Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2003-04-30
2004-12-14
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S451000, C424S452000, C424S464000, C424S489000
Reexamination Certificate
active
06830760
ABSTRACT:
The present invention relates to a physical form of the known drug substance glyburide, also known as glibenclamide, and chemically defined as 5-chloro-N-[2-[4-[[[(cyclohexylamino)-carbonyl]amino]sulfonyl]phenyl]ethyl]-2-methoxybenzamide (Merck Index, Tenth Edition, p. 642), as well as to dosage forms, e.g., tablets and capsules, incorporating said physical form of glyburide.
Specifically, the physical form of glyburide which is the subject matter of this invention is glyburide having a defined particle size distribution. This particle size distribution provides an enhanced rate of dissolution of the glyburide compared to bulk glyburide, and it provides reproducible bioavailability in vivo. The glyburide of the invention can also be incorporated into a tablet or capsule matrix to enhance the physicochemical (e.g., rate of drug dissolution and absorption) properties desired. The preferred rates of dissolution and absorption herein provide for early onset of glyburide absorption, yet avoid the very high and rapidly achieved plasma drug concentrations (“spike”) that would be achieved with prior art formulations when attempting to provide for early onset of absorption. A very high and rapidly achieved concentration can lead to undesirable hypoglycemia. The glyburide of the physical form described in this invention achieves this early rate of absorption, yet also maintains exposure of the patient to drug (as measured by the area under the plasma drug concentration against time curve), and therefore maintains the efficacy of the formulation.
The glyburide of the subject invention, and formulations based on this material, have properties that are particularly suitable for use as oral preprandial secretagogues.
Glyburide of the physical form described in this invention can also be used in formulations combining it with other drugs used in the treatment of type II diabetes. Examples include, but would not be limited to, acarbose or other glycosidase inhibitors, rosiglitazone, pioglitazone or other thiazolidonediones, biguanides such as metformin fumarate, repaglinide and other “aglinides”. Glyburide with the particle size distribution as given in the current invention may be particularly useful in cases where co-formulation with drugs of high dose and high solubility are required. An example of such a drug used for the treatment of type II diabetes is the biguanide known as metformin (including its fumarate and hydrochloride salts).
Glyburide is a commercially available product indicated for the treatment of type II diabetes. Its mode of action is that of an insulin secretagogue, i.e., that of an agent which stimulates the secretion of insulin from patient's beta cells. (See U.S. Pat. Nos. 3,426,067; 3,454,635; 3,507,961 and 3,507,954.) Subsequent to the discovery of glyburide itself, glyburide compositions with enhanced bioavailability to that of the originally developed and marketed formulation became available, for example as described in U.S. Pat. No. 3,979,520 and 4,060,634. These patents describe the use of micronized or high surface area (e.g., 3 to 10 m
2
/g) glyburide in combination with various pharmaceutically acceptable excipients to obtain enhanced bioavailability. Another composition in the prior art relates to the use of a spray dried lactose formulation of micronized glyburide having a narrow distribution of particle sizes. The spray dried lactose in said composition is the preponderant excipient (not less than 70% of the final composition.)
U.S. Pat. No. 5,258,185 describes rapidly absorbable formulations of glyburide prepared by dissolving the drug in liquid polyethylene glycol and/or an alcohol (e.g., ethanol) with a sugar alcohol (e.g., sorbitol) solution and optionally an alkalizing agent (e.g., ammonia). This solution is blended with suitable powdered pharmaceutically acceptable excipients to provide a dry granulation material suitable for compression into tablets. Similarly, Ganley (
J. Pharm. Pharmac
., 36:734-739, 1984) describes an improved formulation of glyburide by including solid polyethylene glycol in a capsule formulation, and Shaheen (
Int. J. Pharm
., 38:123-131, 1987) uses polyethylene glycol and an alkalizing agent, tromethamine, to provide for rapid glyburide release from a tablet formulation.
Because of the poor water solubility of glyburide, the rate of dissolution of the drug from a dosage form is a controlling factor in determining the rate and extent of drug absorption. The rate of dissolution depends on particle size (or particle surface area, which can be related to particle size). Borchert (
Pharmazie
, 31:307-309,1976) demonstrated the importance of this in vivo where studies in rats and dogs showed more extensive absorption of glyburide when a fine particle size material was evaluated against a coarser material, the drug being administered as a suspension. Arnqvist et al (
Ann. Clin. Res
., 15: 21-25, 1983) showed it was possible to micronize glyburide to such an extent that the reduced particle size of glyburide provided, relative to the reference formulation, higher maximum serum concentrations and greater area under the serum concentration time curve after dosing a tablet containing a reduced amount of drug.
None of these studies however show how to define properly the limits of particle size properties required in order to provide for appropriate bioavailability from a solid dosage form containing glyburide. It has been found that the appropriate bioavailability for glyburide is obtained when the particle size reduction of the glyburide is controlled so as not to provide what is classically accepted as “micronized” material, yet is fine enough to provide for the desired rate of dissolution. Also helpful for obtaining the appropriate bioavailability is the choice of excipients used in the formulation. The preferred excipients, known in the art, would be those that allow drug release to occur without substantially influencing the rate of drug dissolution and hence absorption. Such excipients would be highly soluble in water, and hence dissolve rapidly when the dosage form is immersed in an aqueous environment. In this way, the poorly soluble glyburide is liberated as a finely divided suspension. Dissolution of glyburide from this suspension, the rate of which is controlled by the particle size distribution of the suspension, is a prerequisite for absorption. Hence, the absorption characteristics are defined by the particle size distribution of the glyburide. In this way, as modeled by in vitro testing, the preferred dosage form is rapidly converted to a suspension of glyburide particles when the dosage form is ingested. Poorly soluble excipients may result in a dosage form that erodes too slowly. For example, dosage forms prepared with the insoluble excipient dicalcium phospate show slow erosion and consequently slow liberation of glyburide. Some currently marketed glyburide formulations, for example Micronase™, employ such excipients, and as a result can exhibit relatively slow liberation of glyburide into solution. Tablets and capsules prepared according to the current invention using soluble excipients released 80% of their contained glyburide within 20 minutes in a medium of pH 6.4 phosphate buffer with 1% w/w sodium dodecyl sulphate medium and agitation conditions of paddles at 50 rpm.
The appropriate bioavailability of glyburide avoids rapidly achieving a very high maximum (“spiked”) drug concentration in blood plasma. A very high concentration can predispose the patient to undesirable hypoglycemia. Additionally, the appropriate bioavailability of glyburide provides for the adequate extent of drug absorption such that an area under the plasma drug concentration against time curve maintains efficacy. While not being bound by any theory, it appears that it is this combination, i.e., the early onset of glyburide absorption, without producing excessively high maximum plasma drug concentrations, yet also maintaining exposure of the patient to the drug, that permits the glyburide of
Cave Gillian
Nicholson Sarah J.
Bristol--Myers Squibb Company
Page Thurman K.
Rodney Burton
Tran S.
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