Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2001-09-28
2003-12-23
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S451000, C424S464000, C424S485000, C424S486000, C424S487000
Reexamination Certificate
active
06667060
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a National Stage application under 35 U.S.C. 371 of Application No. PCT/EP00/02620 filed Mar. 24, 2000, which claims priority from EP 99201018.1, filed Mar. 31, 1999.
The present invention concerns the use of pregelatinized starch to prevent dose-dumping from a hydrophilic controlled release formulation. It also concerns a hydrophilic controlled release formulation, more in particular a hydrophilic controlled release matrix formulation, and solid dosage forms prepared therefrom, preferably for once daily oral administration. The hydrophilic controlled release formulation comprises pregelatinized starch, one or more active ingredients, one or more viscous hydrophilic polymers and optionally pharmaceutically acceptable formulating agents. Preferred hydrophilic polymers include hydroxypropyl cellulose and hydroxypropyl methylcellulose.
WO 96/14070 discloses an extended release formulation for oral administration comprising cisapride-(L)-tartrate as the active ingredient embedded in a matrix of two hydrophilic viscous polymers, in particular hydroxypropyl cellulose and hydroxypropyl methylcellulose. These hydrophilic polymers swell upon contact with water, thereby forming a gellayer from which the active ingredient is gradually released.
WO 97/24109 describes bioadhesive pharmaceutical compositions and solid dosage forms prepared therefrom, which comprise a pharmaceutically effective amount of an active ingredient, from 80% to 98% (w/w) pregelatinized starch incorporated in the composition as a bioadhesive polymer, and from 1% to 10% (w/w) of a hydrophilic matrix forming polymer. Said dosage forms have a regular and prolonged release pattern for a locally acting ingredient or also for a systemically acting drug, and they are suitable for oral, nasal, rectal and vaginal administration.
EP 0299877 concerns a tablet containing salbutamol or a derivative thereof homogeneously dispersed in a hydrophilic matrix comprising at least one high molecular weight cellulose hydrocolloid as swelling agent, in particular hydroxypropyl methylcellulose 15 Pa.s, and a diluent, in which said diluent comprises one intrinsic diluent and one thickening diluent, in particular pregelatinized maize starch.
EP 0280613 describes a tablet comprising a homogeneous dispersion of dihydroergotamine or one of its derivatives in a water-soluble matrix comprising one or more water-soluble polymeric substances, in particular hydroxypropyl methylcellulose, and a diluent comprising at least one starch derivative, in particular pregelatinized maize starch.
EP 0477061 claims a sustained-release tablet comprising isosorbide 5-mononitrate in homogeneous dispersion in a hydrophilic matrix based on at least one swelling component, in particular hydroxypropyl methylcellulose, and at least one diluent. The latter contains at least one intrinsic diluent and one thickening diluent chosen from polymers such as starch and starch derivatives.
GB 2,195,893 describes a sustained release pharmaceutical composition comprising a pharmacologically active agent in admixture with a) microcristalline cellulose and b) hydroxypropyl methylcellulose wherein the weight ratio of a) to b) is at least 1 to 1, with the proviso that when the active ingredient is other than acetyl salicylic acid in free form or salt form, the active agent is also in admixture with pregelatinized starch.
WO 97/04752 describes a pharmaceutical composition for oral administration of conjugated estrogens. Said conjugated estrogens are coated onto one or more organic excipients comprising hydroxypropyl methylcellulose and pregelatinized starch, the latter being present as a suitable binder.
Controlled release pharmaceutical preparations regulate the release of the incorporated active ingredient or ingredients over time and comprise preparations with a prolonged, a sustained, a slow, a continuous, a retarded or an extended release, so they accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions or promptly dissolving dosage forms. Controlled release of active ingredient(s) allows to simplify the patient's posological scheme by reducing the amount of recommended daily intakes and improves patient's compliance. One should not underestimate the positive psychological effect towards the patient of a once daily intake instead of a twice or multiple daily intake.
A controlled release of active ingredient(s) from a pharmaceutical preparation may be accomplished by homogeneously embedding said active ingredient(s) in a hydrophilic matrix, being a soluble, partially soluble or insoluble network of viscous, hydrophilic polymers, held together by physical or chemical entanglements, by ionic or crystalline interactions, by complex formation, by hydrogen bonds or van der Waals forces. Said hydrophilic matrix swells upon contact with water, thereby creating a protective gellayer from which the active ingredient(s) is (are) slowly, gradually, continuously released in time either by diffusion through the polymeric network, by erosion of the gellayer, by dissolution of the polymer, or by a combination of said release mechanisms. Commonly used hydrophilic polymers for the preparation of controlled release matrices comprise polysaccharides, polyacrylates, and polyalkylene oxides.
An effective oral controlled release preparation, especially a once or twice daily controlled release preparation, preferably retains its pharmacokinetic release profile along its way through the gastro-intestinal tract so as to avoid undesirable fluctuations in drug plasma concentrations or complete dose-dumping. This implies that a controlled release preparation preferably has to provide a controlled release profile and in particular has to avoid dose-dumping in media of varying ionic strength since the gastro-intestinal luminal content exhibits varying values of ionic strength in different regions of the gastro-intestinal tract.
When administering a controlled release preparation to patients in the fed state, food related dose-dumping may be encountered. The problem of food related dose-dumping in fed patients can be attributed to a lot of factors. One of these factors is surely the mechanical forces that are exerted by the stomach on its content and thus on an ingested preparation. Another factor appears to be the ionic strength of the gastro-intestinal juices. Since the ionic strength values encountered in the gastro-intestinal tract vary not only with the region of the tract, but also with the intake of food, a controlled release formulation preferably also has to provide a controlled release profile and in particular has to avoid dose-dumping regardless whether the patient is in fasted or fed conditions. The ionic strength of the gastro-intestinal fluids may range from about 0.01 to about 0.2 (Johnson et al., 1993, Int. J. Pharm., 90, 151-159).
The ionic strength, mostly represented by the symbol &mgr; (sometimes I), is a characteristic of a solution and is defined as
μ
=
1
/
2
∑
i
c
i
·
Z
i
2
wherein c
i
is the molar concentration of the ith ion, Z
i
is its charge, and the summation extends over all the ions in solution (Martin, A., 1993, Physical Pharmacy, Williams & Wilkins, pp 134-135). The ionic strength is thus a property of the solution and not of any particular ion in the solution. The ionic strength is known to constitute a good measure of the non-ideality imposed by all the ions of a solution on the ions produced by a given electrolyte in the solution.
The effect of the ionic strength of the surrounding medium on the disintegration, gelation and viscosity of hydrophilic matrices is described in the literature.
Mitchell et al. (Pharmaceutical Technology. Controlled drug release, vol.2, by Wells, J. I., Rubinstein, M. H. (Eds.), Ellis Horwood Limited, pp. 23-33, 1991) disclose the effect of electrolytes on the disintegration and gelation of hydroxypropyl methylcellulose (HPMC) K15M matrix tablets. At low ionic strength of the surrounding m
Jans Eugene Marie Jozef
Vandecruys Roger Petrus Gerebern
Appollina Mary
Janssen Pharmaceutica N.V.
Young Micah-Paul
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