Sustained release matrix for high-dose insoluble drugs

Details Sustained release matrix for high-dose insoluble drugs Sustained release matrix for high-dose insoluble drugs

2001-04-25

2004-02-10

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S440000, C424S464000, C424S465000, C424S468000, C424S470000, C424S488000

Reexamination Certificate

active

06689386

ABSTRACT:

BACKGROUND OF THE INVENTION
The advantages of controlled release products are well known in the pharmaceutical field and include the ability to maintain a desired blood level of a medicament over a comparatively longer period of time while increasing patient compliance by reducing the number of administrations necessary to achieve the same. These advantages have been attained by a wide variety of methods.
Oral controlled release delivery systems should ideally be adaptable so that release rates and profiles can be matched to physiological and chronotherapeutic requirements. While many oral controlled and sustained release formulations are already known, certain drugs that are relatively insoluble in water and which further have relatively high dose requirements (based on weight) present formulation difficulties which render them unsuitable for inclusion in sustained release formulations. Difficulties in preparing suitable sustained release formulations of insoluble drugs are increased when the dose of the insoluble drug to be delivered to render a therapeutic effect over the desired period of time is relatively high, e.g., 500 mg or greater.
An example of a high dose, insoluble drug is ibuprofen, which is a non-steroidal anti-inflammatory agent (“NSAID”). Several immediate release forms of ibuprofen are commercially available, e.g., Motrin® (available from Upjohn) and Brufen® (available from The Boots Company PLC), and a sustained release ibuprofen formulation, Brufen Retard™, is commercially available from the Boots Company PLC. Indomethacin, another high dose insoluble NSAID, is commercially available in sustained release form as Indocin SR™ from Merck & Co., Inc.
There is still a need in the art for sustained release dosage forms of insoluble NSAIDs that are bioavailable and provide suitable release profiles of the NSAID from the dosage form over a sustained period of time, e.g. for about 12 to about 24 hours.
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 t
50
(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 gastrointestinal fluid.
The present invention is also directed to a sustained release oral dosage form containing ibuprofen as the active agent, which dosage form provides au 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 t
50
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 t
50
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 t
50
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 or 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

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