WO2006123213A1

WO2006123213A1 - Modified release formulations of gliclazide

Info

Publication number: WO2006123213A1
Application number: PCT/IB2006/001241
Authority: WO
Inventors: Deepak Murpani; Ashish Madan
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2005-05-18
Filing date: 2006-05-11
Publication date: 2006-11-23

Abstract

The present invention relates to modified release formulations of gliclazide or salt thereof and processes for their preparation.

Description

MODIFIED RELEASE FORMULATIONS OF GLICLAZIDE

Field of the Invention

The present invention relates to modified release formulations of gliclazide or salts thereof and processes for their preparation. Background of the Invention

Modified release formulations have many advantages over standard immediate release pharmaceutical compositions. For example, modified release formulations have the ability to maintain a desired blood level of a medicament over an extended period of time by minimizing the peak to trough variations in plasma concentrations. They also may increase patient compliance by reducing the number of administrations necessary to achieve a desired therapeutic effect. Several modified release formulations have been reported for soluble drugs; however, moderately to poorly soluble drugs have properties which render them unsuitable for incorporation into modified release formulations. It is often difficult to predict whether a particular modified release formulation will provide the desired release profile for a relatively insoluble drug, and it has generally been found that for such drugs it is necessary to carry out considerable experimentation to obtain modified release formulations having the desired bioavailability when ingested. An example of a relatively insoluble class of drugs, which is difficult to formulate into modified release formulations, is the sulfonylurea class of antidiabetic drugs. Gliclazide is an antidiabetic drag from the sulfonylurea class that has been widely administered orally in the form of tablets. The usual average prescription regimen 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. Modified release sulfonylurea formulations with improved dissolution properties and extended release profiles are therefore a desirable addition to the medical treatment of diabetes.

The prior art discloses the use of acidified and/or alkalized excipient or an inert polar solvent to improve the dissolution profile of the drug or to improve the bioavailability of the drag from immediate/controlled release formulations. For example, U.S. 4,696,815 describes immediate release tablets of sulfonylurea drags based on an acidified and/or alkalized excipient and an inert polar solvent, such as polyethylene glycol. The pH _ . _

- 2 - regulated, immediate release formulations are described as improving the dissolution of acidic, amphoteric or basic antidiabetic sulfonylurea compounds. For example, the alkalized excipient is said to improve the dissolution of glipizide, which is an acid compound. U.S. 6,056,977 discloses a sustained release oral dosage form of sulfonylurea or a salt or derivative thereof in a matrix. Further, this patent teaches the use of an alkalizing agent to obtain complete bioavailability of the drug from the matrix dosage form.

U.S. 6,733,782 discloses a prolonged release matrix tablet of gliclazide. The patent teaches that a continuous and consistent drug release may be achieved which is insensitive to variations in the pH of the dissolution medium. The patent also teaches the use of a glucose syrup, for example maltodextrin, along with cellulose polymers to achieve a controlled and complete release of gliclazide from the formulation.

The prior art teaches the use of specific combinations of glucose syrup and cellulose polymers so as to enable the release of gliclazide in a prolonged and controlled manner. Generally, it is undesirable to use glucose syrup or any other sugar based compound as excipients in the preparation of formulations to be administered for the treatment of diabetes. The use of such excipients may increase the blood sugar levels in diabetic patients.

Surprisingly, we have found that the desired controlled, and substantially complete, release of gliclazide may be obtained using one or more binders along with one or more controlled release polymers. These formulations were found to be bioequivalerit with the innovator formulation (Diamicron^® MR, Les Lab., France) which includes glucose syrup. Further, it was surprisingly observed that by varying the proportion of the one or more binders and the particle size of gliclazide, it is possible to obtain formulations with enhanced bioavailability when compared to the innovator formulation. These formulations are cost effective and easy to manufacture on a commercial scale without requiring complex processing steps.

Summary of the Invention

In one general aspect there is provided a modified release formulation. The modified release formulation includes gliclazide or a salt thereof, one or more controlled release polymers, one or more binders and optionally one or more pharmaceutically acceptable excipients.

Embodiments of the formulation may include one or more of the following features. For example, the gliclazide or salt thereof may have a D₉Q range between less than about 70 μm to greater than about 18 μm or a Dg₀ less than about 18 μm.

The controlled release polymer may be one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof. The one or more controlled release polymers may be present at a concentration of between about 10% and about 40%, based on the weight of the formulation.

The one or more binders may be one or more of vinylpyrrolidone, cellulose, carbopol, gum and mixtures thereof. The one or more binders may be present at a concentration of less than about 10%, based on the weight of the formulation or between about 1% and 6.5%, based on the weight of the formulation. The pharmaceutically acceptable excipients may be one or more of diluents, lubricants, glidants and mixtures thereof.

In another general aspect there is provided a process for the preparation of a modified release formulation. The process includes the steps of: a) mixing gliclazide or a salt thereof with one or more binders and optionally one or more pharmaceutically acceptable excipients to obtain a blend; b) wet granulating the blend of step a) followed by drying to obtain granules; c) mixing the granules of step b) with one or more controlled release polymers to obtain a final blend; and d) compressing the blend of step c) into tablets.

Embodiments of the process may include one or more of the following features. For example, the one or more binders may be one or more of vinylpyrrolidone, cellulose, carbopol, gum and mixtures thereof. The one or more binders may be present at a concentration of less than about 10%, based on the weight of the formulation or between about 1% and 6.5%, based on the weight of the formulation.

The one or more controlled release polymers may be one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, - A -

carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof. The one or more controlled release polymers may be present at a concentration of between about 10% and about 40%, based on the weight of the formulation.

The gliclazide or salt thereof may have a D₉₀ range between less than about 70 μm to greater than about 18 μm or it may have a D₉₀ less than about 18 μm.

In yet another general aspect there is provided a method of treating diabetes. The method includes administering a modified release formulation of gliclazide. The formulation includes gliclazide or a salt thereof, one or more controlled release polymers, one or more binders and optionally one or more pharmaceutically acceptable excipients. Embodiments of the method may include one or more of the following features.

For example, the one or more binders may be one or more of vinylpyrrolidone, cellulose, carbopol, gum and mixtures thereof. The one or more binders may be present at a concentration of less than about 10%, based on the weight of the formulation or at a concentration of between about 1% and 6.5%, based on the weight of the formulation. The one or more controlled release polymers may be one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof. The one or more controlled release polymers may be present at a concentration of between about 10% and about 40%, based on the weight of the formulation. The gliclazide or salt thereof may have a D₉₀ range between less than about 70 μm to greater than about 18 μm or it may have a D₉₀ of less than about 18 μm.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims. Detailed Description of the Invention

The present invention provides for a modified release formulation of gliclazide. The pharmaceutical formulation includes gliclazide or a salt thereof, one or more controlled release polymers, one or more binders and optionally one or more additional pharmaceutically acceptable excipients. The formulations provide a prolonged and substantially complete release of gliclazide or a salt thereof over a specified period of time.

According to one embodiment, the modified release formulation is bioequivalent to the innovator's formulation. Surprisingly, this could be achieved using one or more binders and one or more controlled release polymers. The proportion of binder may be less than about 6% (by weight), between about 0.5% to about 6 %, or between about 1% to about 4%. The formulation includes gliclazide wherein the particle size distribution has a D₉₀ range from less than about 70 μm to greater than about 18 μm, from less than about 61 μm to greater than about 18 μm, or is about 30 + 12 μm. According to another embodiment, the modified release formulations provide superior bioavailability than innovator formulation. Surprisingly, it was observed that by varying the proportion of the one or more binders and by decreasing the particle size of gliclazide, superior bioavailability than innovator formulation could be achieved. The proportion of the one or more binders may be greater than about 6% (by weight), preferably from about 6.5% to about 10%, more preferably from about 7% to about 9%. The formulation includes gliclazide having a particle size distribution in which the D₉₀ is less than about 18 μm.

The term "about" is used herein to mean approximately, in the region of, roughly, or around. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a standard deviation of + 2.

The modified release formulation as described herein may be in the form of a tablet, capsule or granules. Preferably, the modified release formulation is a tablet.

The term "innovator formulation" as used herein refers to tablet formulation, commercially available in France under the trade name Diamicron^® MR manufactured by Les Lab., France.

The amount of gliclazide in the formulation may range from about 30 mg to about 120 mg, preferably from about 30 to about 60 mg. The particle size of gliclazide may be measured by any methods known in the art, for example, using a Malvern Mastersizer. .

- 6 -

The one or more binders may include one or more of vinylpyrrolidone, cellulose, carbopol, gums and mixtures thereof. For example, the binder may be polyvinylpyrrolidone.

The one or more controlled release polymers may include one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof. For example the controlled release polymer may be hydroxypropyl methylcellulose or a mixture of hydroxypropyl methylcelluloses of different viscosities. Hydroxypropyl methylcellulose with a viscosity of 100 cPs and hydroxypropyl methylcellulose with a viscosity of 4000 cPs may be used. The amount of controlled release polymer may range from about 10% to about 40% by weight.

The modified release formulation may optionally contain one or more pharmaceutically acceptable excipients. The one or more pharmaceutically acceptable excipients may include one or more of diluents, lubricants, glidants and mixtures thereof. The diluents may include one or more of dicalcium hydrogen phosphate dihydrate, microcrystalline cellulose, lactose, starch and mixtures thereof. The lubricants and glidants may include one or more of talc, colloidal silicon dioxide, magnesium stearate and mixtures thereof.

The formulations may be prepared by a wet granulation method, dry granulation/slugging method or a direct compression method.

The following non-limiting examples further illustrate the modified release formulations of gliclazide or salt thereof and process of making such formulations.

Examples 1-2

Process of preparation:

1. All ingredients were accurately weighed.

2. Gliclazide, polyvinylpyrrolidone and dibasic calcium hydrogen phosphate dihydrate were sifted through a suitable mesh to obtain a blend.

3. The blend of step 2 was transferred into a granulator and mixed to obtain a homogenous powder mix.

4. The powder mix of step 3 was granulated using purified water.

5. The granules of step 4 were dried in a dryer for suitable time and then screened.

6. Hydroxypropyl methylcellulose Kl 00LV and hydroxypropyl methylcellulose K4M CR were sifted through a suitable sieve to obtain a blend.

7. Granules of step 5 were mixed with the blend of step 6.

8. Magnesium Stearate and colloidal silicon dioxide were sifted through a suitable sieve, separately, and mixed with the blend of step 7 to obtain a final blend.

9. Tablets were compressed using the final blend of step 8. _

- 8 -

The above modified release formulations of gliclazide show the following in vitro dissolution profile in 900 ml pH 7.4 phosphate buffer, at 100 rpm using USP type I method:

Table 1

Table 2 Pharmacokinetic study design

Test (A) : Gliclazide 30 mg MR tablets

Manufactured by Ranbaxy Research Lab. Ltd., India Example No. 1

Test (B): Gliclazide 30 mg MR tablets

Manufactured by Ranbaxy Research Lab. Ltd., India Example No. 2

Reference (C): Diamicron^® 30 mg MR tablets

Manufactured by Les Lab., France & Distributed by Servier Laboratories Ltd. UK

Treatments*: A: Single oral dose of Test product (Fasting) B: Single oral dose of Test product (Fasting) C: Single oral dose of Reference product (Fasting)

*Number of subjects (Human volunteers) = 12 in each case. Table 3

Summary Statistics of Gliclazide Bioequivalence Studies*

Product/Statistics C_max (ng/mL) T_max (h) (ng.h/mL) (ng.h/mL)

Product A

Mean 2067.432 61463.852 66447.012 10.125

CV (%) 27.9 38.1 35.2 49.1

Product B

Mean 2047.464 58011.037 64985.246 7.917

CV (%) 33.0 22.3 27.1 36.7

Product C

Mean 1938.953 56135.382 61645.336 8.000

CV (%) 21.4 25.9 28.6 41.3

Ratio of least squares mean

A/C (%) 104.62 106.39 109.17 -

B/C (%) 102.27 103.88 105.54 -

90% Confidence intervals (A/C)

Lower limit 92.84 95.82 97.69 -

Upper limit 117.91 118.13 121.99 -

90% Confidence intervals (B/C)

Lower limit 90.75 93.56 94.82 -

Upper limit 115.26 115. 35 117.47 -

* Number of subjects (Human volunteers) = 12 in each case.

Example 3

Process of preparation: 1. All ingredients were accurately weighed.

3. The blend of step 2 was transferred into a granulator and mixed to obtain a homogenous powder mix. 4. The powder mix of step 3 was granulated using purified water.

7. The granules of step 5 were mixed with the blend of step 6. 8. Magnesium stearate and colloidal silicon dioxide were sifted through a suitable sieve, separately, and mixed with the blend of step 7 to obtain a final blend.

9. Tablets were compressed using the final blend of step 8. The above modified release formulation of gliclazide shows the following in vitro dissolution profile in 900 ml pH 7.4 phosphate buffer, at 100 rpm using USP type I method:

Table 4

Pharmacokinetic study design:

Table 5

Products evaluated

Test (T): Gliclazide 30 mg MR tablets

Manufactured by Ranbaxy Research Lab. Ltd., India Example No. 3

Reference (R): Diamicron^® 30 mg MR tablets

Manufactured by Les Lab., France & Distributed by Servier i Laboratories Ltd. UK

Treatments*: T: Single oral dose of Test product (Fasting)

R: Single oral dose of Reference product (Fasting)

* Number of subjects (Human volunteers) = 12 in each case. Table 6

Summary Statistics of Gliclazide Bioequivalence Studies*

Product/Statistics 5 C_max (ng/niL) Tmax (h) (ng.h/mL) (ng.h/mL)

Product T

Mean 2133.639 51299.820 65842.034 7.417

CV (%) 27.6 42.9 58.8 36.2

Product R

Mean 1821.219 42549.526 55185.114 7.125

CV (%) 28.8 50.4 63.4 34.3

Ratio of least squares mean

T/R (%) 117.50 124.88 122.61 -

90% Confidence intervals (T/R)

Lower limit 105.41 104.76 96.94 -

Upper limit 130.98 148.85 155.08 -

* Number of subjects (Human volunteers) = 12 in each case.

Process of preparation:

1. All ingredients were accurately weighed.

2. Gliclazide, polyvinylpyrrolidone and dibasic calcium hydrogen phosphate dihydrate were sifted through a suitable mesh to obtain a blend. - .

- 13 -

4. The powder mix of step 3 was granulated using purified water.

5. The granules of step 4 were dried in a dryer for suitable time and then screened. 6. Hydroxypropyl methylcellulose KlOOLV and hydroxypropyl methylcellulose K4M

CR were sifted through a suitable sieve to obtain a blend.

7. The granules of step 5 were mixed with the blend of step 6.

8. Magnesium stearate and colloidal silicon dioxide were sifted through a suitable sieve, separately, and mixed with the blend of step 7 to obtain a final blend. 9. Tablets were compressed using the final blend of step 8.

An alternative process of preparation of the modified release tablets is described below:

1. All ingredients were accurately weighed.

2. Gliclazide, polyvinylpyrrolidone and dibasic calcium hydrogen phosphate dihydrate were sifted through a suitable mesh to obtain a blend. 3. The blend of step 2 was transferred into a granulator and mixed to obtain a homogenous powder mix.

4. The powder mix of step 3 was granulated using purified water.

6. Hydroxypropyl methylcellulose Kl 00LV, hydroxypropyl methylcellulose K4M CR and colloidal silicon dioxide were sifted through a suitable sieve to obtain a blend.

7. The granules of step 5 were mixed with the blend of step 6.

8. Magnesium stearate was sifted through a suitable sieve and mixed with the blend of step 7 to obtain a final blend. 9. Tablets were compressed using the final blend of step 8. Example 7

Process of preparation:

1. AU ingredients were accurately weighed. 2. Gliclazide, polyvinylpyrrolidone and dibasic calcium hydrogen phosphate dihydrate were sifted through a suitable mesh to obtain a blend.

3. The blend of step 2 was transferred in to a granulator and mixed to obtain a homogenous powder mix.

4. The powder mix of step 3 was granulated using purified water. 5. The granules of step 4 were dried in a dryer for suitable time and then screened.

6. Hydroxypropyl methylcellulose Kl 00LV, hydroxypropyl methylcellulose K4M CR and colloidal silicon dioxide were sifted through a suitable sieve to obtain a blend. 7. Granules of step 5 were mixed with the blend of step 6.

8. Magnesium Stearate was sifted through a suitable sieve and mixed with the blend of step 7 to obtain a final blend.

9. Tablets were compressed using the final blend of step 8. Table 7 Pharmacokinetic study design

Products evaluated:

Test (A) : Gliclazide 30 mg MR tablets

Manufactured by Ranbaxy Research Lab. Ltd., India

Example No. 7 Reference (B): Diamicron^® LM 30 mg MR tablets

Manufactured by Les Laboratoires Servier,

Distributed by Servier, Portugal

Studies: 1. Single oral dose of Test & Reference (Fasting)

2. Single oral dose of Test & Reference (Fed)

3. Multiple oral dose of Test & Reference (Fed)

Table 8

Study 1: Single oral dose of Test & Reference (Fasting)

Summary Statistics of Gliclazide Bioequivalence Studies

Product/Statistics C_max (μg/mL) T_max (h) (μg.h/mL) (μg.h/mL)

Product A

Mean 1.3988 35.3416 37.7058 8.61

CV (%) 19.79 32.69 35.56 30.84

Product B

Mean 1.2979 34.3007 36.5858 9.45

CV (%) 22.98 32.83 35.77 24.27 Table 9

Table 10 Study 2: Single oral dose of Test & Reference (Fed)

Summary Statistics of Gliclazide Bioequivalence Studies 5

Product/Statistics C_max(μg/mL) T_ma_x (h) (μg.h/mL) (μg.h/mL)

Product A

Mean 1.8480 44.4950 47.6903 6.05

CV (%) 17.31 35.80 39.08 23.70

Product B

Mean 1.8074 45.3233 48.8308 7.53

CV (%) 16.10 37.95 41.61 18.08

Table 11

Table 12 Study 2: Multiple oral dose of Test & Reference (Fed)

Summary Statistics of Gliclazide Bioequivalence Studies

Product/Statistic T_max (h)

(μg/mL) (μg/mL) (μg.h/mL) Product A

Mean 3.5579 1.8585 44.6048 5.78 CV (%) 34.80 39.37 39.37 21.65 Product B

Mean 3.5473 1.8711 44.9052 5.72 CV (%) 38.08 41.73 41.73 21.86

Table 13

As evident from the above pharmacokinetic data, modified release formulation of

Gliclazide as per Example 7 is bioequivalent to the innovator.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.

Claims

We claim: 1. A modified release formulation comprising gliclazide or a salt thereof, one or more controlled release polymers, one or more binders and optionally one or more pharmaceutically acceptable excipients.

2. The modified release formulation of claim 1, wherein the gliclazide or salt thereof has a D₉₀ range between less than about 70 μm to greater than about 18 μm.

3. The modified release formulation of claim 2, wherein the gliclazide or salt thereof has a D₉₀ less than about 18 μm.

4. The modified release formulation of claim 1, wherein the controlled release polymer comprises one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof.

5. The modified release formulation of claim 5, wherein the one or more controlled release polymers comprise between about 10% and about 40%, based on the weight of the formulation.

6. The modified release formulation of claims 1, wherein the one or more binders comprise one or more of vinylpyrrolidone, cellulose, carbopol, gum and mixtures thereof.

7. The modified release formulation of claim 6, wherein the one or more binders comprise less than about 10%, based on the weight of the formulation.

8. The modified release formulation of claim 7, wherein the one or more binders ^' comprise between about 1% and 6.5%, based on the weight of the formulation.

9. The modified release formulation of claim 1 , wherein the pharmaceutically acceptable excipients comprise one or more of diluents, lubricants, glidants and mixtures thereof.

10. A process for the preparation of a modified release formulation, the process comprising the steps of: a) mixing gliclazide or salt thereof with one or more binders and optionally one or more pharmaceutically acceptable excipients to obtain a blend; b) wet granulating the blend of step a) followed by drying to obtain granules; c) mixing the granules of step b) with one or more controlled release polymers to obtain a final blend; and d) compressing the blend of step c) into tablets.

11. The process of claim 10, wherein the one or more binders comprise one or more of vinylpyrrolidone, cellulose, carbopol, gum and mixtures thereof.

12. The process of claim 11 , wherein the one or more binders comprise less than about 10%, based on the weight of the formulation.

13. The process of claim 12, wherein the one or more binders comprise between about 1 % and 6.5%, based on the weight of the formulation.

14. The process of claim 10, wherein the one or more controlled release polymers comprise one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof.

15. The process of claim 14, wherein the one or more controlled release polymers comprise between about 10% and about 40%, based on the weight of the formulation.

16. The process of claim 15, wherein the gliclazide or salt thereof has a D₉₀ range between less than about 70 μm to greater than about 18 μm.

17. The process of claim 16, wherein the gliclazide or salt thereof has a D₉₀ less than about 18 μm.

18. A method of treating diabetes in a patient in need thereof, the method comprising administering a modified release formulation of gliclazide, the formulation comprising gliclazide or a salt thereof, one or more controlled release polymers, one or more binders and optionally one or more pharmaceutically acceptable excipients.

19. The method of claim 18, wherein the one or more binders comprise one or more of vinylpyrrolidone, cellulose, carbopol, gum and mixtures thereof.

20. The method of claim 18, wherein the one or more binders comprise less than about 10%, based on the weight of the formulation.

21. The method of claim 20, wherein the one or more binders comprise between about 1% and about 6.5%, based on the weight of the formulation.

22. The method of claim 18, wherein the one or more controlled release polymers comprise one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof.

23. The method of claim 22, wherein the one or more controlled release polymers comprise between about 10% and about 40%, based on the weight of the formulation.

24. The method of claim 18, wherein the gliclazide or salt thereof has a D₉₀ range between less than about 70 μm to greater than about 18 μm.

25. The method of claim 24, wherein the gliclazide or salt thereof has a D₉₀ less than about 18 μm.