Title of Invention

MATRIX TABLET FOR THE PROLONGED RELEASE OF GLICLAZIDE AND PROCESS FOR THE PREPARATION THEREOF

Abstract The invention concerns a core tablet for the controlled release of gliclazide which ensures continuous and constant release of the active principle, unaffected by the dissolving medium pH variations, after oral administration.
Full Text FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
&
THE PATENTS (AMENDMENT) RULES 2006
COMPLETE SPECIFICATION
[See Section 10; rule 13]
"MATRIX TABLET FOR THE PROLONGED RELEASE OF GLICLAZIDE AND PROCESS FOR THE PREPARATION
THEREOF"
LES LABORATOIRES SERVIER, of 1 rue Carle Hebert, 92415 Courbevoie Cedex, France,

The following specification particularly describes the nature of the invention and the manner in which it is to be performed:-


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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
5 the solubility of the active ingredient varying according to pH is shown in Figure 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.
More especially, the present invention describes a hydrophilic matrix that can be
10 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 Cmax-Cmin
15 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
20 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
25 relatively high viscosity. It should be noted that the systems described do not have the
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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
5 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%
10 of the total amount of gliclazide has been released between 4 and 6 hours. Moreoever, 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
15 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
20 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
25 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
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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
5 although the solubility of the active ingredient varies according to that same pH. This point
is illustrated by Figure 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 Figure 1 (attached), it can be seen that the release profile of the active ingredient at
10 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
15 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 ether. Advantageously, the cellulose ether is a hydroxypropyl methylcellulose, preferably a mixture of two hydroxypropyl methylcelluloses of different viscosity. The
20 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
25 medium and, on the other hand, enables perfect control of the release kinetics to be
obtained. The percentage of cellulose polymer compound is from 10 to 40 % of the total weight of the tablet and, according to an especially advantageous embodiment, from 16 to 26 % of the total weight of the tablet. The percentage of glucose syrup is from 2 to 20 % of


5
the total weight of the tablet and, preferably, from 4 to 10 % of the total weight of the tablet.
Various excipients can also be added to complete the formulation. Among the
conventionally used diluents, preference is given to the use of calcium hydrogen phosphate
5 dihydrate, which enables improved granule fluidity and improved granule compressibility
to be obtained. Moreover, calcium hydrogen phosphate dihydrate is able to slow down the
dissolution kinetics, that characteristic making it possible to use smaller amounts of
hydroxypropyl methylcellulose to control the dissolution profile of the active ingredient.
The percentage of calcium hydrogen phosphate dihydrate is from 35 to 75 % of the total
10 weight of the tablet, preferably from 45 to 60 % of the total weight of the tablet. Among
the lubricants there may be mentioned by way of example magnesium stearate, stearic acid, glycerol behenate and sodium benzoate and, among the flow agents, preference is given to the use of anhydrous colloidal silica.
The present invention relates also to the preparation of the matrix tablet. Wet granulation is
15 carried out by mixing the active ingredient, glucose syrup and calcium hydrogen phosphate
dihydrate, and then wetting the mixture. This first step enables the creation around the
active ingredient of a hydrophilic environment that promotes its good dissolution, and also
enables the provision of a unit dose that is as consistent as possible. In a"second step, the
granulate obtained above is mixed with the cellulose ether. If desired, the cellulose ether
20 can be granulated directly with the active ingredient in the first step. The mixture is then
lubricated by the addition of colloidal silica and magnesium stearate. The final lubricated compound is then compressed.
The following Examples illustrate the invention but do not limit it in any way.
The preparation of prolonged-release tablets that can be administered by the oral route is
25 carried out according to the following production process :


6

Mixture of gliclazide, maltodextrin and calcium hydrogen phosphate dihydrate, followed by wetting of that mixture with purified water. The resulting wet mass is then granulated, dried and subsequently classified to obtain a granulate having physical characteristics that 5 enable good filling of the moulds of a rapid-compression machine.
Mixture of the granulate obtained in Step A with hydroxypropyl methylcellulose.
SXEZJ2:
Lubrication of the mixture obtained in Step B with colloidal silica and magnesium stearate.
10 &XEEJ2:
Compression of the lubricated mixture obtained in Step C using a rotary compression machine to obtain tablets having a hardness, measured by diametric crushing, of about from 6 to 10 daN.
EXAMELEJL:
15 Example 1 shows the influence of maltodextrin on the in vitro release kinetics. The amount
of maltodextrin ranges from 7.5 tol5 mg per tablet, thus constituting from 4 to 10 % of the total weight of the tablet. The amount of hydroxypropyl methylcellulose remains constant and the amount of diluent, calcium hydrogen phosphate dihydrate, is adjusted to obtain tablets having a constant weight of 160 mg. Production is carried out according to the
20 procedure described in Steps A to D.


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Table 1 : Unit formulation of the tablets (in mg per tablet) and characteristics

Batches
Constituents LP1 LP 2
Gliclazide 30 30
Calcium hydrogen phosphate dihydrate 87.4 79.9
Maltodextrin (*) 7.5 15
Hydroxypropyl methylcellulose 34 34
Magnesium stearate 0.8 0.8
Colloidal silica 0.32 0.32
Final weight 160 160
Active ingredient dissolved at 8 h (%) 73 84
(*) the amount of maltodextrin corresponds to 6 or 12 % of the amount of granulated
5 material (active ingredient + calcium hydrogen phosphate dihydrate + maltodextrin).
Figure 3 represents the curves for the dissolution kinetics of the two formulations used.

0 2 4 6 8 10 12
Time (hours)
Figure 3 : In vitro dissolution kinetics of batches LP1 and LP2


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The amount of maltodextrin, at a constant hydroxypropyl methylcellulose weight, influences the release of the active ingredient for a period of more than 4 hours. The dissolution curve is linearised by increasing the amount of maltodextrin.
EXAMPLE 2:
5 Example 2 shows the influence of hydroxypropyl methylcellulose on the in vitro release
kinetics. The amount of hydroxypropyl methylcellulose ranges from 26 to 42 mg, thus constituting from 16 to 26 % of the total weight of the tablet. Production is carried out according to the procedure described in Steps A to D.
Table 2 : Unit formulation of the tablets (in mg per tablet)

Batches
Constituents LP3 LP4
Gliclazide 30 30
Calcium hydrogen phosphate dihydrate 79.87 94.91
Maltodextrin (*) 7.01 7.97
Hydroxypropyl methylcellulose 42 26
Magnesium stearate 0.8 0.8
Colloidal silica 0.32 0.32
Final weight 160 160
Active ingredient dissolved at 4 h (%) 35 52
10 (*) the amount of maltodextrin corresponds to 6 % of the amount of granulated material
(active ingredient + calcium hydrogen phosphate dihydrate + maltodextrin).
Figure 4 represents the curves for the dissolution kinetics of the two formulations used :
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9
Figure4In vitro dissolution kinetics of batches LP3 and LP4


50
Tablet LP 3 Tablet LP4
■^^

Time (hours)

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The amount of hydroxypropyl methylcellulose in the hydrophilic matrix strongly
influences the release of the active ingredient.
EXAMPT.F. 3
Example 3 shows the influence of the grade of hydroxypropyl methylcellulose used on the
in vitro release kinetics. In each of the batches, the total weight of hydroxypropyl
10 methylcellulose is constant and the relative amount of each of the hydroxypropyl
methylcelluloses of different viscosity is vaiied, thereby making it possible to obtain a slow dissolution batch (LP5) and a rapid dissolution batch (LP7), compared with the reference batch (LP6).
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Table 3 : Unit formulation of the tablets (in mg)

Batches
Constituents LP5 LP6 LP7
Gliclazide 30 30 30
Calcium hydrogen phosphate dihydrate 83.64 83.64 83.64
Maltodextrin (*) 11.24 11.24 11.24
Hydroxypropyl methylcellulose 4000 cP 24 16 8
Hydroxypropyl methylcellulose 100 cP 10 18 26
Magnesium stearate 0.8 0.8 0.8
Colloidal silica 0.32 0.32 0.32
Final weight 160 160 160
Active ingredient dissolved at 4 h (%) 33 46 58
(*) the amount of maltodextrin corresponds to 9 % of the amount of granulated material (active ingredient + calcium hydrogen phosphate dihydrate + maltodextrin).
5 Figure 5 represents the curves for the dissolution kinetics of the three formulations used :
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Figure 5 : In vitro dissolution kinetics of batches LPS to LP7


11
The curves show clearly that the dissolution kinetics of the active ingredient are influenced not only by the total amount of hydroxypropyl methylcellulose used in the hydrophilic matrix but also by the grade of the hydroxypropyl methylcellulose used.
The gliclazide plasma kinetics are measured in 12 subjects after a single administration of tablet LP6. The mean plasma concentration is given in Figure 6.
Figure 6 ; Gliclazide plasma kinetics
Mean plasma concentrations of gliclazide ( in ug/ml) after oral
administration of a tablet according to the invention containing a dose of
30 mg of gliclazide to 12 healthy volunteers

Time (hours)
This curve shows a matrix-type dissolution profile (continuous release of the active ingredient) with monophase plasma kinetics.
-11-


Example 4 shows that the in vitro release kinetics of a tablet containing a dose of 60 mg are similar to that of a tablet containing a dose of 30 mg (batch LP6) for matrix tablets containing the same doses of hydroxypropyl methylcellulose and of maltodextrin.
Table 4 : Unit formulation of the tablets (in mg)

Batch LP8
Constituents
Gliclazide 60
Calcium hydrogen phosphate dihydrate 53.64
Maltodextrin 11.24
Hydroxypropyl methylcellulose 34
Anhydrous colloidal silica 0.32
Magnesium stearate 0.8
Final weight 160 mg
Active ingredient dissolved at 4 h (%) 45
Figure 7 : /« vitro dissolution kinetics of batch LPS
LP8


WE CLAIM:
1. Matrix tablet for the prolonged release of gliclazide, characterised in that it comprises at least the combination of a cellulose polymer compound from 10 to 40% of the total weight of the tablet and a glucose syrup from 2 to 20% of the total weight of the tablet, that combination enabling control of the prolonged release of gliclazide and enabling insensitivity of the dissolution kinetics of gliclazide to variations in pH ranging from 6 to 8.
2. Gliclazide matrix tablet as claimed in claim 1, wherein the cellulose polymer compound comprises at least one hydroxypropyl methylcellulose.
3. Gliclazide matrix tablet as claimed in claims 1 or 2, wherein the cellulose polymer compound comprises a mixture of two hydroxypropyl methylcellulose of different viscosity.
4. Gliclazide matrix tablet as claimed in claims 1 to 3, wherein the cellulose polymer compound comprises a mixture of hydroxypropyl methylcellulose of viscosity 4000 cP and hydroxypropyl methylcellulose of viscosity 100 cP.
5. Gliclazide matrix tablet as claimed in claim 1, wherein the glucose syrup is maltodextrin.
6. Gliclazide matrix tablet as claimed in claims 1, 2, 3, and 4 wherein the percentage of cellulose polymer compound is from 16 to 26 % of the total weight of the said tablet.
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7. Gliclazide matrix tablet as claimed in claims 1 and 5, wherein the percentage of glucose syrup is from 4 to 10 % of the total weight of the said tablet.
8. Gliclazide matrix tablet as claimed in claim 1, wherein calcium hydrogen phosphate dihydrate is used as diluent.
9. Gliclazide matrix tablet as claimed in claims 1 or 8, wherein the percentage of diluent is from 35 to 75 % of the total weight of the said tablet.
10. Gliclazide matrix tablet as claimed in claims 1, 8 and 9, wherein the percentage of diluent is from 45 to 60 % of the total weight of the said tablet.
11. Gliclazide matrix tablet as claimed in 1, wherein the amount of gliclazide is from 12 to 40 % of the total weight of the said tablet.
12. Gliclazide matrix tablet as claimed in claims 1 or 11, wherein it contains a total amount of gliclazide of 30 mg.
13. Gliclazide matrix tablet as claimed in claims 1 or 11, wherein it contains a total amount of gliclazide of 60 mg.
14. Gliclazide matrix tablet as claimed in claim 1, wherein the percentages of cellulose polymer compound and of glucose syrup make possible the release of 50% of the total amount of gliclazide by a time from 4 to 6 hours after administration.
15. Process for the preparation of a matrix tablet as claimed in claim 1, wherein there are used both a wet granulation technique and
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a direct compression technique, comprising the following steps:
STEP A:
Mixture of gliclazide, maltodextrin and calcium hydrogen phosphate dihydrate, followed by wetting of that mixture with purified water. The resulting wet mass is then granulated, dried and subsequently classified to obtain a granulate having physical characteristics that enable good filling of the moulds of a rapid -compression machine.
STEP B;
Mixture of the granulate obtained in Step A with hydroxypropyl methylcellulo se.
STEP C:
Lubrication of the mixture obtained in Step B with colloidal silica and magnesium stearate.
STEP D:

Compression of the lubricated mixture obtained in Step C using a rotary compression machine to obtain tablets having a hardness, measured by diametric crushing, of about from 6 to 10 daN.
Dated this July 18, 2001.
(RANJTfA MEHTA-DUTT)
OF REMFRY AND SAGAR ATTORNEY FOR THE APPLICANTS

Documents:

abstract1.jpg

in-pct-2001-00842-mum-cancelled pages(18-4-2007).pdf

in-pct-2001-00842-mum-claims(granted)-(18-4-2007).pdf

in-pct-2001-00842-mum-claims(granted-(18-04-2007).doc

in-pct-2001-00842-mum-correspondence(15-10-2007).pdf

in-pct-2001-00842-mum-drawing(18-4-2007).pdf

in-pct-2001-00842-mum-form 1(18-4-2007).pdf

in-pct-2001-00842-mum-form 1(18-7-2007).pdf

in-pct-2001-00842-mum-form 18(28-2-2005).pdf

in-pct-2001-00842-mum-form 2(granted)-(18-4-2007).pdf

in-pct-2001-00842-mum-form 2(granted-(18-04-2007).doc

in-pct-2001-00842-mum-form 3(18-4-2007).pdf

in-pct-2001-00842-mum-form 3(18-7-2001).pdf

in-pct-2001-00842-mum-form 5(18-7-2001).pdf

in-pct-2001-00842-mum-form 6(2-1-2002).pdf

in-pct-2001-00842-mum-form 6(26-10-2007).pdf

in-pct-2001-00842-mum-form 6(9-1-2002).pdf

in-pct-2001-00842-mum-form-pct-ipea-409(18-1-2001).pdf

in-pct-2001-00842-mum-form-pct-isr-210(18-1-2001).pdf

in-pct-2001-00842-mum-petition under rule 137(18-4-2007).pdf

in-pct-2001-00842-mum-petition under rule 138(18-4-2007).pdf

in-pct-2001-00842-mum-power of authority(1-7-2001).pdf

in-pct-2001-00842-mum-power of authority(18-4-2007).pdf

in-pct-2001-00842-mum-power of authority(6-10-2007).pdf


Patent Number 211372
Indian Patent Application Number IN/PCT/2001/00842/MUM
PG Journal Number 45/2007
Publication Date 09-Nov-2007
Grant Date 26-Oct-2007
Date of Filing 18-Jul-2001
Name of Patentee LES LABORATOIRES SERVIER
Applicant Address 1 RUE CARLE HEBERT, F-92415 COURBEVOIE, CEDEX
Inventors:
# Inventor's Name Inventor's Address
1 BRUNO HUET DE BAROCHEX 38, RUE DES GRANDS CHAMPS, 45140 INGRE
2 PATRICK WUTHRICH 15, RUE MARCELIN BERTHELOT, 45000 ORLEANS,
3 LOUIS MARTIN 28, ALLEE PIERRE LE MUET 45160 OLIVET,
PCT International Classification Number A61K 9/20 ; A61K 31/64
PCT International Application Number PCT/FR99/02520
PCT International Filing date 1999-10-15
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 99/01082 1999-02-01 France