United States Patent:  6,093,420

Assignee:  Edward Mendell Co., Inc. (Patterson, NY)

Filed:  July 8, 1997

Sustained release dosage forms of high dose insoluble drugs such as ibuprofen and methods for their manufacture are disclosed.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide sustained release dosage forms of insoluble NSAIDs that provide an early onset of action and a sustained release of the NSAID.

It is a further object of the present invention to provide a method for preparing such bioavailable sustained release NSAID dosage forms.

It is a further object of the present invention to provide a sustained release excipient which is suitable for providing sustained release insoluble NSAID dosage forms.

The aforementioned objects and others are achieved by virtue of the present invention, which relates in part to a sustained release dosage form comprising from about 500 mg to about 1000 mg of an insoluble NSAID and an effective amount of a sustained release carrier to release the NSAID over a desired sustained period of time, which releases at least about 6 percent by weight of the NSAID at about 2 hours and provides a t₅₀ (i.e., releases 50% by weight of the NSAID) at from about 12 to about 16 hours, after exposure of the dosage form to simulated gastro-intestinal fluid.

The present invention is also directed to a sustained release oral dosage form containing ibuprofen as the active agent, which dosage form provides an early onset of action, e.g., the dosage form releases at least about 6 percent of the ibuprofen by weight about 2 hours, and/or the dosage form releases at least about 20 percent of the ibuprofen by weight about 4 hours, after exposure to simulated gastrointestinal conditions (such as via an in-vitro dissolution testing method), and which on the other hand provides a t₅₀ at about 12 to about 16 hours.

The present invention is also directed to an sustained release oral solid dosage form including from about 500 mg to about 1000 mg of an insoluble NSAID and a sustained release carrier, and which releases at least 20 percent by weight of the NSAID after about 4 hours and provides a t₅₀ at about 12 to about 16 hours, after exposure of the dosage form to simulated gastric fluid.

Sustained release dosage forms of NSAIDs according to the present invention have the desireable inventive advantage of providing a rapid onset of therapeutic effect of the insoluble NSAID and still provide sustained release of the NSAID so as to provide effective blood plasma levels of the ibuprofen over the entire dosing interval, e.g., about 24 hours. Such sustained release oral ibuprofen dosage forms provide an in-vitro dissolution rate, when measured, e.g., by the USP Dissolution Apparatus (Paddle Type II) of at least 6 percent by weight ibuprofen released after 2 hours, and/or at least about 20 percent by weight ibuprofen released after 4 hours, and which provides a t₅₀ after about 12 to about 16 hours.

In preferred embodiments, the insoluble NSAID is ibuprofen, which preferably comprises from about 500 mg to about 1000 mg of the dosage forms. A non-limiting list of other insoluble NSAIDs that may be used in accordance with the present invention include etodolac, fenoprofen (as the calcium salt), naproxen, mefenamic acid, nabumetone, tolmetin, and the like.

In other preferred embodiments, the sustained release carrier includes xanthan gum and a crosslinking agent, e.g., a galactomannan. In preferred embodiments, the sustained release carrier includes xanthan gum and locust bean gum in a 1:20 to about a 20:1 weight ratio. In preferred embodiments, the xanthan gum comprises from about 5 to about 95 percent by weight of the sustained release carrier. In other preferred embodiments, locust bean gum comprises from about 50 to about 95% by weight of the sustained release carrier.

In preferred embodiments, the dosage forms include from about 500 mg to about 1000 mg of the insoluble NSAID are suitable for dosing on a twice daily basis. In other preferred embodiments, the dosage forms include from about 500 mg to about 1000 mg of the insoluble NSAID and are suitable for dosing on a once daily basis. When administered on a once daily basis, it is preferred that more than one tablet containing 500 mg to 1000 mg of the insoluble NSAID are administered as a single dose to a patient.

In each of the embodiments set forth above, the dosage form is preferably a tablet.

The present invention is also directed to a method of preparing an oral sustained release dosage form of a high dose insoluble NSAID tablet comprising the steps of wet granulating a mixture of xanthan gum, locust bean gum, an inert diluent and insoluble NSAID to form a granulate; and tableting the resultant granulate into tablets containing from about 500 to about 1000 mg insoluble NSAID; wherein the ratio of the total weight of the insoluble NSAID in the tablet to the combined weight of xanthan gum and locust bean gum is from about 1:0.06 to about 1:0.4.

Another aspect of the invention is directed to a sustained release pharmaceutical excipient for use in sustained release oral solid dosage forms of insoluble NSAIDs, including xanthan gum, a crosslinking agent, and from about 20 to about 35 percent by weight of an inert diluent, e.g., dextrose.

In a preferred embodiment, the total combined weight of the xanthan gum and the crosslinking agent is from about 65 to about 80 percent of the excipient. In particularly preferred embodiments, the crosslinking agent is locust bean gum.

In another preferred embodiment of the invention, a sustained release ibuprofen tablet is provided comprising from about 500 to about 1000 mg ibuprofen, and from about 7 to about 40 percent of a hydrophilic gum matrix comprising xanthan gum and a cross-linking agent capable of cross-linking the xanthan gum when said tablet is exposed to an aqueous environment. In preferred embodiments, the cross-linking agent is, e.g., a homopolysaccharide such as locust bean gum, an ionizable gel strength enhancing agent, or mixtures thereof.

Yet another embodiment of the invention is directed to a sustained release tablet containing from about 500 mg to about 1000 mg of an insoluble NSAID in a sustained release matrix including xanthan gum and a crosslinking agent, wherein the total weight of the tablet is from about 110 percent to about 140 percent by weight of the insoluble NSAID, and the xanthan gum and the crosslinking agent comprise from about 7 to about 40 percent of the tablet by weight. In certain embodiments where the weight of NSAID, e.g., ibuprofen in the tablet is about 800 mg, the combined gum weight is from about 119 percent to about 136 percent of the insoluble NSAID.

The invention also provides a method of retarding the release of ibuprofen from a sustained release ibuprofen tablet containing xanthan gum when the tablet is exposed to an aqueous environment comprising replacing from about 5 to about 95 percent by weight of the xanthan gum in a sustained release ibuprofen tablet with a weight equivalent amount of a crosslinking agent, e.g., locust bean gum, wherein the ratio of said xanthan gum to said locust bean gum is from about 1:20 to about 20:1.

In embodiments where the cross-linking agent comprises an ionizable gel strength enhancing agent as defined herein, the ionizable gel strength enhancing agent may comprise from about 1 to about 20% of the total weight of sustained release carrier, e.g., xanthan gum, galactomannan gum and ionizable gel strength enhancing agent.

Yet another aspect of the invention is directed to a sustained release insoluble NSAID tablet comprising from about 500 to about 1000 mg insoluble NSAID; xanthan gum; locust bean gum; and an inert diluent; wherein the combined weight of the xanthan gum and the locust bean gum is from about 7 to about 40 percent by weight of the final tablet weight and the ratio of insoluble NSAID to the combined weight of the xanthan gum and the locust bean gum is from about 1:0.08 to about 1:0.25. In preferred embodiments where the sustained release formulation is dosed on a twice-a-day basis, the tablet releases at least 6% by weight at about 2 hours after exposure of the dosage form to simulated gastrointestinal fluid and releases 50% by weight of the insoluble from about 5 to about 8 hours after such exposure. In other preferred embodiments, the sustained release ibuprofen tablet releases at least 20% at about 4 hours after exposure of the dosage form to simulated gastro-intestinal fluid and releases 50% by weight of the insoluble NSAID at between from about 12 to about 16 hours after said exposure.

By "sustained release" it is meant for purposes of the present invention that the therapeutically active agent, e.g. a high dose insoluble drug such as ibuprofen, is released from the formulation at a controlled rate such that therapeutically beneficial blood levels (but below toxic levels) of the medicament are maintained over an extended period of time, e.g., providing a 12 hour or a 24 hour dosage form.

By "bioavailable" it is meant for purposes of the present invention that the therapeutically active agent, e.g. ibuprofen, is absorbed from the sustained release formulation and becomes available in the body at the intended site of drug action.

By "insoluble", it is meant that the therapeutically active medicament has an aqueous solubility of less than about 10 grams per liter (g/l).

The term "environmental fluid" is meant for purposes of the present invention to encompass, e.g., an aqueous solution such as in-vitro dissolution media, or gastrointestinal fluid.

The term "insoluble NSAID" for purposes of the present invention includes insoluble NSAID, pharmaceutically acceptable salts, complexes, esters, pharmaceutically acceptable isomers thereof, and crystalline forms thereof, with the caveat that the particular form of insoluble NSAID is insoluble as defined herein. All documents cited in this specification are hereby incorporated by reference in their entireties.

The term "high dose" for purposes of the present invention, when referring to an insoluble NSAID, refers to a total daily dose of NSAID. When referring to a dosage form or a formulation, the term "high dose" mean that the dosage form or formulation contains from about 500 mg to about 1000 mg of the insoluble NSAID.

Claim 1 of 46 Claims

1. A sustained release dosage form, comprising from about 500 mg to about 1000 mg of an insoluble NSAID and an effective amount of a sustained release carrier comprising xanthan gum, locust bean gum and a pharmaceutically acceptable inert diluent, wherein the total weight of said dosage form is from about 110 percent to about 140 percent by weight of said insoluble NSAID, said xanthan gum and said locust bean gum comprising from about 7 to about 40 percent by weight of the dosage form, said locust bean gum comprising from about 50% to about 95% of the sustained release carrier, said dosage form providing a dissolution of said NSAID in-vitro when measured by the USP Type II (Paddle) Method, of from about 6 percent by weight of said NSAID released after about 2 hours and a t₅ at about 12 to about 16 hours.

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