WO2006061697A1

WO2006061697A1 - Sulfonylurea compositions and a process for its preparation

Info

Publication number: WO2006061697A1
Application number: PCT/IB2005/003702
Authority: WO
Inventors: Amit Krishna Antarkar; Nirav Mahendra Kamdar; Sangeeta Amalesh Karle; Chriag Bhupendra Shah
Original assignee: Themis Laboratories Private Limited
Priority date: 2004-12-06
Filing date: 2005-11-29
Publication date: 2006-06-15
Also published as: EP1827453A1

Abstract

The present invention provides sustained release pharmaceutical compositions suitable for once a day administration and a process for preparing such compositions comprising sulfonylurea, polymer, disaccharide and / or monosaccharide, exhibiting drug release profile substantially independent of pH of the dissolution medium in pH range 4 to 8.

Description

SULFONYLUREA COMPOSITIONS AND A PROCESS FOR ITS PREPARATION

Field of the Invention:

The present invention relates to pH independent sustained release pharmaceutical composition comprising sulfonylurea and a process for its preparation:

Background of the Invention:

Diabetes mellitus is a major health care problem characterized by marked increase in glucose levels in the blood. Other complication of diabetes includes heart disease, foot complications, diabetic neuropathy, gastroparesis and kidney disease. In gastroparesis the vagus nerve is damaged. The muscles of the stomach and intestines do not work normally, and the movement of food is slowed or stopped.

Solid dosage forms when administered orally passes from stomach to intestine and resides mainly in intestine, which is the absorption site for majority of the drugs. The pH of the intestinal fluid generally varies from 6 to 8. Depending on the fasting or fed state, the pH of the stomach ranges from 1.5 - 5 and gastric emptying time ranges from 2 - 4 hours. Gastric emptying time is further increased in gastroparesis condition. In fed state, the acidic contents of the stomach are emptied into the duodenum, dropping the pH of the duodenum to 4.5 - 5. The pH of the duodenum is slowly brought back to normal by pancreatic secretion.

Sulfonylurea is insulin secretion enhancer used in the treatment of type Il diabetes mellitus. Representative examples includes acetohexamide, chlorpropamide, glipizide, gliclazide, glibenclamide, glimepiride, gliquidone, glisoxepid, glibornuride, gliamilide, glycopyramide, glisentide, glisolamide, glicetanile, gliflumide, glymidine, glyparamide, tolpyrramide, glyhexamide, phenbutamide, tolazamide, tolbutamide and tolcyclamide, carbutamide, glybuthiazole, glybuzole, glypinamide phenbutamide, glyclopyamide and glycylamide and their pharmaceutically acceptable salts. They are generally dosed several times a day with food depending on the condition and severity of diabetes. Multiple dosing results in peaks and troughs of drug concentration in the blood. Most sulfonylureas are hydrophobic weak acid, insoluble in water and acidic pH and soluble towards neutral to alkaline pH of the intestine from 6 - 8. Their solubility increase with increasing pH. Sulfonylurea being administered with food will remain in stomach and duodenum, the contents of which are acidic in nature (pH 4 - 5) for about 2 to 5 hours. pH in the gastro-intestinal tract varies and therefore the release of sulfonylurea (pH dependant solubility) from the dosage form is dependant on its presence and the time period of its presence in the specific gastro-intestinal location. Variation in any of these conditions will result in inconsistent and irregular delivery of sulfonylurea from the dosage form which is not a desirable feature. To achieve consistent and regular delivery of sulfonylurea from the dosage form, condition to be fulfilled is to formulate a dosage form that releases sulfonylurea independent of pH in a wider pH range prevalent in the gastro- intestinal tract.

PCT publication WO00/18373 discloses matrix tablet for prolonged release of gliclazide, comprising a combination of cellulose polymer compound and glucose syrup. The composition contains 2 to 20%w/w of glucose syrup as one of the essential ingredients. The publication state that the combination of cellulose compound and glucose syrup (maltodextrin) ensures prolonged, continuous and consistent release of gliclazide which is insensitive to the variations in pH of the dissolution medium from pH 6 to 8. However, the PCT publication WO00/18373 fails to provide matrix tablet that release gliclazide insensitive to the variation in the pH from 4 - 6, which is the pH of the stomach and duodenum in the fed state where the tablet resides for about 2 - 5 hours. Sulfonylurea being administered with food would remain in contact with acidic pH (pH 4 - 6) of stomach and duodenum for about 2 to 5 hours. This contact time in acidic pH is further increased in gastroparesis which is one of the complications of diabetes mellitus. None of the dosage formulation disclosed in the prior art releases sulfonylurea independent of pH in a wide pH range prevalent in the gastro-intestinal tract. There is a long standing need in the industry to provide pharmaceutical composition comprising sulfonylurea that exhibits independent drug release profile in a wide pH range prevalent in the gastro-intestinal tract in the fed state.

Objects of the Invention The object of the present invention is to provide once a day sustained release pharmaceutical compositions comprising sulfonylurea that provides consistent blood levels with minimized peaks and trough of drug concentration in the blood. Another object of the invention is to provide sustained release pharmaceutical compositions comprising sulfonylurea exhibiting substantially independent drug release profile in a wider pH range prevalent in the gastro-intestinal tract.

It is yet another object to provide a sustained release pharmaceutical composition comprising sulfonylurea exhibiting s ubstantially pH independent in-vitro drug release profile in wide pH range. It is yet another object of the invention to provide a process for preparation of such pharmaceutical composition. Summary of the Invention

The present invention provides sustained release pharmaceutical compositions comprising sulfonylurea for once a day administration that provides consistent blood levels of sulfonylurea with minimized peaks and troughs of sulfonylurea concentration in blood thereby enabling patient compliance with the treatment of type Il diabetes mellitus. The pharmaceutical composition of the present invention comprises sulfonylurea, polymer, disaccharide and / or monosaccharide exhibiting drug release profile substantially pH independent over a wider pH range. The present invention further provides process for preparing such pharmaceutical compositions.

Brief Description of the Drawings

Figure 1 shows the % cumulative release profile of gliclazide from the matrix tablets as of example 1 in dissolution medium of pH 4.5, 6.8 and 7.4 Figure 2 shows the % cumulative release profile of gliclazide from the matrix tablets as of example 2 in dissolution medium of pH 4.5, 6.8 and 7.4

Description of the Invention:

Pharmaceutical composition of the present invention is in the form of matrix tablet and comprises sulfonylurea, polymer, disaccharide and / or monosaccharide exhibiting the release of said sulfonylurea substantially independent of the pH over a wide pH range.

The matrix tablet of the present invention can be prepared by wet granulation method or dry granulation method or direct compression method. Wet granulation method is the preferred method which comprises step of: • Mixing drug, polymer, disaccharide and / or monosaccharide and optionally pharmaceutical acceptable additive in a suitable mixer to obtain drug mixture;

• Wetting the drug mixture with a suitable solvent optionally containing binder to obtain wet mass;

• Optionally screening the wet mass followed by drying in a suitable dryer; • Optionally sizing and screening the dried mass through suitable screen to obtain dried granules of required size;

• Mixing the dried screened granules with lubricants and flow regulating agent to obtain lubricated granules;

• Compressing the lubricated granules into tablet of suitable shape, size, thickness and hardness using a suitable tablet compression machine or tablet press. The solvent used for wetting the drug mixture is selected from water, alcohol, methylene chloride, acetone or their suitable mixture. Alcohol includes methanol, ethanol and isopropanol. Solvent or solvent mixture used for wetting the drug mixture optionally contains binder. In direct compression method, the drug is mixed with polymer, disaccharide and / or monosaccharide and optionally pharmaceutical additive to obtain directly compressible mixture that can be compressed into tablet. In dry granulation method, the mixture of drug with atleast one excipient is compacted or slugged. The resulting mass is screened to obtain granules of desired mesh size followed by mixing with other ingredients and lubricants if required and compression.

Although solubility of sulfonylurea varies with pH, it was surprisingly found that the pharmaceutical composition comprising sulfonylurea, polymer, disaccharide and / or monosaccharide exhibits release of sulfonylurea substantially independent of pH. As seen in figure 1 and figure 2, the release profile of sulfonylurea (gliclazide) is substantially independent of the pH of the dissolution medium over a wide pH range (pH 4.5 - 7.4) for about 8 to 10 hours. It may be noted that the invention disclosed in the PCT publication WO00/18373 releases gliclazide independent to the variation in the pH range from 6 to 8. The pharmaceutical composition of the present invention releases gliclazide (sulfonylurea) substantially independent to the variation in a wider pH range i.e. 4 to 8, which is more desirable.

This would also ensure consistent and regular release of drug in the stomach and upper gastro-intestinal tract where the pH in fed state is from 4 to 5.5. This also ensures consistent and regular release of the drug in diabetic patients suffering from gastroparesis where the gastric emptying time is prolonged. Further the pharmaceutical composition of the present invention exhibits linear drug release profile for a period of atleast 8 hours. 50% of the drug is released from the pharmaceutical composition from about 4 to 8 hours preferably from about 4 to 6 hours in dissolution media of pH from 4.5 to 7.4. Sulfonylurea is selected from gliclazide, glibenclamide, glimepiride, glipizide and gliquidone and is preferably gliclazide. The particle size of sulfonylurea is less than 150 microns, preferably less than 100 microns and more preferably less than 50 microns. The percentage of sulfonylurea in the pharmaceutical composition ranges from about 0.001 %w/w to about 90%w/w of the composition, preferably from about 1%w/w to about 45% w/w and more preferably from about 1.25%w/w to about 40%w/w. The unit dose of sulfonylurea may vary from active to active but generally ranges from about 0.01 mg to about 200mg. The unit dose of gliclazide in the present invention generally ranges from about 15mg to about 120mg. The unit dose of glipizide, glibenclamide and glimepiride in the present invention generally ranges form about 0.1 mg to about 20mg. Polymer is selected from cellulose ethers, acrylic acid polymers and copolymer, methacrylic acid copolymer, acrylates, polymethacrylates, xanthan gum, guar gum, locust bean gum, polyethylene oxide, alginic acid and its salt such as sodium, potassium, ammonium, calcium salt, high molecular weight polyethylene glycol or their mixtures and is preferably cellulose ethers. The preferred cellulose ethers are selected from alkylcellulose, hydroxyalkylcellulose and carboxyalkylcellulose such as methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), and carboxymethylcellulose (CMC) and its pharmaceutical acceptable salts such as sodium, potassium and calcium salt. Preferred polymers are HPMC and sodium CMC. Cellulose ethers are available in various grades depending on their viscosities from about 3 cps to about 1 ,00,000 cps. The pharmaceutical composition of the present invention contains atleast one polymer having viscosity greater than 1000 cps when measured at 25.deg. centigrade.

The nominal viscosity at 20⁰C of a 2%w/w aqueous solution of HPMC is not less than 3000cps. The nominal viscosity at 25°C of a 1%w/w aqueous solution of HPC or HEC or CMC or its salt such as sodium CMC is not less than 1500cps. Such polymers having lower viscosity can also be used provided the composition contains atleast one polymer having relative high viscosity as mentioned above. The amount of the cellulose ether used in the composition is upto about 75%w/w of the composition, preferably from about 5% to about 50%w/w of the composition, more preferably from about 7.5% to about 30%w/w and most preferably from about 10% to about 20%w/w of the composition.

The disaccharide and / or monosaccharide content vary from about 15% to about 80% w/w of the composition, preferably from about 20% to about 70%w/w of the composition. Disaccharide is selected from lactose, sucrose, maltose, galactose, trehalose and maltitol or their mixtures and is preferably lactose. Monosaccharide is selected from glucose, fructose, galactose, dextrose, mannose, xylose, arabinose, ribose, ribulose or their mixtures and is preferably dextrose. The composition optionally comprises other pharmaceutical acceptable additives. Pharmaceutical acceptable additives include diluents, binder, flow regulating agent, lubricant, surfactant, alkalizing agents, pH modifiers, buffering agent's colorants or their mixtures.

Diluents are selected from glucose, mannitol, sorbitol, compressible sugar, sugar alcohol, monobasic sodium phosphate, dibasic sodium phosphate, tribasic sodium phosphate, calcium phosphate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, crosslinked carboxymethylcellulose and its salts such as sodium, potassium and calcium salt, sodium starch glycolate, pregelatinized starch, starch 1500, crospovidone, cyclodextrins and its derivatives, carboxymethylcellulose and its salts such as sodium, potassium and calcium salt, starch, calcium sulfate, microcrystalline cellulose or their mixture.

Binder is selected from cellulose ethers, xanthan gum, guar gum, acacia, tragacanth, gelatin, carragenan, locust bean gum, karaya gum, agar, chitosan, polyvinyl alcohol, polyvinylpyrrolidone (povidone) and gelatin and their mixture preferably cellulose ethers and povidone. Cellulose ethers is preferably selected from alkylcellulose, hydroxyalkylcellulose and carboxyalkylcellulose and includes methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC) and its salt such as sodium, potassium, calcium etc. Flow regulating agent and lubricants are selected from talc, colloidal silicon dioxide, glyceryl monostearate, sodium benzoate, sodium lauryl sulfate, glyceryl behenate, stearic acid and its salt such as magnesium stearate, calcium stearate or their mixture. The invention is further illustrated with non-limiting examples.

Example 1:

Table 1: Gliclazide matrix tablet comprising a mixture of one polymer and disaccharide

Example 1

Ingredients mg / tablet

Gliclazide 30

HPMC kIOOM 20.7

Lactose 104.3

Povidone K 30 2

Talc 4

Magnesium stearate 2

Colloidal silicon dioxide 2

Total Weight 165

Example 1 deals with the preparation of matrix tablet comprising a mixture of cellulose polymer (HPMC) and disaccharide (lactose monohydrate). The process involves mixing gliclazide, HPMC K100M (Methocel K100M) and lactose monohydrate in a suitable mixer to obtain drug mixture. The drug mixture was wet granulated using a mixture of isopropyl alcohol and water. The resulting wet granules were dried in a suitable drier. The dried granules were milled and sifted through desired mesh to obtain granules of desired particle size. These granules were blended with talc, Colloidal silicon dioxide and magnesium stearate. The resulting granules were compressed using a rotary compression machine to obtain tablets of desired hardness.

Example 2 - 5:

Table 2: Gliclazide matrix tablet comprising a mixture of atleast two polymers and disaccharide or monosaccharide

Example 2 Example 3 Example 4 Example 5

Ingredients mg / tablet mg / tablet mg / tablet mg / tal

Gliclazide 30 30 30 30

HPMC k 4M 18 - - 18

HPMC K 100M - 20 20.7 -

Sodium carboxymethylcellulose 5 10 48.3 5

HPMC E05 2 - - 2

Povidone K 30 - 2 2 ^•-

Lactose 42.3 95 56 -

Dextrose - - - 42.3

Dibasic calcium phosphate 61.2 - - 61.2 dihydrate

Talc 4 4 4 4

Magnesium stearate 2 2 2 2

Colloidal silicon dioxide - 2 2 -

Total Weight 164.5 165 165 165

Examples 2 - 5 deals with the preparation of matrix tablets comprising a mixture of two cellulose polymers (HPMC and sodium CMC) and a disaccharide (lactose monohydrate) or monosaccharide. The process involves mixing gliclazide, HPMC K4M (Methocel K4M) / HPMC K100M (Methocel K100M), sodium CMC (Ceekol 30,000), lactose monohydrate or dextrose and dibasic calcium phosphate dihydrate in a suitable mixer to obtain drug mixture. The drug mixture was wet granulated using HPMC E05 / povidone k30 solution in a mixture of isopropyl alcohol and water. The resulting wet granules were dried in a suitable drier. The dried granules were milled and sifted through desired mesh to obtain granules of desired particle size. These granules were blended with talc, colloidal silicon dioxide and magnesium stearate. The resulting granules were compressed using a rotary compression machine to obtain tablets of desired hardness.

Example 6: Table 3: Gliclazide matrix tablet comprising a mixture of two HPMC polymers of different viscosities and disaccharide

Example 5 Ingredients mg / tablet

Gliclazide 30

HPMC K 4M 22.5

HPMC K 100LV 5

Povidone K 30 2

Lactose 39

Dibasic calcium phosphate dihydrate 58.5

Talc 4

Magnesium stearate 2

Colloidal silicon dioxide 2

Total Weight 165

Example 6 deals with the preparation of gliclazide matrix tablets comprising a mixture of two HPMC polymers of different viscosities and a disaccharide (lactose). The process involves mixing gliclazide, HPMC K100M (Methocel K100M) and HPMC K100LV (Methocel K100LV), lactose monohydrate and dibasic calcium phosphate dihydrate in a suitable mixer to obtain drug mixture. The drug mixture was wet granulated using povidone k30 solution in a mixture of isopropyl alcohol and water. The resulting wet granules were dried milled and sifted through desired mesh and were blended with talc, colloidal silicon dioxide and magnesium stearate. The resulting granules were compressed using a rotary compression machine to obtain tablets of desired hardness.

Sustained release matrix tablet containing gliclazide (example 1 - 6) when analyzed in phosphate buffer of pH 4.5, pH 6.8 and pH 7.4 exhibits in-vitro drug release profile of N. MT 35% of gliclazide released after 1 hour; from about 10% to about 60% of gliclazide released after 3 hours;

N. LT 40% of gliclazide released after 8 hours; and

N. LT. 60% of gliclazide released after 10 hours.

Where "NMT" and "NLT" stands for "Not More Than" and "Not Less than" respectively. One way ANOVA was performed on the mean value of the rate of drug released from 6 tablets of example 1 in three different dissolution media of pH 4.5, 6.8 and 7.4. The result indicates that statistically there is no significant difference in the rate of drug released at 5% level.

The present invention provides pharmaceutical compositions comprising sulfonylurea suitable for once a day administration and exhibiting in-vitro drug release profile substantially independent of the pH of the dissolution medium of wide pH range ensuring less fluctuation and provides consistent and regular release of the drug in blood irrespective of the pH that is prevalent in the gastro-intestinal tract thereby minimizing inter and intra subject variation.

Claims

Claims: We Claim

1. A sustained release pharmaceutical composition comprising sulfonylurea, polymer, disaccharide and or monosaccharide, wherein the release of sulfonylurea is substantially independent of pH of the dissolution medium in pH range 4 to 8.

2. A composition as claimed in claim 1 , wherein the polymer is selected from cellulose ethers, acrylic acid polymers and copolymer, methacrylic acid copolymer, acrylates, polymethacrylates, xanthan gum, guar gum, locust bean gum, polyethylene oxide, alginic acid and its salt such as sodium, potassium, ammonium, calcium salt, polyethylene glycol or their mixtures.

3. A composition as claimed in claims 1 and 2, wherein the polymer is cellulose ether selected from methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose , sodium carboxymethylcellulose, calcium carboxymethylcellulose or their mixture.

4. A composition as claimed in claims 1 - 3, wherein the polymer is cellulose ether from 1 % to 75%w/w of the composition, preferably from about 5% to about 50%w/w of the composition, more preferably from about 7.5% to about 30%w/w and most preferably from about 10% to about 20%w/w of the composition.

5. A composition as claimed in claim 1 , wherein the disaccharide and or monosaccharide is from about 15% to about 80% w/w of the composition, preferably from 20% to 70%w/w of the composition and is selected from lactose, sucrose, maltose, galactose, trehalose maltitol, dextrose or their mixtures and is preferably lactose.

6. A composition as claimed in claim 1 , wherein the composition further comprises pharmaceutical acceptable additives selected from diluents, binder, flow regulating agent, lubricant, surfactant, alkalizing agents, pH modifiers, buffering agent's colorants or their mixtures.

7. A composition as claimed in claim 6, wherein the lubricant is selected from talc, colloidal silicon dioxide, glyceryl monostearate, sodium benzoate, sodium lauryl sulfate, glyceryl behenate, stearic acid and its salt such as magnesium stearate, calcium stearate or their mixture and diluent is selected from microcrystalline cellulose and dibasic calcium phosphate dihydrate or their mixtures.

8. A composition as claimed in claim 1, wherein the sulfonylurea is from about 0.001 %w/w to about 90%w/w of the composition, preferably from about 1%w/w to about 45% w/w and more preferably from about 1.25%w/w to about 40%w/w of the composition and has particle size less than 100 microns and preferably less than 50 microns.

9. A sustained release tablet composition of claims 1 to 8, wherein the sulfonylurea is gliclazide present from 15mg to 120mg.

10. A process for the preparation of sustained release pharmaceutical composition comprising sulfonylurea wherein the process steps comprise of:

(a) Mixing drug, atleast one polymer, disaccharide and or monosaccharide and optionally pharmaceutical acceptable additive in a suitable mixer to obtain drug mixture;

(b) Optionally wetting the drug mixture with a suitable solvent optionally containing binder to obtain wet mass;

(c) Optionally screening the wet mass followed by drying in a suitable dryer;

(d) Optionally sizing and screening the dried mass through suitable screen to obtain dried granules of required size;

(e) Mixing drug mixture of step a) or granules of step d) with lubricants to obtain lubricated granules;

(f) Compr essing the lubricated granules into tablet using a suitable tablet compression machine.

11. A process as claimed in claim 10, wherein the polymer is selected from cellulose ethers, acrylic acid polymers and copolymer, methacrylic acid copolymer, acrylates, polymethacrylates, xanthan gum, guar gum, locust bean gum, polyethylene oxide, alginic acid and its salt such as sodium, potassium, ammonium, calcium salt, polyethylene glycol or their mixtures.

12. A process as claimed in claims 10 and 11 , wherein the polymer is cellulose ether selected from methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose , sodium carboxymethylcellulose, calcium carboxymethylcellulose or their mixture

13. A process as claimed in claims 10 - 12, wherein the polymer is cellulose ether from 1 % to 75%w/w of the composition, preferably from about 5% to about 50%w/w of the composition, more preferably from about 7.5% to about 30%w/w and most preferably from about 10% to about 20%w/w of the composition.

14. A process as claimed in claim 10, wherein the disaccharide and or monosaccharide is from about 15% to about 80% w/w of the composition, preferably from 20% to 70%w/w of the composition and is selected from lactose, sucrose, maltose, galactose, trehalose maltitol, dextrose or their mixtures and is preferably lactose.

15. A process as claimed in claim 10, wherein the pharmaceutical acceptable additives selected from diluents, binder, flow regulating agent, lubricant, surfactant, alkalizing agents, pH modifiers, buffering agent's colorants or their mixtures.

16. A process as claimed in claim 15, wherein the lubricant is selected from talc, colloidal silicon dioxide, glyceryl monostearate, sodium benzoate, sodium lauryl sulfate, glyceryl behenate, stearic acid and its salt such as magnesium stearate, calcium stearate or their mixtures and diluent is selected from microcrystalline cellulose and dibasic calcium phosphate dihydrate or their mixtures.

17. A process as claimed in claim 10, wherein the sulfonylurea is from about 0.001 %w/w to about 90%w/w of the composition, preferably from about 1 %w/w to about 45% w/w and more preferably from about 1.25%w/w to about 40%w/w of the composition and has particle size preferably less than 100 microns and more preferably less than 50 microns.

18. A process as claimed in claims 10 and 17, wherein the sulfonylurea is gliclazide present in an amount from 15mg to 120mg.

19. A process as claimed in claims 10 - 18, wherein release of gliclazide from the tablet is substantially independent of pH of the dissolution medium in pH range 4 to 8.

20. A sustained release pharmaceutical tablet composition comprising gliclazide, hydroxypropylmethylcellulose, lactose and or dextrose.

21. A sustained release pharmaceutical tablet composition comprising gliclazide, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, lactose and or dextrose.

22. A sustained release pharmaceutical tablet composition comprising gliclazide, hydroxypropylmethylcellulose of two different viscosities, lactose and or dextrose.

23.A sustained release pharmaceutical tablet composition as claimed in claims 20 - 22, wherein the composition further comprises dibasic calcium phosphate dihydrate.

24. A sustained release pharmaceutical tablet composition as claimed in claims 20 - 23, wherein the release of sulfonylurea is substantially independent of pH of the dissolution medium in pH range 4 to 8.