Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2000-01-07
2003-03-25
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S485000, C424S494000, C424S500000, C424S458000, C424S468000
Reexamination Certificate
active
06537578
ABSTRACT:
FIELD OF THE INVENTION
The invention is directed to controlled release pharmaceutical formulations, and more particularly to controlled release formulations incorporating sulfonylurea and derivative compounds which are suitable for 24 hour administration to a patient in need of treatment related thereto.
BACKGROUND OF THE INVENTION
The advantages of controlled release products are well known and documented in the pharmaceutical art. Advantages include the ability to maintain a desirable blood level of a medicament over an extended period, such as twenty four hours, by minimizing the peak to trough variations in plasma concentrations. Also, patient compliance is increased by reducing the number of administrations necessary to achieve a desired therapeutic effect. 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 controlled and sustained release formulations are already known, certain moderately to poorly soluble drugs present formulation difficulties which render them unsuitable for sustained release carriers which might be acceptable for other drugs, such as those that are relatively soluble. It is often impossible to predict whether a particular sustained release formulation will provide the desired release profile for a relatively insoluble drug, and it has generally been found that it is necessary to carry out considerable experimentation to obtain sustained release formulations having the desired bioavailability when ingested, particularly for drugs that are poorly soluble in water.
An example of relatively insoluble drugs which are difficult to formulate into controlled reelease formulations is the sulfonylurea class of antidiabetic drugs. Sulfonylureas are effective to control blood sugar levels in diabetics, in particular, type II diabetic patients who are unable to achieve control through dietary restriction alone. Sulfonylureas are believed to stimulate the release of insulin from the pancreatic islet cells via receptors that are reported to be ATP sensitive potassium channels.
In humans, acute stimulation of insulin secretion by sulfonylureas in response to a meal is believed to be of major importance, thus the sulfonylureas require endogenous insulin secretion in order to achieve beneficial results. Fasting insulin levels are not elevated even on long-term administration, but the postprandial insulin response continues to be enhanced after at least 6 months of treatment. The insulinotropic response to a meal occurs within 30 minutes after an oral dose of Glipizide (a sulfonylurea) in diabetic patients, but elevated insulin levels do not persist beyond the time of the meal challenge. It is also believed that extrapancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. For example, although the mechanism by which sulfonylureas lower blood glucose during long-term administration has not been clearly established, it has been reported that these drugs enhance the sensitivity of tissue insulin receptors after prolonged treatment. The subject is generally reviewed in Goodman and Gilman's,
The Pharmacological Basis of Therapeutics,
the disclosure of which is incorporated by reference herein in its entirety.
The sulfonylureas are considered to be subdivided into two subcategories: the first generation agents, e.g., tolbutamide, chlorpropamide, tolazamide, acetohexamide, and the second generation agents, e.g., glyburide (glibenclamide), glipizide and gliclazide.
Tolbutamide is practically insoluble in water but forms water-soluble salts with alkali. Tolbutamide is commercially available in 250 mg or 500 mg immediate release tablets. The immediate release formulation is typically administered twice to three times a day.
Tolazamide is also relatively insoluble in water. The solubility at pH 6.0 (mean urinary pH) is 27.8 mg per 100 ml. Tolazamide is commercially available in 100 and 250 mg immediate release tablets. The immediate release formulation is typically administered twice a day. Acetohexamide practically insoluble in water and ether, soluble in pyridine and dilute solutions of alkali hydroxides, and slightly soluble in alcohol and chloroform. Acetohexamide is commercially available in 250 and 500 mg, immediate release tablets. The immediate release formulation is typically administered twice a day.
Chlorpropamide is soluble in water at pH 6.0 (2.2 mg/ml) and practically non-soluble in water at pH 7.3.
Glyburide is sparingly soluble in water and soluble in organic solvents. Glyburide is available as tablets of 1.25 mg, 2.5 mg. and 5 mg strengths for oral administration and is typically administered twice a day.
Glipizide is insoluble in water and alcohol but soluble in alkali, e.g., 0.1N sodium hydroxide. The immediate release formulation is typically administered twice a day.
The first generation agents vary widely in their pharmacokinetics, with acetohexamide, tolbutamide and tolazamide having a half-life of about 4 to 7 hours, necessitating repeated doses throughout the day, whereas chlorpropamide has a half life of from 24 to 48 hours. The second generation agents are about a hundred times more potent, by weight, than are the first generation agents, but generally have a shorter half-life, ranging from about 1.5 to 5 hours.
Glipizide, is representative of the second generation sulfonylureas. Gastrointestinal absorption of glipizide is uniform, rapid and essentially complete, providing peak plasma levels concentrations about 1 to 3 hours after a single oral dose. Normal subjects demonstrate an elimination half-life ranging from about 2 to about 4 hours after both intravenous and oral administration. In addition, glipizide does not accumulate in the plasma following repeated oral dosing. Glipizide tablets are available, e.g., in 5 and 10 mg immediate release formulations (e.g., as Glucotrol®, marketed by Pratt Pharmaceuticals).
Immediate release tablets formulated with a sulfonylurea based on an acidified and/or alkalized excipient and an inert polar solvent, such as polyethylene glycol, are described by U.S. Pat. No. 4,696,815. These pH regulated, immediate release formulations are described as improving the dissolution of acidic, amphoteric or basic antidiabetic sulfonylurea compounds, respectively. For example, the alkalized excipient is said to promote improved dissolution of glipizide, which is an acid compound. An analogous immediate release formulation with an acidified and/or alkalized excipient, an inert polar solvent and polyvinylpyrrolidone is also described by U.S. Pat. No. 4,696,815.
Erodible poly(orthoester) or poly(orthocarbonate) devices for implantation or insertion into a patient are described by U.S. Pat. No. 4,346,709, for delivering a drug in a controlled manner, including oral hypoglycemic drugs such as the sulfonylurea hypoglycemics, acetohexamide, glypinamide, chlorpropamide, tolazamide, tolbutamide, phenformin.
A controlled release delivery system using melt spun biodegradable polymers as a carrier or host material for a bio-effecting agent such as a pharmaceutical active or a hormonal compound, including glipizide, for e.g., oral administration, is described by U.S. Pat. No. 5,518,730.
Controlled release microspheres for administration by, e.g., the oral route and comprising polylactic acid and a water soluble physiologically active substance and having a mean particle size of from about 0.01 mu m to 300 mu m are described by U.S. Pat. No. 5,100,669 as including active substances such as the antidiabetic agents glipizide, glymidine sodium, phenformin hydrochloride, methformin, buformin hydrochloride.
Uniformity and predictability of therapeutic levels of sulfonylureas and resulting blood sugar levels are considered to be desirable in the management of diabetes patents, and in particular, for the management of type II diabetic patients. For example, in tests with art-known extended release glipizide (formulations based on orally ingestible osmotic devices, as
Baichwal Anand R.
Bhagwat Dileep
Diehl, II Donald
Penwest Pharmaceuticals Co.
Webman Edward J.
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