MXPA01007378A - Core tablet for controlled release of gliclazide after oral administration - Google Patents

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.

Description

MATRIX TABLET THAT MAKES POSSIBLE THE PROLONGED RELEASE OF GLICLAZIDE AFTER THE ADMINISTRATION BY THE ORAL PATH DESCRIPTION OF THE INVENTION The present invention relates to a matrix tablet which makes possible the prolonged release of gliclazide, the release being insensitive to variations in the pH of the dissolution medium, and which ensures regular and continuous blood levels after absorption of the galenic form through the oral route. Gliclazide, a compound of the formula (I): is a sulfonylurea compound that has an antidiabetic property at the doses usually administered to humans. Gliclazide has been administered to date 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 it can vary from 1 to 4 tablets per day in several administrations, depending on the severity of the diabetes. One of the objects of the present invention was to obtain an oral form that can be administered in a simple daily administration. On the one hand, this makes it easier for the patient to use it and, on the other hand, makes possible the best compliance with the treatment. Another objective of the invention was that the oral form should have prolonged release. Of course, 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 maximum peaks or concentrations 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 can occur as a result of the "peak effect", which are accompanied by hydroelectrolytic and metabolic disorders associated with variations in the plasma levels of the active ingredient.

The main objective 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 present form the dissolution of the active ingredient varies greatly according to the pH. This characteristic, associated with the gliclazide itself, imposes absorption problems for the active ingredient. The phenomenon of the solubility of the active ingredient that varies according to pH is shown in Figure 1 (attached). The solubility is very weak at acidic pHs and increases as the pH rises. It was thus important, for this active ingredient, to develop a new galenic form which makes possible the release of glycyzide which is independent of the pH of the dissolution medium. More especially, the present invention describes a hydrophilic matrix which can be administered by the oral route and which makes possible the prolonged and controlled release of the active ingredient, gliclazide, without the pH which influences the kinetics of dissolution within 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 variations. The rate of release must be reproducible and must be correlated with the blood concentrations observed after administration. Among the mechanisms that can be used to control the diffusion of a soluble active ingredient, a main mechanism can be selected, which is the diffusion of the active ingredient through a gel formed after the swelling of a hydrophilic polymer placed in contact with the liquid of dissolution (in vi tro) or with the gastrointestinal fluid. { in vivo). Many polymers have been described as capable of making it possible for such a gel to be formed. The main polymers are cellulose compounds, especially cellulose ethers such as hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose and hydroxypropylmethylcellulose and, among the various commercial grades of these 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 equation in the release kinetics to be obtained. The production processes currently used for the production of such matrix tablets are either direct compression, after mixing of the various excipients and the active ingredient (s), or wet base 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 (corn starch hydrolyzate), which makes possible the release of the active ingredient which 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. In addition, the matrix tablet according to the invention makes possible the prolonged release of gliclazide which results in human blood levels of 400 to 700 ng / ml, 12 hours at most after a simple administration by the oral route, of a tablet containing a dose of 30 mg of gliclazide, and at blood levels of 250 to 1000 ng / ml after a daily administration of a tablet containing a dose of 30 mg of gliclazide. The unit dose may vary according to the age and weight of the patient, and the nature and severity of the diabetes. This is generally in intervals of 30 to 120 mg, in a simple 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, said tablet contains a dose of 60 mg of gliclazide. A particularly 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 dose, which is in the range of 30 to 120 mg, for a simple daily administration, corresponds to the absorption of 1 to 4 tablets containing a dose of 30 mg or 1 or 2 tablets that contain 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 simple daily administration and, on the other hand, surprisingly and especially advantageously, makes it possible to reduce the amount of ingredient active in each tablet, without the plasma concentrations of glycyzide being modified or altered. The formulation to date in existence contained a dose of 80 mg of gliclazide. The specific combination of the above described compounds also, surprisingly, makes it possible that the kinetics of dissolution within said matrix is not affected by the pH, 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 in a range of 6.2 to 7.4, which occurs in the intestinal environment. Thus, within a pH range of 6 to 8 corresponding to the elevation portion of the curve shown in Figure 1 (attached), it can be seen that the release profile of the active ingredient at between 0 and 12 hours it is the same, regardless of the pH of the dissolution medium of the matrix tablet containing 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 which is innovative in terms of its composition and function since, in particular, it makes it possible for the active ingredient it contains, that is, the gliclazide, is released in a prolonged and controlled manner, regardless of the pH conditions of the dissolution medium.

The polymeric cellulose compound used in that hydrophilic matrix is a high viscosity cellulose ether. Advantageously, the cellulose ether is a hydroxypropylmethylcellulose, preferably a mixture of two hydroxypropylmethylcelluloses of different viscosity. The other compound in the composition of said matrix is a glucose syrup and, advantageously, maltodextrin is used, which is a glucose syrup having an equivalent degree of dextrose (ED) of 1 to 20. The combination of those two types of compounds on the one hand makes it possible to obtain a formulation in which the release profile of the. The active ingredient is insensitive to variations in the pH of the dissolution medium and, on the other hand, makes it possible to obtain perfect control of the release kinetics. The percentage of the cellulose polymer compound is from 10 to 40% of the total weight of the tablet and, according to a particularly advantageous embodiment, from 16 to 26% of the total weight of the tablet. The percentage of glucose syrup is 2 to 20% of the total weight of the tablet and, preferably, 4 to 10% of the total weight of the tablet. Various excipients can also be added to complete the formulation. Among the diluents conventionally used, preference is given to the use of calcium acid phosphate dihydrate, which makes it possible to obtain improved flowability of the granule and improved compressibility of the granule. In addition, the calcium acid phosphate dihydrate is able to retard dissolution kinetics, making it possible to use smaller amounts of hydroxypropylmethylcellulose to control the dissolution profile of the active ingredient. The percentage of calcium acid phosphate dihydrate is from 35 to 75% of the total weight of the tablet, preferably from 45 to 60% of the total weight of the tablet. Among the lubricants which may be mentioned by way of example are magnesium stearate, stearic acid, glycerol behenate and sodium benzoate and, among the flow agents, preference is given to the use of the anhydrous colloidal silica. The present invention also relates to the preparation of the matrix tablet. The wet-based granulation is carried out by mixing the active ingredient, the glucose syrup and the calcium acid phosphate dihydrate, and then wetting the mixture. This first step makes possible the creation around the active ingredient, of a hydrophilic environment that promotes its good dissolution, and also makes possible 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 can be directly granulated 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 in no way limit it. The preparation of prolonged-release tablets that can be administered by the oral route, is carried out according to the following production process: STEP A: Mixture of gliclazide, maltodextrin and calcium acid phosphate dihydrate, followed by wetting that mixture with purified water. The resulting wet mass is then granulated, dried and subsequently classified to obtain a granulate having physical characteics that make possible the good filling of the molds of a rapid compression machine.

STEP B: Mixture of the granulate obtained in Step A with hydroxypropylmethylcellulose.

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 diametral crushing, of about 6 to 10 daN.

EXAMPLE 1 Example 1 shows the influence of maltodextrin on the release kinetics in vi tro.

The amount of maltodextrin is in the range of 7.5 to 15 mg per tablet, thereby constituting 4 to 10% of the total weight of the tablet. The amount of hydroxypropylmethylcellulose remains constant and the amount of diluent, calcium acid phosphate dihydrate, is adjusted to obtain tablets having a constant weight of 160 mg. The production is carried out according to the procedure described in Steps A to D.

Table 1: Unit formulation of the tablets (in mg per tablet) and characteristics (*) The amount of maltodextrin corresponds to 6 or 12% of the amount of granulated material (active ingredient + calcium acid phosphate dihydrate, + maltodextrin).

Figure 3 represents the curves for the dissolution kinetics of the two formulations used.

Figure 3: Kinetics of dissolution in vi tro of lots LP1 and LP2 1 0 1 2 Time (hours) The amount of maltodextrin, at a constant weight of hydroxypropylmethylcellulose, influences the release of the active ingredient for a period of more than 4 hours. The dissolution curve is linearized by increasing the amount of maltodextrin.

EXAMPLE 2: Example 2 shows the influence of hydroxypropylmethylcellulose on the in vitro release kinetics. The amount of hydroxypropylmethylcellulose is in the range of 26 to 42 mg, thus constituting 16 to 26% of the total weight of the tablet. The 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) (*) The amount of maltodextrin corresponds to 6% of the amount of granulated material (active ingredient + calcium acid phosphate dihydrate + maltodextrin).

The ! Figure 4 represents the curves for the dissolution kinetics of the two formulations used: Figure 4: Kinetics of dissolution in vi tro of lots LP3 and LP4 Time (hours) The amount of hydroxypropylmethylcellulose in the hydrophilic matrix strongly influences the release of the active ingredient.

EXAMPLE 3: Example 3 shows the influence of the degree of hydroxypropylmethylcellulose used on the in vitro release kinetics. In each of the tablets, the total weight of the hydroxypropylmethylcellulose is constant, and the relative amount of each of the hydroxypropylmethylcelluloses of different viscosity is varied, which makes it possible to obtain a slow dissolution batch (LP5) and a rapid dissolution batch (LP7), compared to a reference batch (LP6).

Table 3: Unit formulation of the tablets (in mg) (*) The amount of maltodextrin corresponds to 9% of the amount of granulated material (active ingredient + calcium acid phosphate dihydrate + maltodextrin).

Figure 5 represents the curves for the dissolution kinetics of the three formulations used: Figure 5: Kinetics of dissolution in vi tro of lots LP5 to LP7 Time (hours) The curves clearly show that the dissolution kinetics of the active ingredient are influenced not only by the total amount of the hydroxypropylmethylcellulose used in the hydrophilic matrix, but also by the degree of the hydroxypropylmethylcellulose used. The plasmatic kinetics of gl iclazide are measured in 12 subjects after a simple administration of the LP6 tablet. The mean plasma concentration is given in Figure 6.

Figure 6: Plasma kinetics of glycazide Mean plasmatic concentrations of gliclazide (in μg / ml) after oral administration of a tablet according to the invention containing a dose of 30 mg of glycazide to 12 healthy volunteers Time (hours) This curve shows a matrix-like dissolution profile (continuous release of the active ingredient) with the monophasic plasma kinetics.

EXAMPLE 4: Example 4 shows that the kinetics of in vitro delivery of a tablet containing a dose of 60 mg are similar to those of a tablet containing a dose of 30 mg (lot LP6) for the matrix tablets containing the same doses of hydroxypropylmethylcellulose and maltodextrin.

Table 4: Unit formulation of the tablets (in mg) Figure 7: Kinetics of dissolution in vi tro of the LP8 batch Time (hours)

Claims (20)

1. Matrix tablet for the prolonged release of gliclazide, characterized in that it comprises at least the combination of a cellulose polymer compound and a glucose syrup, this combination making possible the control of the prolonged release of gliclazide and which makes possible the insensitivity of the kinetics of dissolution of gliclazide to variations in pH.

2. Gliclazide matrix tablet according to claim 1, characterized in that the cellulose polymer composition comprises at least one hydroxypropylmethylcellulose.

3. Gliclazide matrix tablet according to either claim 1 or claim 2, characterized in that the cellulose polymer composition comprises a mixture of two hydroxypropylmethylcelluloses of different viscosity.

4. Gliclazide matrix tablet according to any of claims 1 to 3, characterized in that the cellulose polymer composition comprises a mixture of hydroxypropylmethylcellulose with a viscosity of 4000 cP and hydroxypropylmethylcellulose with a viscosity of 100 cP.

5. Gliclazide matrix tablet according to claim 1, characterized in that the glucose syrup is maltodextrin.

6. Gliclazide matrix tablet according to any one of claims 1 to 4, characterized in that the percentage of cellulose polymer compound is from 10 to 40% of the total weight of said tablet.

7. Gliclazide matrix tablet according to any of claims 1, 2, 3, 4 and 6, characterized in that the percentage of the cellulose polymer compound is from 16 to 26% of the total weight of the tablet.

8. Gliclazide matrix tablet in accordance with either claim 1 or claim 5, characterized in that the percentage of glucose syrup is from 2 to 20% of the total weight of said tablet.

9. Gliclazide matrix tablet according to any of claims 1, 5 and 8, characterized in that the percentage of glucose syrup is from 4 to 10% of the total weight of the tablet.

10. Gliclazide matrix tablet according to claim 1, characterized in that calcium acid phosphate dihydrate is used as a diluent.

11. Gliclazide matrix tablet according to claim 1 or claim 10, characterized in that the percentage of diluent is from 35 to 75% of the total weight of the tablet.

12. Gliclazide matrix tablet according to any of claims 1, 10 and 11, characterized in that the percentage of diluent is 45 to 60% of the total weight of the tablet.

13. Gliclazide matrix tablet according to claim 1, characterized in that the amount of gliclazide is from 12 to 40% of the total weight of the tablet.

14. Gliclazide matrix tablet according to either claim 1 or claim 13, characterized in that it contains a total amount of gliclazide of 30 mg.

15. Gliclazide matrix tablet in accordance with either claim 1 or claim 13, characterized in that it contains a total amount of gliclazide of 60 mg.

16. Gliclazide matrix tablet according to claim 1, characterized in that the percentages of the cellulose polymer compound and the glucose syrup make possible a constant profile of gliclazide release for a pH of the dissolution medium in the range of 6 to 8 .

17. Gliclazide matrix tablet according to claim 1, characterized in that the percentages of the cellulose polymer compound and the glucose syrup make possible the release of 50% of the total amount of glycyzide for a time of 4 to 6 hours.

18. Gliclazide matrix tablet according to claim 1, characterized in that the percentages of the cellulose polymer compound and the glucose syrup make possible the prolonged release of the gliclazide, which results in human blood levels of 400 to 700 ng / ml, 12 hours at most after a simple administration of the tablet by the oral route.

19. Process for the preparation of a matrix tablet, according to claim 1, characterized in that a wet-based granulation technique and a direct compression technique are used, which comprises the following steps: STEP A: mixture of glycazide, maltodextrin and phosphate calcium acid dihydrate, followed by wetting that mixture with purified water. The resulting wet mass is then granulated, dried and subsequently classified to obtain a granulate having physical characteristics that make possible the good filling of the molds of a rapid compression machine. STEP B: mix the granulate obtained in Step A with hydroxypropylmethylcellulose. 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 diametral crushing, of approximately 6 to 10 daN.

20. The gliclazide matrix tablet according to claim 1, for use in the treatment of diabetes.