Zero-order sustained release delivery system for carbamazephine derivatives

A zero-order sustained-release delivery system for delivery of carbamazepine or a derivative thereof. A polymeric matrix formulation of carbamazepine comprises hydrophilic polymer or hydrophilic/hydropholic polymer mixture which permits carbamazepine or carbamezepine derivative to be released from the polymer matrix in zero-order release kinetics.

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 91966); 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 91983); 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 zero-order
 release kinetics of a pharmaceutical agent comprising a hydrophilic
 polymer, a mixture of hydrophilic polymers or a mixture of hydrophilic and
 hydrophobic polymers alone or in combination with the other
 pharmaceutically acceptable constituents.
 Still another aspect of the invention is a controlled-release drug delivery
 system wherein carbamazepine or a carbamazepine derivative is released
 from the matrix at a predictable, controllable, continuous, zero-order
 release kinetics.
 DEFINITIONS
 As used herein:
 "HPMC" means hydroxypropyl methylcellulose.
 "SEM" means scanning electron micrograph.
 "DSC" means differential scanning calorimetry.
 "Zero-order release rate" or "zero order release kinetics" means a
 constant, linear, continuous, sustained and controlled release rate of
 carbamazepine or a carbamazepine derivative from polymer matrix, i.e. the
 plot of mass of carbamazepine or carbamazepine derivative released vs.
 time is linear.
 "Pharmaceutically active agent", "active drug" or "active ingredient" means
 carbamazepine or a carbamazepine derivative having low solubility which is
 released by zero order kinetics. These derivatives are represented by
 compounds:
 10,11-dihydro-10-oxo-5H-dibenz/b,f/azepine-5-carboxamide/(oxcarbazepine);
 10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide;
 10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-benzoyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(4-methoxybenzoyloxy)-10,11-dihydro-5H-dibenz/b,f/azepine-5-carbomamide;
 10-(3-methoxybenzoyloxy)-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(2-methoxybenzoyloxy)-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(4-nitrobenzoyloxy)-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(3-nitrobenzoyloxy)-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(2-nitrobenzoyloxy)-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(4-chlorobenzoyloxy)-10,11-dihydro-5H -dibenz/b,f/azepine-5-carboxamide;
 10-(3-chlorobenzoyloxy)-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(2-acetoxybenzoyloxy)-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-propionyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-butyryloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-pivaloyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-[(2-propyl)pentanoyloxy]-10,11-dihydro-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10-[(2-ethyl)hexanoyloxy]-10,11-dihydro-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10-stearoyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-cyclopentanoyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-cyclohexanoyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-phenylacetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(4-methoxyphenyl)acetoxy-10,11-dihydro-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10-(3-methoxyphenyl)acetoxy-10,11-dihydro-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10-(4-nitrophenyl)acetoxy-10,11-dihydro-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10-(3-nitrophenyl)acetoxy-10,11-dihydro-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10-nicotinoyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-isonicotinoyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(4-aminobutanoyloxy)-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(2-amino-3-methylbutanoyloxy)-10,11-dihydro-5H-dibenz/b,f/
 -azepine-5-carboxamide;
 10-chloroacetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-bromoacetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-formyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-ethoxycarbonyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(2-chloropropionyloxy)-10,11-dihydro-5H
 -dibenz/b,f/azepine-5-carboxamide;
 10,11-dihydro-10-hydroxyimino-5H-dibenz/b,f/azepine-5-carboxamide;
 10,11-benzyloxyimino-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-acetyloxyimino-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10,11-dihydro-10-propionyloxyimino-5H-dibenz/b,f/azepine-5-carboxamide;
 10-butyroyloxyimino-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10,11-dihydro-10-pivaloyloxyimino-5H-dibenz/b,f/azepine-5-carboxamide;
 10,11-dihydro-10-[(1-napthoyloxy)imino]-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10-benzoyloxyimino-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10,11-dihydro-10-succinoyloxyimino-5H-dibenz/b,f/azepine-5-carboxamide;
 10,11-dihydro-10-glutaroyloxyimino-5H-dibenz/b,f/azepine-5-carboxamide;
 10,11-dihydro-10-isobutoxycarbonyloxyimino-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10,11-dihydro-10-methoxyimino-5H-dibenz/b,f/azepine-5-carboxamide;
 10,11-dihydro-10-(S)-(-)-camphanoyloxyimino-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10,11-dihydro-10-[(3-methoxybenzoyloxyimino)]-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10,11-dihydro-10-nicotinoyloxyimino-5H-dibenz/b,f/azepine-5-carboxamide;
 10,11-dihydro-10-ethoxycarbonyloxyimino-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10-butoxycarbonyloxyimino-10,11-dihydro-5H-dibenz/b,f/
 azepine-5-carboxamide; and
 10-benzyloxycarbonyloxyimino-10,11-dihydro-5H-dibenz/b,f/
 azepine-5-carboxamide.

DETAILED DESCRIPTION OF THE INVENTION
 The present invention relates to a controlled and sustained release oral
 drug delivery system comprising carbamazepine or a carbamazepine
 derivative. Carbamazepine or the derivative thereof is formulated within a
 polymeric matrix, said matrix optionally further containing additional
 pharmaceutically acceptable constituents and additives. The polymer in the
 polymeric matrix permits carbamazepine or its derivative to be released
 from the matrix by zero-order release kinetics.
 I. Components of the Oral Drug Delivery System
 The drug delivery system of the invention contains at least two components,
 namely a pharmaceutically active agent and a hydrophilic polymer.
 One component of the drug delivery system of the invention is a
 pharmaceutically active agent. Pharmaceutically active agent is selected
 from the group consisting of an antiepileptic drug carbamazepine or any of
 carbamazepine derivative having the same properties.
 Carbamazepine derivatives which possess the same or similar zero-order
 release kinetics properties from the polymer matrix are:
 10,11-dihydro-10-oxo-5H-dibenz/b,f/azepine-5-carboxamide/(oxcarbazepine);
 10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide;
 10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-benzoyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(4-methoxybenzoyloxy)-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(3-methoxybenzoyloxy)-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(2-methoxybenzoyloxy)-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(4-nitrobenzoyloxy)-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(3-nitrobenzoyloxy)-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(2-nitrobenzoyloxy)-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(4-chlorobenzoyloxy)-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(3-chlorobenzoyloxy)-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(2-acetoxybenzoyloxy)-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-propionyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-butyryloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-pivaloyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-[(2-propyl)pentanoyloxy]-10,11-dihydro-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10-[(2-ethyl)hexanoyloxy]-10,11-dihydro-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10-stearoyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-cyclopentanoyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-cyclohexanoyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-phenylacetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(4-methoxyphenyl)acetoxy-10,11-dihydro-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10-(3-methoxyphenyl)acetoxy-10,11-dihydro-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10-(4-nitrophenyl)acetoxy-10,11-dihydro-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10-(3-nitrophenyl)acetoxy-10,11-dihydro-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10-nicotinoyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-isonicotinoyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(4-aminobutanoyloxy)-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(2-amino-3-methylbutanoyloxy)-10,11-dihydro-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10-chloroacetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-bromoacetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-formyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-ethoxycarbonyloxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-(2-chloropropionyloxy)-10,11-dihydro-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10,11-dihydro-10-hydroxyimino-5H-dibenz/b,f/azepine-5-carboxamide;
 10,11-benzyloxyimino-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10-acetyloxyimino-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10,11-dihydro-10-propionyloxyimino-5H-dibenz/b,f/azepine-5-carboxamide;
 10-butyroyloxyimino-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10,11-dihydro-10-pivaloyloxyimino-5H-dibenz/b,f/azepine-5-carboxamide;
 10,11-dihydro-10-[(1-napthoyloxy)imino]-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10-benzoyloxyimino-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide;
 10,11-dihydro-10-succinoyloxyimino-5H-dibenz/b,f/azepine-5-carboxamide;
 10,11-dihydro-10-glutaroyloxyimino-5H-dibenz/b,f/azepine-5-carboxamide;
 10,11-dihydro-10-isobutoxycarbonyloxyimino-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10,11-dihydro-10-methoxyimino-5H-dibenz/b,f/azepine-5-carboxamide;
 10,11-dihydro-10-(S)-(-)-camphanoyloxyimino-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10,11-dihydro-10-[(3-methoxybenzoyloxyimino)]-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10,11-dihydro-10-nicotinoyloxyimino-5H-dibenz/b,f/azepine-5-carboxamide;
 10,11-dihydro-10-ethoxycarbonyloxyimino-5H-dibenz/b,f/
 azepine-5-carboxamide;
 10-butoxycarbonyloxyimino-10,11-dihydro-5H-dibenz/b,f/
 azepine-5-carboxamide; and
 10-benzyloxycarbonyloxyimino-10,11-dihydro-5H-dibenz/b,f/
 azepine-5-carboxamide.
 Carbamazepine derivatives and their preparation has been disclosed in the
 European Patent Application 96110490.8, filed on Jun. 28, 1996, published
 on Jan. 1, 1997 and 97108465.2, filed on May 26, 1997, hereby incorporated
 by reference.
 In the drug delivery system of the invention, the drug is present in amount
 from about 100 mg to about 1,200 mg per tablet, preferably from about 200
 mg to about 500 mg per tablet.
 The second component of the delivery system is the polymeric matrix
 comprising at least one hydrophilic polymer but may contain two or more
 hydrophilic polymers in admixture. When hydrated, the polymer forms a gel
 layer around the dry tablet core. The matrix of the invention is made of
 low or high viscosity erodible polymers or mixtures thereof.
 Polymers are mixed with drug in a weight ratio of polymer to drug from
 about 1:99% to about 99:1%, preferably from about 5:95% to about 90:10%,
 most preferably from about 10:90% to about 80:20%, depending on the
 viscosity grade of the polymer, on the tablet dimension and shape and on
 the desired release rate.
 The polymer matrix/carbamazepine formulation is preferably fabricated into
 tablets, capsules or granules for oral use. Rate of carbamazepine release
 from the tablets is controlled by the erosion mechanism of the polymer
 from which carbamazepine is released by zero-order kinetics. Examples of
 hydrophilic polymers which are suitable as the matrix for the zero-order
 release kinetics delivery system of the invention are hydrophilic
 cellulose derivatives.
 In general, for producing a tablet on an industrial scale, the drug and
 polymer are granulated alone or in combination as described below.
 Lubricants, glidents and other additives may be added and the mixture is
 compressed into tablets.
 Preferred hydrophilic cellulose derivatives are methyl cellulose,
 hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl
 cellulose, hydroxyethyl methylcellulose, carboxy methylcellulose and
 sodium carboxy methylcellulose. The most preferred hydrophilic cellulose
 derivative is hydroxypropyl methylcellulose (HPMC).
 HPMC is particularly preferred for use with carbamazepine or a
 carbamazepine derivative because of very low water solubility of
 carbamazepine or its derivative. HPMC is available in a low, normal or
 high viscosity grades. The viscosity of the polymer controls the release
 rate of the drug from the formulation and affects its zero-order release
 kinetics. Specific HPMCs which are most suitable for the current
 formulation are Methocel K100M, K15M, F4M, E4M, K4M, K100LV, K3, E15LV,
 E15LN, E15CLV, E5O, E5 and E3, commercially available from Colorcon,
 Orpington, England.
 Viscosity grade and molecular weights of various hydrophilic polymers are
 seen in Table 1.
 TABLE 1
 Viscosity Grade Number Average
 Methocel 2%, 20.degree. C. mPa.s Molecular Weight Mn
 E3, K3 3
 E5 5 10,000
 E15LV, E15LN, E15SLV 15 15,000
 E50 50 22,000
 K100LV 100 26,000
 K4M, F4M, E4M 4,000 86,000
 K15M 15,000 120,000
 K100M 100,000 246,000
 The polymers useful in the current invention are preferably methocels
 having viscosity grade from about 3 to about 100,000 mPa.cndot.s at 2% of
 concentration at 20.degree. C. Table 1 lists the suitable HPMCs by their
 viscosity at 20.degree. C. and by their molecular weight.
 The hydrophilic polymers listed in Table 1 are preferred because they allow
 the zero-order release rate of the active agent from the polymeric matrix
 formulation, such as an erodible tablet. When the tablet erodes within the
 digestive system, carbamazepine or its derivatives are released from the
 matrix in zero-order release kinetics and are readily absorbed.
 While the drug/matrix may be formulated into granules, capsules or other
 solid pharmaceutical compositions, the erodible tablet form is most
 preferred.
 In general, the ratio of drug:polymer is varied depending on the size and
 shape of the tablet, on the drug amount and drug release rate, and depends
 also on the molecular weight and viscosity grade of the polymer, which in
 general will be from about 3 to about 100,000 mPa.cndot.s, preferably from
 about 5 to about 15,000 mPa.cndot.s at 2% concentration at 20.degree. C.
 temperature.
 Typically, when the viscosity grade of the polymer is higher, the release
 of the drug is slower. When the shape of the tablet is flatter, i.e. when
 the ratio of a tablet diameter to a tablet width is higher, the drug
 release is faster. Taking these parameters into consideration, the tablet
 is formulated according to the drug release requirement to be more flat,
 that is, having a large surface for faster release or more cylindrical,
 that is, having smaller surface for slower release. Additionally, for
 slower release of the drug the higher viscosity grade polymer is used and
 vice-versa.
 The polymeric matrix of the drug delivery of the invention may additionally
 also contain a hydrophobic polymer. Suitable hydrophobic polymers are
 hydrophobic cellulose derivatives, such as ethyl cellulose, fats, such as
 glycerol palmitostearate, waxes, such as beeswax, glycowax, castrowax,
 carnaubawax, glycerol monostearate or stearylalcohol, hydrophobic
 polyacrlamide derivatives and hydrophobic methacrylic acid derivatives.
 When using a hydrophobic polymer, in order to provide zero-order release,
 such hydrophobic polymer is used only in a mixture of hydrophilic and
 hydrophobic polymers. In such a mixture, the hydrophobic polymer controls
 the water penetration rate into the delivery system. Incorporation of
 hydrophobic polymer into the polymer matrix and the ratio of hydrophilic
 to hydrophobic polymer thus changes the erosion characteristics of the
 tablet. The hydrophobic polymer shows down the water penetration into the
 tablet and thus slows the tablet erosion.
 The hydrophobic polymer is added to the hydrophilic polymer in amount from
 about 0.1 to about 10%, preferably from about 1% to about 5%, of the total
 polymer. Ratios of hydrophilic to hydrophobic polymer are from about
 99.9:0.1 to about 90:10, preferably from about 99:1 to about 95:5.
 In one embodiment, the polymeric matrix comprises either a hydrophilic
 cellulose derivative alone or a mixture of two or more hydrophilic
 cellulose derivatives. In another embodiment, the polymeric matrix
 comprises hydrophilic cellulose derivative alone or a mixture of said
 hydrophilic cellulose derivatives in combination with any one of the above
 hydrophobic polymers or a mixture of such hydrophobic polymers. In still
 another embodiment, hydrophilic cellulose derivative or a mixture thereof,
 in combination with any of said hydrophobic polymers or a mixture of said
 hydrophobic polymers, may additionally contain other components, such as
 pharmaceutically acceptable additives and constituents.
 The other pharmaceutically acceptable constituents of the polymeric matrix
 of the drug delivery of the invention are selected from the groups of
 proteins, arabinogalactans, chitosans, polysaccharides, hydrophilic
 polyacrylamide derivatives and hydrophilic methacrylic acid derivatives.
 Proteins which are suitable as the matrix carriers are, for example, egg
 albumin, human albumin, bovine alumin, soy protein, gelatin, casein. The
 protein can be used in the native or denatured state.
 Polysaccharides which are suitable are .beta.-cyclodextrans and starch
 derivatives.
 Additionally, the delivery system of the invention optionally contains
 release accelerating agents, an example of which are polyethylene glycol,
 salts and surfactants. Other pharmaceutically acceptable accelerating
 agents may also be added, as known in the art of pharmaceutical sciences.
 When incorporating a release accelerating agent, the use of polyethylene
 glycol in the tablet is preferred since it enhances the solubility of
 carbamazepine and causes enhancement of amorphism of the carbamazepine.
 The present formulation may also contain a pharmaceutically acceptable
 binder. Pharmaceutically acceptable binders suitable for use in the
 present formulations are selected from those routinely used by formulators
 and include sucrose, gelatin, acacia, tragacanth, cellulose derivatives,
 povidone, polyethylene glycols and other binders known to those familiar
 with pharmaceutical formulations.
 If desired, other additives, such as lubricants, stabilizers and glidents,
 conventionally used for pharmaceutical formulations, may be included in
 the present formulations.
 The formulations of the invention are prepared by procedures known in the
 art, such as, for example, by the dry or wet method. The method selected
 for manufacturing affects the release characteristics of the finished
 tablet. In one method, for example, the tablet is prepared by wet
 granulation in the presence of either water or an aqueous solution of the
 hydrophilic polymer or using other binder as a granulating fluid. In
 alternative, organic solvent, such as isopropyl alcohol ethanol and the
 like, may be employed with or without water. The drug and polymer may be
 granulated alone or in combination. Another method for preparation of the
 tablet which may be used requires using a drug-polymer dispersion in
 organic solvents in the presence or absence of water. Because
 carbamazepine or its derivative has very low solubility in water it is
 advantageous to reduce the carbamazepine particle size, for example, by
 milling it into fine powder and in this way to control the release
 kinetics of the drug and enhance its solubility.
 The drug delivery of the invention can utilize any suitable dosage unit
 form. Specific examples of the delivery system of the invention are
 tablets, tablets which disintegrate into granules, capsules, sustained
 release microcapsules or any other means which allow for oral
 administration. These forms may optionally be coated with pharmaceutically
 acceptable coating which disintegrates in the digestive system.
 Such coating may comprise a biodegradable polymer, a coloring and/or
 flavoring agent or any other suitable coating. The technique of preparing
 coated tablet, microcapsule or capsule formulations are known in the
 pharmaceutical sciences.
 The amount of carbamazepine, or a derivative thereof, in the formulation
 varies depending on the desired dose for efficient drug delivery. The
 actual amount of the used drug is dependent on the patient's age, weight,
 sex, medical condition, disease or any other medical criteria. The actual
 drug amount is determined according to intended medical use by techniques
 known in the art. The pharmaceutical dosage formulated according to the
 invention may be administered once or more times per day, as determined by
 the attending physician.
 Typically, carbamazepine is formulated in tablets or other pharmaceutical
 composition in amounts of about0.001 to about 1 g, preferably from about
 0.2 to about 0.8 g of carbamazepine per day for children. For adults, the
 daily dose is typically from about 0.001 to about 1.2 grams per day.
 However, some patients receive up to 1.6-2.4 grams daily. Preferably, the
 daily amount for adults in between about 0.8 and about 1.2 grams per day
 formulated to be released slowly to maintain therapeutic levels of
 carbamazepine in patient's blood between about 4-12 .mu.g/ml. Above this
 concentration, patients may experience adverse effects.
 The daily dose can be formulated in a single tablet or more than one
 tablet, depending on the daily dose of carbamazepine and the number of
 times the formulation is to be administered.
 Carbamazepine, formulated according to the invention, is delivered once or
 twice a day, depending on the release kinetics from the tablet. In rare
 instances, tablets may be formulated for more frequent administration than
 twice a day.
 II. Crystalline Properties of Carbamazepine in Sustained Release
 Hydrophilic Matrix Tablets Based on Hydroxypropyl Methylcellulose
 The effect of hydrophilic polymer, represented by hydroxypropyl
 methylcellulose (HPMC), on the crystal habit properties of carbamazepine
 in erodible polymeric matrix tablets and in aqueous solutions was
 investigated using differential scanning calorimetry (DSC), X-ray powder
 diffraction and scanning electron microscopy (SEM).
 The results indicated that HPMC inhibits the transformation of
 carbamazepine to carbamazepine dihydrate crystals in the gel layer of
 hydrated tablets and in aqueous solutions, depending on HPMC
 concentration. HPMC thus seems to participate and seems to be involved in
 carbamazepine crystallization process and seems to induce amorphism of
 carbamazepine crystals. While not intended to be bound by any proposed
 mechanism, obtained results show that the hydrophilic polymer may serve as
 a template or microsubstrate for nucleation in the crystallization
 process. The interaction between the drug and polymer may occur by
 hydrogen bonding where the hydroxyl groups of the polymer attach to the
 drug at the site of water binding, and inhibit its transformation to the
 dihydrate form.
 Carbamazepine exists in several polymorphic forms of anhydrous
 carbamazepine and also as two crystalline modifications of carbamazepine
 dihydrate. Anhydrous carbamazepine seen in FIG. 1A is practically
 insoluble in water and when suspended in water, it rapidly transforms into
 large crystals of carbamazepine dihydrate (FIG. 1B).
 As seen in FIG. 1A, anhydrous crystals are not homogeneous in size and some
 of them appear as aggregates. When carbamazepine crystals of FIG. 1A are
 suspended in water, they rapidly form large whisker-shaped crystals. These
 large whisker-shaped crystals are visible in FIG. 1B.
 The thermograms of the anhydrous carbamazepine form measured by
 differential scanning calorimetry (DSC) revealed that anhydrous
 carbamazepine was completely converted to dihydrate.
 The above discussed properties greatly affect carbamazepine utility as a
 pharmaceutical drug of choice for treatment of epilepsy and trigeminal
 neuralgia. Polymorphic forms and/or crystalline forms of carbamazepine
 change the physical and chemical properties, such as solubility of the
 drug, the drug bioavailability and its release from the formulations. In
 order to provide a formulation which assures a steady, continuous, linear,
 zero-order release rate, the polymeric matrix of specific properties was
 designed. The properties of various polymers on the release rate of
 carbamazepine were determined.
 Since the carbamazepine readily forms dihydrate crystals, the investigation
 of these crystal properties were undertaken wherein a conversion of
 carbamazepine into carbamazepine dihydrate was determined and influence of
 hydrophilic polymers on such conversion was investigated both in solutions
 or in the gel layer of hydrated tablets.
 For the below described studies, materials were obtained as follows.
 Carbamazepine was obtained from Taro, Herzliya, Israel. Carbamazepine
 derivatives are obtained as described in the EP 96110490.8 and EP
 97108465.2 applications, referenced above. Three viscosity grades of
 hydroxypropyl methylcellulose (HPMC), namely Methocel K100LV, Methocel K4M
 and Methocel K100M were obtained from Colorcon, Orpington, England. Sodium
 dodecyl sulfate (SDS) was purchased from BDH Poole, England.
 Carbamazepine (200 mg) was mixed with HPMC using a pestle and a mortar in
 ratio as indicated, and the erodible tablets were prepared.
 Cylindrical tablets were prepared by direct compression of
 carbamazepine-polymer blends, using a laboratory press fitted with a 10 mm
 flat-faced punch and die set, and applying a pressure of 567 MN/m.sup.2.
 All tablets contained 200 mg carbamazepine, unless otherwise indicated.
 The effect of HPMC on the crystal habit of carbamazepine was examined in
 formulating containing 50% Methocel K100LV, 50% Methocel K4M and/or 50%
 Methocel K100M.
 The dissolution rates of the tablets were monitored using a tablet
 dissolution tester (model 7ST Caleva, USA). The USP Basket Method I was
 used. Rotation speed was 100 rpm, and dissolution medium was 700 ml of 1%
 SDS aqueous solution (in order to provide sink conditions), maintained at
 37.degree. C. Carbamazepine levels were monitored at 288 nm
 spectrophotometrically using Uvikon 930 Kontron spectrophotometer,
 obtained from Kontron, Switzerland. Dissolution studies were performed in
 triplicate for each batch of tablets.
 Suspensions of carbamazepine (5% w/v) containing water or 1% SDS aqueous
 solution were shaken at 37.degree. C. with stirring (50 rpm). Samples from
 the sediment were taken after 1 day, dried at room temperature for 2 days,
 and analyzed by differential scanning calorimetry, X-ray powder
 diffraction and scanning electron microscopy (SEM). Carbamazepine
 anhydrous powder was analyzed using the same methods.
 Analysis of carbamazepine in HPMC solutions and in dry mixtures of HPMC was
 performed. Suspension of carbamazepine (5% w/v) containing 1% SDS aqueous
 solution with Methocel K4M at different concentrations, namely 0.5, 1, 2,
 5 and 10 mg,/ml were shaken for 1-7 days at 37.degree. C. with stirring
 (50 rpm). Samples from the sediment were taken, at various time intervals,
 dried at room temperature for 2 days and analyzed by DSC, X-ray powder
 diffraction and SEM.
 The degree of conversion of anhydrous carbamazepine to the dihydrate form,
 measured by DSC, was calculated according to the ratio obtained from the
 dehydration enthalpies of carbamazepine suspended in 1% SDS aqueous
 Methocel solution and 1% SDS aqueous solution without Methocel. Dry
 mixtures containing different ratios of HPMC (Methocel K4M) and
 carbamazepine were also analyzed by DSC in order to investigate the
 influence of HPMC on the polymorphic transformation of carbamazepine.
 Gel layers of the tablets were analyzed. Tablets were hydrated using the
 USP Basket Method I under the same conditions described in the dissolution
 studies. At various time intervals the tablets were removed from the
 baskets, the gel layer was scratched and dried at room temperature for at
 least 24 hours. The gel layer was analyzed by DSC, X-ray powder
 diffraction and scanning electron microscopy (SEM). Used analytical
 methods are described in Example 4.
 As discussed above, the release of the drug from large dihydrate crystals
 is unpredictable due to their changing chemical and physical properties,
 several alternative conditions affecting such conversion were investigated
 in suspensions and also in solid tablet forms.
 FIGS. 2A-F show the respective SEM photographs of carbamazepine crystals
 obtained after 1 and 7 days from HPMC solutions containing different
 concentrations, such as 1 mg, 5 mg or 10 mg/ml of HPMC. As seen in FIG. 2,
 HPMC has a significant influence on the morphology of the crystals. The
 crystals obtained from HPMC solutions appear to be amorphous. At a
 concentration of 1 mg/ml polymer, the precipitate is seen as an aggregate
 composed of small crystals. At higher concentrations of polymer the
 precipitate appears as an aggregate composed of smaller crystals adhering
 to larger ones. Even after 7 days the carbamazepine dihydrate crystals
 formed had a deformed structure compared with carbamazepine dihydrate
 solution without HPMC which was in the form of well-developed
 whisker-shaped crystals as seen in FIG. 1B.
 The X-ray diffraction patterns (data not shown) of carbamazepine crystals
 obtained from Methocel K4M solutions at HPMC concentrations of 1 and 10
 mg/ml after 1 day revealed an amorphous structure as indicated by the
 broader peaks compared with the strong reflections of carbamazepine
 anhydrous powder. The X-ray diffraction patterns of carbamazepine obtained
 from 1 mg/ml HPMC solution indicated that the sample consisted of a
 mixture of carbamazepine and carbamazepine dihydrate crystals while the
 crystals obtained from 10 mg/ml HPMC solutions contained solely the
 anhydrous form, thus supporting SEM results seen in FIGS. 2A and 2C.
 The DSC thermograph (data not shown) of HPMC Methocel K4M powder revealed a
 slight change in baseline at 145.degree. C., which is characteristic of
 the glass transition temperature. This transition could be detected more
 clearly at a low heating rate of 0.5.degree. C./min. A broad endothermic
 peak was observed at 0-100.degree. C. which is attributed to the water
 absorbed on the polymer. No indication of crystallinity was recorded in
 the thermogram. The polymer was therefore considered amorphous.
 Formulations containing Methocel K100LV and K100M, analyzed by SEM, DSC and
 X-ray, in the same way as described for Methocel K4M revealed the same
 behavior.
 Results are summarized in Tables 2 and 3.
 Table 2 shows the influence of Methocel K4M concentration on the degree of
 conversion of carbamazepine to carbamazepine dihydrate after 24 hours.
 TABLE 2
 Methocel K4M concentration Degree of Conversion
 (mg/ml) (%)
 0 100
 0.5 77.0
 1 23.1
 2 0
 5 0
 10 0
 Table 2 shows that after 24 hours at HPMC concentration of 2 mg/ml and
 higher, carbamazepine did not convert to dihydrate. At concentrations of 1
 mg/ml and lower, Methocel K4M inhibited the transformation to
 carbamazepine dihydrate only partially. The degree of conversion thus
 depended on Methocel K4M concentration. After 7 days, as seen in Table 3,
 carbamazepine was transformed completely to dihydrate at all examined
 concentrations.
 Table 3 shows degree of conversion of carbamazepine to carbamazepine
 dihydrate in solution containing 5 mg/ml Methocel K4M as a function of
 time.
 TABLE 3
 Time (days) Degree of conversion (%)
 1 0
 2 0.97
 3 8.8
 4 21.5
 7 100
 Table 3 shows that the transformation of carbamazepine to the dihydrate
 form is time-dependent.
 Similarly to the above described investigation performed in solutions of
 carbamazepine in the presence and absence of hydrophilic polymers, studies
 were performed to determine carbamazepine crystal properties in Methocel
 K4M/carbamazepine power mixture and in hydrated solid tablet forms.
 Results of these studies are seen in FIGS. 3 and 4.
 FIGS. 3A-E presents the DSC thermographs of dry mixtures of Methocel K4M
 and carbamazepine in different ratios of 0:100 (FIG. 3A), 20:80 (FIG. 3B),
 30:70 (FIG. 3C), 50:50 (FIG. 3D) and 80:20 (FIG. 3E). As seen in FIG. 3,
 carbamazepine exhibited a small endothermic peak at 170.4.degree. C. which
 is characteristic of the transition of the .beta.-form to the
 .alpha.-form. This transition occurs by solid-solid transformation. The
 increase of the endothermic peak at 170.4.degree. C. with increasing HPMC
 concentration in HPMC-carbamazepine mixtures indicates that HPMC alters
 the transformation mode of the .beta.-form to the .alpha.-form. The
 transition occurs by solid-liquid transformation, with a minimum at
 177.degree. C. and a decrease in the enthalpy of melting of the
 .alpha.-form at 192.5.degree. C. This decrease indicates that part of the
 .beta.-form melted at 177.degree. C. and did not convert to the
 .alpha.-form. The endothermic peak at 177.degree. C. was dependent on HPMC
 concentration in the mixture. Only a fraction of the .beta.-form converted
 to the .alpha. form by solid-solid transformation, and melted at
 192.5.degree. C. This explains the decrease in the enthalpy of melting at
 192.5.degree. C. The broad peak that appears at 20-100.degree. C. is
 related to the water adsorbed to the polymer.
 FIGS. 4A and 4B present the DSC thermograms of samples obtained from the
 gel layer of the hydrated tablets containing 50% polymer after 6 and 20
 hours. As seen in FIG. 4, in the gel layer of hydrated tablets the
 transformation of carbamazepine to the dihydrate form is inhibited. Such
 inhibition is indicated by the broad peak that appears at 20-100.degree.
 C. The broad peak is attributed to water absorbed to the polymer and not
 to the dehydration of carbamazepine dihydrate which appears as a sharp
 peak with minimum at 80.degree. C.
 As seen from the DSC analysis shown in FIGS. 4A and 4B, HPMC inhibited the
 transformation of carbamazepine to carbamazepine dihydrate in the gel
 layer. The broad peak obtained at 20-100.degree. C. is related to water
 adsorbed to the polymer and not to the carbamazepine dihydrate form which
 is characterized by a sharp peak at 80.degree. C. The increase of the
 endothermic peak at 178.degree. C. is related to the influence of HPMC on
 the polymorphic transition of the .beta.-form to the .alpha.-form which
 induces solid-liquid transformation. The X-ray patterns of carbamazepine
 in the gel layer had peak reflections similar to the X-ray pattern of
 anhydrous carbamazepine, further supporting the conclusion that HPMC
 inhibits the transformation of carbamazepine to carbamazepine dihydrate in
 the gel layer. The X-ray diffraction of the gels reveals that HPMC induces
 amorphism of carbamazepine. The broad peaks obtained compared with the
 X-ray patterns of anhydrous carbamazepine crystals and
 50:50/HPMC:carbamazepine physical mixture, points to a change in the
 crystallinity of carbamazepine with the formation of less ordered
 structure and amorphous appearance.
 The above results are further supported by the SEM photographs of
 carbamazepine crystals in the gel layer seen in FIG. 5 which reveal
 spherulite morphology with less organized crystal structures and amorphous
 appearance.
 FIG. 5 presents the corresponding SEM photographs to thermograms seen in
 FIGS. 4A and 4B, obtained after 6 hours of hydration of carbamazepine
 (FIG. 5A). As seen in FIG. 5A, carbamazepine in the gel had transformed to
 an amorphous form. Tablets hydrated for 20 hours showed the same behavior,
 as seen in FIG. 5B.
 FIGS. 6A-E present the respective X-ray diffraction patterns of the gel
 samples compared with carbamazepine powder, Methocel K4M powder, and 50:50
 polymer-drug physical
 The DSC, X-ray and SEM results (FIGS. 4, 5, and 6), both in solution and in
 the tablet gel layer, indicate an interaction between carbamazepine and
 the polymer. These results are also supported by the DSC results of
 carbamazepine-HPMC dry mixtures.
 From the above described results, it is clear that hydrophilic polymers,
 such as HPMC, inhibit the transformation of carbamazepine to carbamazepine
 dihydrate in the gel layer, participate in its crystallization process and
 induce carbamazepine amorphism. The polymer herein may serve as a template
 or microsubstrate for nucleation in the crystallization process. The
 interaction between the drug and polymer appears to occur by hydrogen
 bonding. The hydroxyl groups of the polymer apparently attach to the drug
 at the site of water binding, and thus its transformation to the dihydrate
 form in inhibited.
 The crystalliztion process which occurs at the gel layer is of major
 importance when dealing with absorption characteristics of the drug since
 differences in properties of polymorph, crystallinity and solubility
 affects the release and bioavailablility of the drug. Since HPMC induces
 amorphism of the drug and inhibits its transformation to the dihydrate
 form, it also affects its solubility in water or other media because
 amorphous crystals dissolve faster than highly crystalline ones. In the
 process of the invention, the bioavailablility of the drugs is improved
 and the continuous and linear zero-order release kinetics is assured.
 III. Effect of Various Conditions on Carbamazepine Dissolution Rate
 Effect of various conditions such as HPMC concentration, viscosity grade of
 the polymer, additives, rotations speed of baskets, incorporation of PEG
 4,000, PEG 20,000 and NaCl to the matrix, SDS concentration in the
 dissolution medium, etc., on release rate of carbamazepine from the
 tablets was also investigated. Results are described in FIGS. 7-15.
 A. The Effect of HPMC Concentration on Drug Release Rate from the Matrix
 and on the Dissolution Rate
 Matrices containing Methocel K4M and carbamazepine were prepared as
 described above and in Example 2 for preparation of tablets. The polymer
 concentrations in the matrix were 10-80% w/w.
 Results which are seen in FIG. 7 show that increasing the concentration of
 Methocel K4M in the tablets decreased the release rate of carbamazepine
 from the matrix.
 The increasing concentration of Methocel increased the viscosity and
 strength of the gel layer formed and thereby decreased the erosion rate of
 the tablets. Drug release from the matrix followed zero-order release
 kinetics in the concentration ranges 20-80% Methocel K4M. In a formulation
 containing 10% Methocel K4M, the tablet disintegrated relatively fast
 because of the formation of noncontinuous gel layer. A formulation
 containing 20% Methocel K4M provided an initial small burst effect
 followed by zero order kinetics.
 This study shows and confirms that by changing the amount of the HPMC in
 the matrix, the drug delivery is conveniently engineered to release the
 drug in zero-linear release kinetics. As seen in FIG. 7, for example when
 the 60% release of the drug is desired within 6 hours, 30% concentration
 of the HPMC K4M is conveniently used. When the lower amount, such as 30%
 of the drug is to be released in 6 hours, the 50% concentration of the
 HPMC K4M is selected. When the really slow release of the drug is desired,
 then the composition of the tablet contains 80% of the HPMC K4M.
 B. The Effect of Viscosity Grade of HPMC on the Drug Release Rate from
 Matrix and on the Dissolution Rate
 Matrices containing carbamazepine and HPMC of various viscosity
 grades--Methocel K100LV, Methocel K4M, Methocel K15M and Methocel K100M
 were prepared as described in Example 2 for preparation of tablets. Two
 concentrations of the polymer in the matrix were examined, namely 30%
 (w/w) and 50% (w/w). In matrices containing 30% polymer, lower viscosity
 grades of Methocel, such as Methocel E15 and Methocel E5 were also
 examined.
 Results are seen in FIGS. 8 and 9. These figures show that carbamazepine
 release rate from matrices containing Methocel K100LV, a lower viscosity
 grade of Methocel, was higher than matrices containing Methocel K4M, K15M
 and K100M.
 As seen in FIG. 8, Methocel K100LV (50%) released about 60% of the drug
 within 6 hours. Carbamazepine release rate was similar from matrices
 containing 50% Methocel K4M, K15M and K100M.
 FIG. 9 shows that when the concentrations of the polymer is lowered to 30%,
 its viscosity plays a role in the release rate. Lower viscosity grades of
 Methocel, such as Methocel E15 and Methocel E5, in 30% concentration did
 show a higher release than those of having a higher viscosity. Drug
 release from formulations containing the lower viscosity grade of Methocel
 E5 was the highest, reaching 100% release in 3 hours. Carbamazepine
 release rate from formulation containing 30% of high viscosity Methocel
 K100M was slower compared to carbamazepine release from lower viscosity
 grades of Methocel.
 Carbamazepine release rate from the various viscosity grades was by
 zero-order kinetics.
 These results support finding that the formulation and the method of the
 invention are successful in achieving the sustained zero-order release of
 which rate can be controlled by proper selection of the polymer and its
 viscosity.
 C. The effect of Incorporation of Additives on Carbamazepine Release Rate
 Additives NaCl, PEG 4,000 and PEG 20,000, were sieved through 60 mesh sieve
 and incorporated into the matrix tablet at concentration of 20% w/w at the
 expense of the polymer. For these studies, the drug concentration in the
 matrix was 50%. Tablets containing 30% Methocel K4M, where the total
 tablet weight was 0.4 g, were also prepared for comparison. The
 dissolution rate from the matrices was examined as described above in
 section II.
 The incorporation of 20% NaCl, PEG 20,000 or PEG 4,000 into the matrix
 tablets increased the release rate of carbamazepine in comparison to
 formulations containing 50% Methocel K4M or 30% Methocel K4M.
 As seen in FIG. 10, there was a slight difference in the release rate from
 the matrices containing the additives. Carbamazepine release rate from
 tablets containing 20% NaCl was the highest. The incorporation of 20% PEG
 4,000 or PEG 20,000 to the matrices caused softening of the tablets when
 hydrated.
 In all these instances, carbamazepine release from the different
 formulations was by zero-order release kinetics.
 This study shows that by adding certain pharmaceutically acceptable
 additives to the polymer matrix, the release rate can be affected.
 D. The Effect of Rotation Speed of the Baskets on the Release Rate
 The dissolution rate of matrices containing 40% Methocel K4M were examined
 using 50, 100 and 200 rpm rotations.
 Results are seen in FIG. 11. Increasing the rotation rate of the baskets
 from 50 to 200 rpm increased the release rate of carbamazepine from the
 matrix. The reason for the faster release in the case of higher rotation
 speed appears to lie in the increase rate of matrix dissolution.
 As seen in FIG. 11, the highest release of the drug was achieved when 200
 rpm rotation speed was used. Carbamazepine release was examined by
 zero-order kinetics for the different hydrodynamic conditions.
 This study shows that the release of the drug from the formulation is
 affected by hydrodynamic conditions.
 E. The Effect of the Medium Composition on Drug Release Rate from the
 Matrix
 The dissolution rate from matrices containing 40% Methocel K4M were
 examined in medium containing 0.5% SDS and 1% SDS in water.
 Results are seen in FIG. 12. As seen in FIG. 12, carbamazepine release
 rates were similar in medium containing 1% SDS in water and 0.5% in water.
 The drug solubility in medium containing 1% SDS in water (3.3 mg/ml) was
 significantly higher than its solubility in medium of 0.5% SDS in water
 (1.468 mg/ml).
 This shows that drug release from the matrix occurs by erosion of the
 tablet and the contribution of diffusion to the release mechanism can be
 neglected.
 F. Carbamazepine Release from Matrix Tablets Based on HPMC Containing 400
 mg and 600 mg Carbamazepine
 Matrix tablets containing 400 mg carbamazepine and 30% Methocel K4M were
 prepared as described. Tablet diameter was 12 mm. Drug release from the
 matrix was examined as described in Example 3.
 Matrix tablets containing 600 mg carbamazepine and 30% Methocel K100LV were
 prepared similarly. Tablet diameter was 15 mm. Drug release from the
 matrix was examined as described in Example 3.
 Carbamazepine release from the formulation containing 400 mg and 600 mg was
 by zero-order kinetics as presented in FIGS. 13-15.
 As seen in FIG. 13, the polymer comprising 30% of the Methocel K4M
 containing 400 mg of carbamazepine released more than 60%, that is about
 240 mg of drug in 8 hours.
 As seen in FIG. 14, the polymer K4M (30%) containing 600 mg of the drug was
 able to release 60% (360 mg) of 600 mg of drug in 8 hours.
 As seen in FIG. 15, release of the drug (600 mg) was further enhanced by
 formulating the drug in 30% K100LV, low viscosity polymer resulting in
 about 80% release of the carbamazepine, that is, about 480 mg of drug was
 released in 8 hours.
 These studies further show that the release-rate depends on the amount of
 the drug within the polymer as well as on the selected polymer and on its
 properties and that all these parameters may be advantageously utilized to
 prepare oral formulations of the drug where the amount of the drug is
 released in a continuous and sustained manner in zero-order release rate.
 G. Erosion Studies
 The erosion of matrices containing 30%, 40% and 50% Methocel K4M and 30% of
 Methocel K100LV were studied. Tablet erosion tests were performed using
 USP I Basket Method at the same conditions described in dissolution
 studies. At various times intervals the tablets were removed from the
 baskets and dried for at least 24 hours at 37.degree. C. until a constant
 weight was obtained. The percentage of tablet eroded was calculated from
 the weight loss of the tablets.
 Carbamazepine release rate from the different formulations examined
 followed the rate of matrix dissolution. This shows that drug release is
 controlled solely by erosion of the tablet.
 H. The Influence of HPMC on the Crystal Morphology and Structure of
 Carbamazepine in the Gel Layer
 Tablets containing 50% carbamazepine and 50% Methocel K4M were prepared and
 hydrated in medium containing 1% SDS in water, using tablet dissolution
 tester at the same conditions used for measurements of the release rate of
 the drug.
 At various time intervals the tablets were removed and the gel layer was
 peeled, dried at room temperature and analyzed by DSC, X-ray and SEM. For
 comparison, a suspension containing carbamazepine in 1% SDS water solution
 was prepared and the crystals obtained were analyzed by DSC, X-ray and
 SEM.
 Analysis of carbamazepine in the gel layer by DSC, X-ray and SEM revealed
 that the HPMC inhibits the transformation of carbamazepine to
 carbamazepine dihydrate and that carbamazepine in the gel layer becomes
 more amorphic. This shows that HPMC interacts with carbamazepine,
 participates in its crystallization and changes its crystal morphology.
 UTILITY
 The invention is useful for efficacious and controlled oral delivery of
 carbamazepine or its derivatives having low water solubility. The drug
 delivery system has the ability to release the drug from the erodible
 tablet in zero-order release kinetics.
 The delivery system of the invention is useful for delivery of accurate and
 continuous amounts of the drug where such delivery can be designed by
 changing the viscosity of the polymer, drug concentration or by other
 variables described above.
 EXAMPLE 1
 Assay of the Active Agent
 This example describes assay for determination of concentrations of the
 active agent.
 Carbamazepine concentrations were determined spectrophotometrically at 288
 nm in 1% sodium dodecyl sulfate (SDS) in water. This medium was selected
 since it enhances significantly the solubility of the drug. The
 concentrations were determined from a suitable calibration curve.
 EXAMPLE 2
 Preparation of Erodible Tablets
 This example describes process used for preparation of carbamazepine
 erodible tablets.
 Carbamazepine (200/mg) and HPMC in different amounts were thoroughly mixed
 using a pestle and a mortar to produce different HPMC/carbamazepine
 ratios. All tablets contained 200 mg carbamazepine unless otherwise
 stated.
 Cylindrical tablets were prepared by direct compression of drug-polymer
 blends using a laboratory press fitted with a 10 mm (or 12 mm) flat-faced
 punch and die set applying a 5 ton force.
 When NaCl, PEG 4,000 or PEG 20,000 were incorporated into the dry matrix,
 they were sieved through a 60 mesh sieve and thoroughly mixed with the
 drug and polymer using a pestle and mortar.
 Hydroxypropyl methylcellulose (HPMC) was added in an amount from 0-99% per
 tablet (% wt/wt) as indicated in FIGS. 7-12.
 EXAMPLE 3
 Dissolution Rate Studies
 This example describes a process used in dissolution rate studies.
 The dissolution rate from the tablets were monitored using tablet
 dissolution tester (model 7st, Caleva, USA). The USP I Basket Method was
 used, rotating at 100 rpm in 700 ml medium containing 1% SDS in water
 maintained at 37.degree. C. The drug levels were monitored
 spectrophotometrically (Uvicone 930 Kontron spectrophotometer,
 Switzerland). Dissolution rate studies were performed in triplicate for
 each batch of tablets.
 EXAMPLE 4
 Analytical Methods
 This example describes analytical methods and equipment used in the studies
 leading to the invention.
 Differential Scanning Calorimetry
 The thermal analysis of the samples was performed using a Differential
 Scanning Calorimeter (DSC, Mettler TA4000 with measuring cell DSC 30E,
 Switzerland). Samples were measured into aluminum pans. Lids were crimped
 and holes were made in lids in order to allow dehydration of samples. The
 thermal behavior of the samples was studied under nitrogen purge at
 heating rates of 10.degree. C. min.sup.-1 over a temperature range of
 0.degree. C. to 250.degree. C. When the glass transition temperature of
 HPMC was examined the heating rate was 0.5.degree. C. min.sup.-1.
 X-Ray Diffraction
 X-ray powder diffraction of the samples was recorded by Philips automated
 diffractometer using Cu-K .alpha. radiation (40 kV, 35 mA) at a scanning
 rate of 0.5.degree. per 20 min.sup.-1.
 Scanning Electron Microscopy
 Samples of hydrated tablets were sliced across the gel layer. The samples
 were washed and then treated with increasing concentration of ethanol, 5
 minutes at each concentration, for dehydration. In order to complete the
 dehydration the samples were transferred in solution of freon 113:ethanol
 with increasing concentrations of freon (25, 50, 75, 100%). The samples
 with 100% freon were incubated in the hood for 0.5 hour. The
 cross-sectioned tablets were mounted on stubs and coated with a polaron
 sputter coater, Model E5100. The film thickness obtained was approximately
 75 .ANG.. Scanning electron photomicrographs were recorded using a Philips
 505 SEM, applying voltage of 20 V. Samples of powders were coated and
 analyzed under the same conditions described for the hydrated tablets.