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Title:  Sustained release pharmaceutical preparation

United States Patent:  5,968,554

Inventors:  Beiman; Elliott (Morristown, NJ); Landsman; Fred (Princeton, NJ)

Assignee:   Cascade Development, Inc. a subsidiary of Cardinal Health, Inc. (Paradise Valley, NV)

Appl. No.:  111188

Filed:  July 7, 1998

Abstract

The present invention pertains to a sustained release drug delivery system hich comprises a core of active ingredient, an enteric coating, a second coating of active ingredient and lastly a readily gastric-soluble protective coating. 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.

SUMMARY OF THE INVENTION

The present invention meets the unfulfilled needs of the pharmaceutical industry by providing a medicament that has a given proportion of a required dose separated by an enteric coating. The microcapsules according to the invention immediately release a portion of the drug into the stomach while allowing a portion of the drug to pass into the duodenum wherein the enteric coating dissolves and the drug is thereby slowly absorbed by the intestines. The unprotected portion of the microcapsule rapidly dissolves in the stomach and that portion of the drug dose quickly enters the bloodstream. The enterically coated portion of the drug begins to dissolve in the small intestine where a substantial increase in pH occurs to then controllably release the remainder of the active. In the intestines, the enteric coating or membrane dissolves or disperses in the intestinal fluid. Depending upon the relatively pH solubility of the active agent, the percentage of total active inside or outside of the enteric coating can be adjusted so that excess plasma drug concentrations are minimized and steady long-term release of the drug is maximized.

Thus, there is disclosed an oral dosage delivery form adapted to deliver a pH dependent water soluble therapeutic agent comprising:

(a) a core comprising said therapeutic agent in an amount sufficient to deliver from 25-75% of an effective amount of said therapeutic agent over the intended delivery time;

(b) an enteric polymer coating over said core;

(c) a coating of said therapeutic agent over said enteric polymer coating in an amount sufficient to deliver from 25-75% of an effective amount of said therapeutic agent over the intended delivery time; and

(d) a low pH soluble protective coating over said coating of said therapeutic agent.

The core is typically formed around a biologically inert sphere such as a non-pareil. A non-pareil, as known to those skilled in the art, is a sugar particle that is widely used in the pharmaceutical industry. The core of the therapeutically active agent may also contain other ingredients such as adhesives, anti-tack agents, disintegrants, antifoaming agents and lubricants. Especially preferred for use with phenytoin sodium is sodium lauryl sulfate. The presence of the sodium lauryl sulfate, enhances the solubility of this compound. This is especially true in the gastric fluids. The enteric polymer coating solution may also contain components such as plasticizers and anti-tack agents.

The final protective coating should be a material that rapidly dissolves or disperses in the gastric juices. This is required so as to accomplish the administration of from 25-75% of the dose in the stomach.

Thus, there is more specifically disclosed an oral dosage delivery form comprising:

(a) a core comprising phenytoin sodium, sodium lauryl sulfate and a disintegrant, said core containing 25-75% by weight of an effective amount of said phenytoin sodium over the intended delivery time;

(b) an enteric coating over said core, said enteric coating comprising an ethylacrylate methacrylic acid copolymer and a plasticizer;

(c) a coating over said enteric coating comprising phenytoin sodium, sodium lauryl sulfate and a disintegrant, said coating containing 25-75% by weight of an effective amount of said phenytoin sodium over the intended delivery time; and

(d) a low pH soluble protective coating over said coating comprising phenytoin sodium.

The present invention also relates to 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 a therapeutic agent wherein said agent's solubility is pH dependent;

(b) preparing an enteric coating aqueous solution comprising a material that does not dissolve or disperse in gastric juices;

(c) preparing a top coating solution comprising a material that does dissolve or disperse in gastric juices;

(d) charging an air suspension coating machine with biologically inert spherical pellets;

(e) spraying 25-75 weight % of said suspension of therapeutic agent while said air suspension coating machine is in operation to coat said inert pellets; thereafter

(f) spraying said enteric coating aqueous solution to coat the pellets of step (e); thereafter

(g) spraying the remainder of said suspension of therapeutic agent to coat the pellets of step (f); and thereafter

(h) spraying the top coat solution to coat the pellets of step (g).

It is the inventors' work in the field of preparing medicaments through the use of fluidized bed or air suspension coating machines that led to the discoveries resulting in the inventive oral dosage forms and methods for their production. As the dosage form itself is ultimately tied to its method of production, claims directed to the dosage form itself and its method of production are appropriate.

As mentioned previously, the core of the inventive delivery form may be formed around an inert seed, such as non-pareils, with a 10 to 100 mesh. The core may also contain a disintegrant and processing aids. As used herein and in the claims, the phrase "enteric polymer coating" means any coating that does not dissolve in the acidic environment of the stomach, but does dissolve at a pH of 5.0 or higher. Representative enteric polymer coatings may be selected from the group consisting of ethylcellulose, hydroxypropylcellulose and carboxymethylcellulose. Ethylcellulose is a common, microencapsular coating which will not readily dissolve or disperse in the stomach. Other aqueous or solvent based enteric coatings may be used as long as they do not readily dissolve or disperse in the gastric juices of the stomach but do dissolve or disperse in the intestinal fluid. Blends of various enteric polymers may also be used. For example, acrylic resins, shellac, wax or other film forming materials which will dissolve or disperse in the intestine but remain intact in the stomach, are possible alternatives. Most preferably, the enteric polymer coating comprises a water based emulsion polymer. A useful enteric coating is an ethylacrylate methacrylic acid copolymer sold under the trademark Eudragit.RTM. by Rhom GmbH of Domstadt, Germany. A preferred enteric polymer coating is Eudragit.RTM. L30D which has a molecular weight of about 250,000 and is generally applied as a 25-75% aqueous solution. The most preferred enteric coating is Eudragit.RTM. L30D-55 and is applied as a 45-55 weight % aqueous solution. Other Eudragits.RTM. such as HP50, HP55, L100 and S100 would also be useful.

The coating of the therapeutic agent over the enteric coating may be identical to the composition of the core, except for the inert seed, or it may vary to some extent. The therapeutic agent itself will remain the same, however, the disintegrate(s), lubricant(s), tackifying agent(s), partitioning agent(s), processing aid(s) and the like may vary.

The low pH soluble protective coating may be any material that readily dissolves in the stomach fluids (pH of about 1.5 to 3.0) and provides protection to the underlying coating of the therapeutic agent. At least, the protective coating will prevent abrasion to the coating of the therapeutic agent, reduce water absorption and reduce adhesion between individual dosage forms. Representative of useful materials for the protective coating include Methocel.RTM. and other cellulosics and sugars that are water soluble.

One aspect of the present invention relates to the discovery that pH dependent water soluble therapeutic agents, such as phenytoin sodium, can be placed in the dosage delivery form according to this invention, to yield sustained blood plasma concentrations of the therapeutic agent. More specifically, the present invention provides that from 40 to 60% of the therapeutic agent be present in the core of the dosage delivery form and that the remainder of the therapeutic agent be present in the coating over the enteral polymer coating. It has been discovered that for therapeutic agents which have solubilities that vary according to the pH, the present invention is effective in overcoming variable blood plasma concentrations that these therapeutic agents typically exhibit. More specifically, for phenytoin sodium, it has been discovered that about 50% by weight of a given dose should be in the core and about 50% should be in the coating over the enteric polymer coating. Most preferably, the core contains about 48% by weight of the phenytoin sodium and about 52% by weight of the phenytoin sodium should be in the coating over the enteric coating. It will be understood by the skilled artisan that the effective amounts are over an intended delivery time 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 nitrogenous compounds such as the chlorides, fluorides, maleates, succinates, tartates, carbamates, acetates, sulfates, phosphates, lactates, citrates and the like. The alkali metal and alkaline earth metal salts of organic nitrogenous compounds which have pH dependent solubilities will also benefit from the oral dosage form of this invention. These representative salts of pharmaceutically active compounds experience a shift in water solubility as the pH of the environment in which it resides (i.e., stomach versus intestinal tract) changes.

Those skilled in the art will appreciate that following oral administration of a drug, the dissolution rate is of primary importance in determining eventual levels attained in the blood and tissues. If the drug is too insoluble in the environment of the gastrointestinal tract to dissolve at an appreciable rate, it cannot diffuse to the gastrointestinal wall and be absorbed. These are factors to relate to the "prolonged action" of the dosage form.

In part, the present invention takes advantage of the major variations in acidity in the animal body for various body compartments; the high acidity (about pH 1) of the stomach, the relatively neutral environment of the lumen (about 6.6); the plasma (about 7.4); and most body tissues and organs (cerebro-spinal fluid, pH 7.4).

Most drugs are weak acids or bases, and the degree of their ionization, as determined by the dissociation constant (pKa) of the drug and pH of the environment, influences their solubilities. The dissociation constant (pKa) is the negative log of the acidic dissociation constant and is the preferred expression for both acids and bases. An acid with a small pKa (i.e., about 1.0) placed in an environment with a pH of 7 would be almost completely ionized and would be classified as a strong acid. In contrast, when a weak base passes from the strongly acidic environment of the stomach into the less acidic intestinal lumen, the extent of ionization decreases. The concentration of unionized species for a base with a pKa of about 4.0 is about 10 times that of the ionized species and since the neutral molecule freely diffuses through the intestinal mucosa, the drug is well absorbed.

The split of the active agent outside or inside the enteric coating, in part, can be co-related to the reduction in the extent of absorption from the intestine for acids with a pKa of less than about 2.5 and for bases with a pKa of greater than about 8.5. With these and other factors in mind, a dosage form in accordance with the present invention can be prepared that accomplishes relatively consistent levels of the active in the blood serum.

Thus, representative pharmaceutically active salts that will benefit from the dosage form of the present invention include: diphendyramnine hydrochloride (Benadryl.RTM.), dimenhydrinate (Dramnamine.RTM.), bromodiphenhydramine hydrochloride (Ambodryl.RTM.), doxylamine succinate (Decapryn.RTM. succinate), phenyltoloxamine dihydrogen citrate (Bristamin.RTM.), carbinoxyamine maleate (Clistin.RTM.), chlorpheniramine maleate, promethazine hydrochloride (Phenergan.RTM.), cyclizine hydrochloride (Marezine.RTM.), diltiazam hydrochloride (Cardizem.RTM.), disopyramide phosphate (Norpace.RTM.), iodihippurate sodium (Hippuran.RTM.), phenylpropanolamine hydrochloride, propranolol hydrochloride (Inderal.RTM.), thiopental sodium, mephenesin carbamate, hydroxyzine hydrochloride, benactyzine hydrochloride, methamphetamine hydrochloride, phenylpropanol-amine hydrochloride, ephdrine sulfate and iproniazid phosphate.

While there are many and varied active agents that may beneficially utilize the dosage form of the present invention, it is important to consider each active agent's reaction to the gastric and intestinal environments. These considerations will dictate the actual manufacturing procedure.

The division on the given dosage between the enteric coating can be controlled through the manufacturing process. Those skilled in the art will be able to adjust the air suspension of a fluidized bed, a rotor (rotating disc), or a Wurster column device to accomplish the desired result. Spray rates through appropriate nozzles are also known to those proficient in the trade.

Claim 1 of 17 Claims

1. An oral dosage delivery form adapted to deliver a pH dependent water soluble therapeutic agent comprising:

(a) a core comprising said therapeutic agent in an amount sufficient to deliver from 25-75% of an effective amount of said therapeutic agent over the intended delivery time;

(b) an enteric polymer coating over said core;

(c) a coating of said therapeutic agent over said enteric polymer coating in an amount sufficient to deliver from 25-75% of an effective amount of said therapeutic agent over the intended delivery time; and

(d) a low pH soluble protective coating over said coating of said therapeutic agent.

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If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

 


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