Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-05-18
2001-08-07
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S451000, C424S452000, C424S464000, C424S465000, C424S468000, C424S469000, C424S470000, C424S489000, C424S501000
Reexamination Certificate
active
06270797
ABSTRACT:
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not Applicable.
BACKGROUND OF THE INVENTION
1. Field of The Invention
The present invention relates to a sustained release pharmaceutical composition for delivering glipizide over a prolonged period of time. The invention uses glipizide with a hydrocolloid forming agent and other substances for the sustained release of glipizide. The present invention is also directed to a method for producing the sustained release composition.
2. Description of Related Art
Glipizide is an oral blood-glucose lowering drug that is used to manage hyperglycemia in patients with non-insulin dependent diabetes mellitus. Glipizide stimulates insulin secretion from the beta cells of pancreatic-islet tissue, increases the concentration of insulin in the pancreatic vein, and may increase the number of insulin receptors.
Glipizide (1-cyclohexyl-3-[[p-[2-(5-methylpyrazinecarboxamido) ethyl]phenyl]sulfonyl]urea), is an oral blood glucose lowering drug within the sulfonylurea class. Glipizide is generally a white, odorless compound. It is insoluble in water and alcohol, has a molecular weight of 445.55 and a pKa of 5.9.
Monolithic systems (e.g. tablets) composed of hydrophilic and/or hydrophobic polymers and other excipients are commonly used for manufacturing sustained release dosage compositions of glipizide. Such systems, however, often result in a first order (non-linear) kinetic release of glipizide. Glipizide is disproportionately released quickly after a patient ingests the sustained release glipizide composition, which results in a spike in the level of medication present in the patient's blood stream. This results in an uneven and inconsistent dosage of glipizide during the beginning of the prolonged period of time as compared to the latter portion of the prolonged period and this presents a significant drawback because diabetic patients can suffer various side effects from experiencing sudden spikes of glipizide.
U.S. Pat. No. 5,945,125 (the “'125 patent”) naming Kim Chemg-ju as inventor, describes a process of manufacturing a controlled release tablet with a water swellable polymer, non-crosslinked polyethylene oxide, with an average molecular weight in the range of 900,000 to 5,000,000. The water swellable polymer is chosen such that the swelling rate of the polymer is equal to the dissolution rate of the swollen polymer. The '125 patent is generally directed to controlled release compositions. Although the '125 patent mentions glipizide as one of several drugs that may be used therewith, it does not particularize the formulation and in vivo release profile for glipizide. Yet, the '125 patent does discuss release profiles, in greater detail, for other pharmaceutical drugs mentioned therein.
Glucotrol-XL® is a registered trademark of Pfizer Inc., for glipizide-GITS (Gastrointestinal Therapeutic System). Glucotrol-XL® extended release tablets containing 2.5 to 20 mg glipizide, are commercially available to the public by prescription. The extended release of Glucotrol-XL® tablets is based on the osmotic and hydrostatic pressure system for drug release. However, these tablets typically possess lag times of 1 to 2 hours before the drug is released into the circulatory or endocrine system of the patient. The lag times may vary depending on the volume of fluids available in the patient's gastrointestinal (G.I.) tract at the time of administration of the drug. This is because the release of the drug is dependent upon hydration and osmotic pressure generation. As water from the G.I. tract enters the glipizide-GITS tablet, pressure increases in the osmotic layer of the tablet and pushes against the drug layer of the tablet, thereby releasing glipizide into the gastrointestinal lumen.
The technology to commercially manufacture Glucotrol-XL® is complicated and costly. It is complicated because the process requires manufacturing a bilayer tablet with a drug compartment (an active layer) and an osmotic compartment (pharmacologically inert). The tablet is then coated with a semipermeable membrane polymer and an aperture is laser drilled on the drug compartment side for drug release. A further film coating is then applied. This process is costly because each of the steps of manufacture requires specialized manufacturing equipment whose cost can exceed one million dollars. In addition, a great amount of time and precision is required to produce the Glucotrol-XL® tablets.
Studies by Berelowitz M, Fischette C, Cefalu W, Schade DS (Diabetes Care 1994 Dec; 17(12): 1460-4.), show that sustained release glipizide taken once a day by diabetic patients provides an effective mean glipizide concentration (>50 ng
l) twenty-four (24) hours after dosing, even at the lowest dosage level of 5 mg. Extended release glipizide was significantly more effective than immediate release glipizide in reducing fasting plasma glipizide (FPL) levels. Both the immediate release and sustained formulations of glipizide equally reduced postprandial plasma glipizide levels. Glipizide-GITS, however, exerted its control in the presence of lower plasma glipizide concentration in comparison to the concentration of plasma glipizide in patients who ingested the immediate release glipizide. The sustained release glipizide also showed significantly lower insulin and C-peptide levels. This suggests that Glipizide-GITS improves insulin sensitivity.
What is needed is a pharmaceutical composition for the sustained release of glipizide that is relatively simple to manufacture on a commercial level and is also relatively inexpensive.
What is also needed is an efficient delivery system for sustained release glipizide.
What is also needed is a pharmaceutical composition for the sustained release glipizide that releases glipizide in conformity to a zero order kinetics.
What is further needed is a pharmaceutical composition for the sustained release of glipizide that is effective at low plasma glipizide levels.
What is further needed is a pharmaceutical composition for the sustained release of glipizide that is effective at low insulin and C-peptide levels.
What is further needed is a pharmaceutical composition for the sustained release of glipizide that tends to increase insulin sensitivity.
What is further needed is a pharmaceutical composition for the sustained release of glipizide that may be produced in granulated, powder, tablet, slug and/or capsule (including caplet) form.
What is further needed is a method to manufacture a sustained release glipizide composition that results in a composition that meets one or more of the above-described characteristics.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a simple, cost effective and efficient delivery system for sustained release glipizide on a commercial scale which results in a pharmaceutical composition that exhibits substantially the same therapeutic effect as presently available glipizide compositions.
The present invention provides a monolithic matrix system for glipizide using hydrocolloid forming agents. The hydrocolloid forming agent is at least about 50% of the matrix weight. Glipizide is insoluble in water and when fabricated into matrix sustained release preparations, results in a release rate that is mainly dependent on the dissolution rate of the matrix rather than dependent on the diffusion through the matrix. In order to achieve an approximately zero order release rate (a linear constant release rate) over a prolonged period of time, a slow swelling composition with simultaneous erosion of the matrix of the composition is necessary. In the present invention selection of the proper molecular weight of the hydrophilic polymer and degree of substitution and combinations thereof is important for attaining an approximately zero order release rate of glipizide though the matrix. The hydrophilic polymers and their combinations are chosen to equate the swelling rate of the polymer matrix to the dissolution rate o
Gidwani Suresh Kumar
Singnurkar Purushottam
Tewari Prashant Kumar
Cobrin & Gittes
Di Nola-Baron Liliana
Page Thurman K.
USV Limited
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