Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-03-31
2001-10-02
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S468000, C424S469000, C424S484000, C424S488000, C424S489000, C424S499000, C424S500000, C424S502000
Reexamination Certificate
active
06296873
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
This invention concerns a zero-order sustained release drug delivery system suitable for administration of carbamezepine and carbamezepine derivatives released by zero-order kinetics. In particular, the invention concerns the drug delivery system comprising a polymer matrix made of a hydrophilic polymer or a mixture thereof and a pharmaceutically active agent carbamezepine or carbamezepine derivative incorporated into the polymer matrix. The polymer or the polymer mixture forms the matrix for incorporation of carbamezepine or carbamezepine derivative released from the polymer matrix by zero-order release kinetics.
BACKGROUND ART AND RELATED ART DISCLOSURES
Carbamezepine is a well-established antiepileptic compound. It is regarded as a first-line drug in the treatment of patients suffering from partial seizures, with and without second generalization, and in patients with generalized tonic clonic seizures (Porter, R. J., Penry, J. K., pp. 220-231,
Advances in Epileptology
, Meinardi, H., Rowan, A. J., Eds., Swets & Zeitlinger, Amsterdam (1977) and
Acta Neurol. Scand.,
64, Suppl. 88 (1981)). Besides being an antiepoleptic compound, carbamazepine has also proved effective in the treatment of trigeminal neuralgia and in patients suffering from manic depressive episodes (
Neurol. Neurosurg. Psychiat.,
29:265-267
9
1966);
Arch. Neurol.,
19:129-136 (1968);
Excerpta Medica,
139-147 (1984); and
Excerpta Medica,
93-115, (1984)).
Although the half-life of carbamazepine is relatively long, between 25 and 85 hours, after a single dose due to autoinduction, its effect is substantially reduced after repeated dosing (
J. Clin. Pharmacol.,
23:241-244 (1982);
J. Ther. Drug Monit.,
3:63-70 (1981); and
Europ. J. Clin. Pharmacol.,
8:91-96 (1975)). Due to its increased metabolism, pronounced daily fluctuations in the serum concentration of carbamazepine were observed and are of concern.
Because there is a correlation between peak concentrations of carbamezepine and central nervous system (CNS) side effects, especially in patients receiving polytherapy (
Epilepsia,
28:507-514 (1987);
Epilepsia,
28:286-299 (1987);
Epilepsia,
21:341-350 (1980);
Epilepsia,
25:476-481 (1984) and
Arch. Neurol.,
41:830-834 (1984)), it is of great clinical importance to assure a steady level of carbamazepine during a 24-hour carbamazepine delivery.
Using conventional carbamazepine formulations, however, this can only be achieved by dividing the total daily intake into several, typically 3-4 doses per day. This is very bothersome for ambulatory patients and laborious for medical personnel in institutions and may, therefore, result in compliance problems.
The availability and introduction of slow release carbamazepine formulations would be, therefore, regarded as a major clinical advantage. To date, such formulation has not been available, mainly due to physical and chemical properties of carbamazepine.
It is well known that differences due to polymorphism and pseudopolymorphism observed in certain pharmaceuticals are of importance because physical and chemical properties of different crystalline forms of these pharmaceuticals vary. Differences in these chemical or physical properties, such as for example, solubility, can affect their bioavailability and effective clinical use (
J. Pharm. Sci.,
58:911-929 (1969)).
Several polymorphs of carbamazepine have been described in
Thermomicroscopy in the Analysis of Pharmaceuticals
, Pergamon, N.Y., p. 227 (1971);
Pharmazie,
11:709-711 (1975); and
Yakaguku Zasshi,
104:786-792 (1988). Pseudopolymorphs, such as the dihydrate solvate and an acetone were disclosed in
Int. J. Pharm.,
14:103-112
9
1983);
Int. J. Pharm.,
20:307-314 (1984); and
Pharmacology,
27:85-94 (1983).
In the presence of water, carbamazepine is known to transform rapidly to carbamazepine dihydrate. Carbamazepine dihydrate crystals grow by the whisker mechanism (
Int. J. Pharm.,
20:307-314 (1984)) and conversion has been shown by x-ray powder diffraction to be 95% complete after 1 hour (
J. Pharm. Sci.,
80:496-500 (1991)).
The inhibition of formation of large crystals of carbamazepine dihydrate are of great importance for its pharmaceutical formulation since the formation of large crystals of carbamazepine dissolve slowly and unpredictably and, therefore, cause bioavailability problems and may result in unpredictable and uncontrollable drug delivery.
Some attempts to overcome the above problems were made. For example, Khanna S. C., et al., U.S. Pat. No. 4,857,336, have described an oral dosage form for administration of carbamaepine wherein a core comprising a paste of a fine carbamazepine powder dissolved in a protective colloid, a .hydrophilic swelling agent and, optionally, a water-soluble osmosis inducing-agent was encapsulated in a water-permeable shell impermeable to the components of the core. The water-permeable encapsulation shell permits a water passage through the cell for the transport of the water soluble core components into the surrounding aqueous body fluid. However, in this arrangement the delivered amount is not strictly controllable because it depends on the amount of water present in the surrounding environment, on the permeability of the shell to the water and on the overall kinetics of carbamazepine release from the colloid and its transport through the shell. Additionally, the manufacturing of the past masses is inconvenient and laborious due to the need for encapsulation and additionally requires use of organic solvents which may affect the drug properties.
In an attempt to solve the above problems, the U.S. Pat. No. 5,284,662, has improved the oral formulation for delivery of carbamazepine by reducing the usage of the organic solvents, particularly in core preparations, thus avoiding possible formation of unsuitable pasty masses in manufacture and resulting in somehow easier processing. However, similarly to the above described formulation, this formulation does not eliminate or inhibit crystallization and therefore also results in unpredictable drug delivery.
The primary aim of this invention is to provide a controllable, predictable and true zero-order release dosage formulation of carbamazepine or a carbamazepine derivative released by zero-order kinetics using a simple, fast, easy and more practical manufacturing process than those currently available and described in the two patents cited above.
The delivery system of the invention comprises carbamazepine or a carbamazepine derivative formulated as an erodible tablet or other oral formulation based on a polymeric matrix of a hydrophilic polymer or a combination of a hydrophilic and a hydrophobic polymer containing carbamazepine or a carbamazepine derivative. The polymer matrix permits zero-order release kinetics of the drug.
All patents, patent applications or publications cited herein are hereby incorporated by reference.
SUMMARY
One aspect of the invention relates to a controlled-release oral drug delivery system comprising, as an active ingredient, a pharmaceutical agent carbamazepine or a derivative thereof, which is formulated within a polymeric matrix comprising a hydrophilic, or a mixture of hydrophilic and hydrophobic polymer, said system optionally further containing additional pharmaceutically acceptable constituents, wherein the pharmaceutical agent is released from said matrix by zero-order kinetics.
Another aspect of the invention is an erodible tablet for controlled-release oral drug delivery comprising carbamazepine or a carbamazepine derivative formulated within a polymeric matrix comprising hydrophilic or a mixture of hydrophilic and hydrophobic polymer according to the invention.
Yet another aspect of the invention is an erodible tablet comprising carbamazepine or a carbamazepine derivative, a hydrophilic polymer, a mixture of hydrophilic polymers or a mixture of hydrophilic and hydrophobic polymers alone or in combination with other pharmaceutically acceptable constituents.
Another aspect of the invention is a polymeric matrix for z
Friedman Michael
Katzhendler Ifat
Channavajjala Lakshmi S.
Page Thurman K.
Verny Hana
Yissum Research Development Company of the Hebrew University of
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