the coating of the therapeutic agent.

2. The release form of an oral dosage according to claim 1 characterized in that the therapeutic agent is selected from the group consisting of sodium phenytoin, di-phenhydramine hydrochloride, di-enhydrinate, bromodi-phenylamine hydrochloride, doxylamine succinate, dihydrogen citrate, phenyl toloxamine, carbinoxyamine maleate, methylene hydrochloride, chlorpheniramine maleate, promethazine hydrochloride, cyclicine hydrochloride, diltiazan hydrochloride, di sopyramide phosphate, sodium iodohipurate, phenylpropanolamine hydrochloride, propranolol hydrochloride, sodium thiopenate, mephenesin carbamate , hydroxyzine hydrochloride, benacticine hydrochloride, methamphetamine hydrochloride, phenylpropanolamine hydrochloride, ephedrine sulfate, phendimetrazine bitartate and iproni azide phosphate.

3. An oral dosage form according to claim 1 characterized in that the core additionally comprises at least _: i. A component selected from the group consisting of adhesives, antimicrobial agents, disintegrants, antifoams, lubricants and sodium lauryl sulphate is selected.

4. The oral dosage form according to claim 1 characterized in that the enteric polymeric coating additionally comprises at least one component selected from the group consisting of plasticizers and anti-adhesive agents.

5. The oral dosage form according to claim 1 characterized in that the enteric polymer is selected from the group consisting of ethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylic resins, lahellac, wax, ethylacrylate methacrylic acid copolymers and mixtures thereof.

6. The oral dosage form according to claim 5 characterized in that the ethylacrylate methacrylic acid copolymer has a molecular weight of about 250,000.

7. The oral dosage form according to claim 2, characterized in that the low pH soluble protective coating is selected from the group consisting of water soluble cellulose and sugars.

8. The oral dosage form according to claim 1 characterized in that the core is 45-55% of said effective amount.

9. The oral dosage form according to claim 8 characterized in that the core is 48-52% of said effective amount.

The oral dosage form according to claim 1 characterized in that the therapeutic agent is sodium phenytoin and the sodium phenytoin is a mixture with sodium lauryl sulfate.

11. An oral dosage dosage form, characterized in that it comprises: (a) a core comprising sodium phenytoin, sodium lauryl sulfate and a disintegrant, said core contains 25-75% by weight of an effective amount of sodium phenytoin over a proposed release time; (b) an enteric coating on the core, the enteric coating comprises a copolymer of methacrylic methacrylate acid and a plasticizer; (c) a coating on the enteric coating comprising sodium phenytoin, sodium lauryl sulfate and a disintegrant, the coating contains 25-75% by weight of an effective amount of sodium phenytoin over the proposed release time; and (d) a soluble protective coating of low pH on the coating comprising sodium phenytoin.

12. The method of preparing a prolonged-release pharmaceutical dosage form, characterized in that it comprises the steps of: (a) preparing an aqueous suspension of the therapeutic agent wherein said solubility of the agent is pH dependent; (b) preparing an aqueous solution of the enteric coating comprising a material that does not dissolve or disperse in the gastric juices; (c) preparing a top coating solution comprising a material that dissolves or disperses in the gastric juices; (d) loading a coating machine by air suspension with biologically inert spherical pills; (e) spraying 25-75% by weight of the suspension of the therapeutic agent while the air suspension coating machine is in operation with the inert coating pills; then (f) spraying the aqueous enteric coating solution the coating of the pills of step (e); then (g) spraying the remainder of the therapeutic agent suspension onto the coating of the pills of step (f); and then (h) spraying the solution of the top coating onto the coating of the pills of step (g).

13. The method according to claim 12, characterized in that the therapeutic agent is selected from phenytoin sodium, di-phenhydramine hydrochloride, dimenhydrinate, bromodihydrohydrate, phenytolamine hydrochloride, doxylamine succinate, phenol-1-toloxamine dihydrogen citrate, carbinoxy-amine maleate , methacrynic acid hydrochloride, pheniramine chloride maleate, promethazine hydrochloride, cyclicine hydrochloride, diltiazan hydrochloride, disopyramide phosphate, sodium iodohipurate, phenylpropanolamine hydrochloride, propranolol hydrochloride, thiopental sodium, mephenesin carbamate, hydroxyzine hydrochloride , benacticma hydrochloride, me tamfetamine hydrochloride, phenylpropanolamine hydrochloride, ephedrine sulfate, fendimet razina bitartate and iproniazide phosphate.

14. The method according to claim 12, characterized in that the aqueous solution of the enteric coating comprises a copolymer of ethylacrylate methacrylic acid.

15. The method according to claim 12, characterized in that the aqueous suspension comprises sodium phenytoin, a disintegrant and sodium lauryl sulfate.

The method according to claim 14 characterized in that the copolymer has a molecular weight of 250,000.

17. The method according to claim 12 characterized in that 45-55% by weight of the suspension is sprayed in step (e). 10 fifteen twenty ^ ^^^^^^^^ Éwjg ^ s? ^^^ a ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^ jj ^^ jg ^ g ^