Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-07-31
2004-05-11
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S468000, C424S469000, C424S470000, C424S484000, C424S488000
Reexamination Certificate
active
06733782
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a matrix tablet that enables the prolonged release of gliclazide, the release being insensitive to variations in the pH of the dissolution medium, and that ensures regular and continuous blood levels after absorption of the galenic form by the oral route.
PRIOR ART OF THE INVENTION
Gliclazide, a compound of formula (I):
is a sulphonylurea compound having an antidiabetic property at the doses usually administered to humans.
Gliclazide has hitherto been administered by the oral route in the form of tablets containing a dose of 80 mg. The usual average prescription is two tablets per day in two administrations, but may vary from 1 to 4 tablets per day in several administrations depending upon the severity of the diabetes.
One of the aims of the present invention was to obtain an oral form that can be administered in a single daily administration. On the one hand this makes it easier for the patient to use and, on the other hand, it enables better compliance with the treatment.
Another aim of the invention was that the oral form should have prolonged release. Indeed, in certain patients an immediate-release form can result in high short-term concentrations in the blood. A prolonged-release form makes it possible for such peaks in the blood to be avoided and enables a consistent concentration in the blood to be obtained in humans. This makes it possible to reduce the undesirable effects that may occur as a result of the “peak effect”, which are accompanied by hydroelectrolytic- and metabolic-type disorders associated with variations in the plasma levels of the active ingredient.
The main aim of the invention was to obtain an oral form in which the rate of release of the active ingredient is controlled and reproducible. In fact, in the current form the dissolution of the active ingredient varies greatly according to pH. This characteristic, associated with gliclazide itself, poses absorption problems for the active ingredient. The phenomenon of the solubility of the active ingredient varying according to pH is shown in
FIG. 1
(attached). The solubility is very weak at acid pHs and increases as pH rises.
It was thus important, for this active ingredient, to develop a new galenic form that makes possible gliclazide release that is independent of the pH of the dissolution medium.
DISCLOSURE OF THE INVENTION
More especially, the present invention describes a hydrophilic matrix that can be administered by the oral route and that enables prolonged and controlled release of the active ingredient, gliclazide, without the pH influencing the in vitro dissolution kinetics of the said matrix.
That form for the prolonged release of gliclazide, for use in the treatment of diabetes, makes it possible to provide more consistent plasma levels and smaller C
max
-C
min
variations. The rate of release must be reproducible and must be correlated with blood concentrations observed after administration.
Among the mechanisms that can be used to control the diffusion of a soluble active ingredient one principal mechanism may be selected, that being the diffusion of the active ingredient through a gel formed after the swelling of a hydrophilic polymer placed in contact with the dissolution liquid (in vitro) or with gastro-intestinal fluid (in vivo).
Many polymers have been described as being capable of enabling such a gel to be formed. The main polymers are cellulose compounds, especially cellulose ethers, such as hydroxypropyl cellulose, hydroxyethylcellulose, methylcellulose and hydroxypropyl methylcellulose and, among the various commercial grades of those ethers, those of relatively high viscosity. It should be noted that the systems described do not have the theoretical possibility of allowing a zero order to be obtained in the release kinetics equation.
The production processes currently used for the production of such matrix tablets are either direct compression, after mixing the various excipients and the active ingredient(s), or wet granulation.
The gliclazide matrix tablet described in the present invention combines in a novel manner at least one cellulose polymer compound and a glucose syrup (maize starch hydrolysate), enabling release of the active ingredient that is perfectly prolonged and controlled.
The controlled release is linear for a period of more than eight hours and is such that 50% of the total amount of gliclazide has been released between 4 and 6 hours after administration. Moreover, the matrix tablet according to the invention enables prolonged release of gliclazide that results in humans in blood levels of from 400 to 700 ng/ml 12 hours at most after a single administration by the oral route of a tablet containing a dose of 30 mg of gliclazide, and in blood levels of from 250 to 1000 ng/ml after a daily administration of a tablet containing a dose of 30 mg of gliclazide.
The unit dosage may vary according to the age and weight of the patient and the nature and severity of the diabetes. It generally ranges from 30 to 120 mg, in a single administration, for a daily treatment. The percentage of gliclazide in the matrix tablet is from 12 to 40% of the total weight of the tablet. According to an advantageous embodiment of the invention, the said tablet contains a dose of 60 mg of gliclazide. An especially preferred embodiment of the invention is the provision of tablets containing a dose of 30 mg of gliclazide. In those very advantageous examples of the invention, the unit dosage, which ranges from 30 to 120 mg, for a single daily administration, corresponds to the absorption of from 1 to 4 tablets containing a dose of 30 mg or of 1 or 2 tablets containing a dose of 60 mg. The matrix tablet as described by the Applicant on the one hand makes it possible to have an oral form that can be administered in a single daily administration and, on the other hand, surprisingly and especially advantageously, makes it possible to reduce the amount of active ingredient in each tablet without the plasma concentrations of gliclazide being modified or altered. The formulation hitherto in existence contained a dose of 80 mg of gliclazide.
The specific combination of the compounds described above also, surprisingly, makes it possible for the in vitro dissolution kinetics of the said matrix to be unaffected by the pH although the solubility of the active ingredient varies according to that same pH. This point is illustrated by
FIG. 2
(attached), which shows that a matrix as formulated is insensitive to variations in pH over a range of from 6.2 to 7.4 occurring in the intestinal environment. Thus, within a pH range of from 6 to 8 corresponding to the rising part of the curve shown in
FIG. 1
(attached), it can be seen that the release profile of the active ingredient at between 0 and 12 hours is the same, irrespective of the pH of the dissolution medium of the matrix tablet containing the said active ingredient.
Thus, by the characteristic combination of at least one cellulose polymer compound and a glucose syrup, the Applicant has created a hydrophilic matrix that is innovative in terms of both its composition and its function since, in particular, it enables the active ingredient that it contains, gliclazide, to be released in a prolonged and controlled manner, irrespective of the pH conditions of the dissolution medium.
The cellulose polymer compound used in that hydrophilic matrix is a high-viscosity cellulose either. Advantageously, the cellulose ether is a hydroxypropyl methylcellulose, preferably a mixture of two hydroxypropyl methylcelluloses of different viscosity. The other compound in the composition of the said matrix is a glucose syrup and, advantageously, maltodextrin is used, which is a glucose syrup having an equivalent degree of dextrose (ED) of from 1 to 20. The combination of those two types of compounds on the one hand enables a formulation to be obtained in which the release profile of the active ingredient is insensitive to variations in the pH of the dissolution medium and, on the other hand, enables perfect control of t
De Barochez Bruno Huet
Martin Louis
Wuthrich Patrick
Les Laboratories Servier
Page Thurman K.
Sheikh Humera N.
The Firm of Hueschen and Sage
LandOfFree
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