Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-03-01
2004-02-24
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S489000, C424S464000, C424S451000
Reexamination Certificate
active
06696091
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides a solid dosage formulation of topiramate and process for producing the solid dosage formulation. More particularly, the solid dosage formulation comprises core particles which are coated with a taste mask coating to provide coated partides which can be sprinkled onto food to ease administration to patients who have difficulty swallowing tablets or capsules, e.g., pediatric patients.
BACKGROUND OF THE INVENTION
The pharmaceutical industry employs a variety of dosage formulations for orally administering medicinal agents to patients. Typical formulations for oral administration include liquid solutions, emulsions, or suspensions, as well as solid forms such as capsules or tablets (as used herein, the term “tablet” means any shaped and compressed solid dosage form, including caplets). Since these conventional solid dosage formulations are usually intended for adults who can easily swallow large tablets whole, the often disagreeable taste of the active ingredient need not be taken into account in formulating the medicine, except for the provision of means to prevent the taste from being apparent during the short time that the medicine is in the mouth. Such means may include the provision of an appropriate coating on the tablet, the use of a capsule form (the gelatin outer shell of the capsule keeps the active ingredient inside until the capsule has been swallowed), or simply firmly compressing a tablet so that it will not begin to disintegrate during the short time that it is intended to be in the mouth.
Children, older persons, and many other persons have difficulty swallowing whole tablets and even capsules. Therefore, it is often desirable to provide the medicine either in liquid form or in a chewable solid form or an alternative solid form, e.g., small particles which can be sprinkled onto soft food and swallowed intact with the food, in addition to the tablet or capsule intended to be swallowed whole. Even where the medicine can be formulated as a liquid, it is desirable to provide a chewable solid form or an alternative solid form such as microspheres which can be sprinkled onto soft food (e.g., baby food) because it is often more convenient and easier to administer.
A major requirement of any such solid form is that it must be palatable, since an unpalatable formulation greatly increases the risk of a patient neglecting to take a medication. A further requirement of any solid dosage form is that it must be bioavailable; that is, once the formulation reaches the stomach, the individual particles should release the active ingredient rapidly and completely to ensure that substantially all of the active ingredient is absorbed. In cases where the active ingredient is particularly unpalatable and somewhat unstable, it may be difficult, if not impossible, to identify a solid form that fulfills both of these requirements (i.e., palatable and bioavailable).
A number of references are known which describe pharmaceutical compositions of unpalatable medicinal agents which are coated with a taste masking coating in order to hide the unpleasant taste. Julian et al., in U.S. Pat. No. 4,851,266, describe chewable medicament tablets made by coating granules of a medicament (especially, acetyl p-aminophenol) with a blend of cellulose acetate or cellulose acetate butyrate and polyvinyl pyrrolidone (also known as “PVP” and referred to hereinafter by its United States Pharmacopeia (USP) name as “povidone”). Mehta, in U.S. Pat. No. 5,084,278, discloses a pharmaceutical composition comprised of a pharmaceutical core of an active dose of a compound and a microencapsulating polymer which coats the pharmaceutical core and is capable of taste-masking the active compound. Bhardway, et al., in U.S. Pat. No. 5,578,316, describe medicament cores coated with methacrylate ester copolymers which mask the bitter and unpleasant taste of the medicament.
A variety of chlorosulfate and sulfamate esters of 2,3:4,5-bis-O-(1-methylethylidene)-&bgr;-D-fructopyranose, and their anticonvulsant activity in mammals, and thus their utility in treating diseases such as epilepsy and glaucoma, are described in U.S. Pat. No. 4,513,006. More specifically, the compound 2,3:4,5-bis-O-(1-methylethylidene)-&bgr;-D-fructopyranose sulfamate, hereinafter referred to as “topiramate”, is presently available for marketing as a tablet product in strengths of 25, 50, 100, 200, 300 and 400 mg as adjunctive therapy for the treatment of adults with partial onset seizures (TOPAMAX® (topiramate) tablets). Topiramate can be prepared following the processes disclosed in U.S. Pat. Nos. 4,513,006 and 5,387,700, and preferably, by the process described in Examples 1 to 3 of U.S. Pat. No. 5,387,700. Difficulty in identifying a chewable solid form of topiramate has ensued due to the extremely bitter taste of topiramate and problems associated with stability of the active agent, especially upon exposure to moisture and heat which are known to cause degradation of topiramate. Degradation of topiramate is readily detected by changes in physical appearance, i.e., discoloration to brown or black, and by the formation of sulfate ions which can be readily detected by standard techniques know to those of ordinary skill in the art (e.g., HPLC).
Accordingly, it is an object of the invention to provide a stable solid formulation of topiramate for use in children and other patients who have difficulty swallowing conventional solid forms (e.g., tablets, capsules) which is both palatable and bioavailable. It is a further object of the invention to provide a palatable solid formulation of topiramate that can be sprinkled onto soft food prior to consumption (i.e., a “sprinkle formulation”) and which provides immediate release of the active ingredient in the stomach.
SUMMARY OF THE INVENTION
The present invention is directed to a process for forming a pharmaceutical composition comprising:
(a) preparing core particles comprising an active agent of topiramate;
(b) drying the core particles from step (a) to form dried core particles;
(c) coating the dried core particles from step (b) with a taste masking mixture to form coated particles; and
(d) drying the coated particles from step (c) to form the pharmaceutical composition wherein the amount of taste masking mixture ranges from about 7% by weight to about 15% by weight of the pharmaceutical composition, preferably, about 9 to about 13%, and most preferably, about 11% by weight of the pharmaceutical composition.
In another aspect of the invention is a pharmaceutical composition comprising:
(a) core particles containing an active agent of topiramate, wherein the core particles have an initial particle size between about 0.100 mm and 2.5 mm; and
(b) a taste mask coating, wherein the taste mask coating comprises between about 7% by weight and about 15% by weight of the pharmaceutical composition, preferably, about 9 to about 13%, and most preferably, about 11% by weight of the pharmaceutical composition and wherein the coated particles of the pharmaceutical composition have a final particle size of about 0.100 mm to about 2.5 mm.
In one embodiment of the invention, the core particles comprise the active agent of topiramate and at least one excipient; preferably, the core particles comprise the active agent of topiramate, a binder and a diluent; more preferably, the core particles comprise the active agent of topiramate, a binder and sugar spheres.
In a class of the invention is a pharmaceutical composition comprising about 85 to about 93% by weight core beads, and about 7 to about 15% by weight of a coating; wherein the core beads comprise about 18 to about 21% by weight of topiramate, about 8 to about 11% by weight of povidone, and about 58 to about 61% by weight of sugar spheres; and the coating comprises about 6 to about 9% by weight of cellulose acetate, and about 2 to about 5% by weight of povidone.
In a subclass of the invention is the pharmaceutical composition comprising about 89% by weight of core beads and about 11% by weight coating, wherein the core bead
Gibbs Irwin S.
Kotwal Pramod M.
Thakur Madhav S.
Appollina Mary
Joynes Robert M.
Ortho-McNeil Pharmaceutical , Inc.
Page Thurman K.
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