Technical Field of the Invention
The present invention relates to a process of improving the aqueous solubility of sulfonylureas by co-pulverization of sulphonyl urea and cyclodextrin.
Background of the Invention
Sulfonylureas are oral antidiabetic agents widely used for the treatment of type 2 diabetes. The sulfonylureas have poor aqueous solubility due to which their dissolution in the gastrointestinal fluids and subsequent absorption is slow. The oral antidiabetic must effectively control the plasma glucose levels especially after food intake when the glucose levels are higher than normal in a diabetic patient. This can be achieved by rapid absorption of the sulfonylurea taken just before or immediately after food. Increasing the dissolution of the sulfonylurea in the gastrointestinal fluids would help rapid absorption and faster onset of antidiabetic action.
Attempts have been made to improve the aqueous solubility of sulfonylureas, for example, by increasing the surface area of sulfonylurea by particle size reduction. US 4,060,634 discloses fine crystallizate of glyburlde with a surface area of at least 3 to 10 m2/9 prepared by dissolving glyburlde in a water soluble organic solvent and adding this solution to cold water or an acidic aqueous solution with stirring and collecting the precipitate of glyburlde as fine particles. The reduction of particle size may increase the dissolution of sulfonylurea to some extent but the inherent solubility remains the same.
US 3,883,648 describes preparing a solid dispersion of glyburlde to improve its dissolution by dissolving glyburlde in a polyglycol by heating, cooling and granulating the solid thus obtained.
US 4,696,815 discloses an oral antidiabetic formulation comprising a sulfonylurea and a basic excipient and polyvinylpyrrolidone. In presence of basic excipient such as sodium hydroxide or ammonium hydroxide the solubility of the
sulfonylurea is improved. However, use of a basic excipient would require special apparatus due to it's corrosive nature.
US 6,464,988 discloses an inclusion complex of glipizide with a non-ionic surfactant and a cyclodextrin prepared by dissolving a nonoionic surfactant in a solvent such as water and wetting a cyclodextrin of particle size 10-250^m with this solution; mixing the semisolid mixture so formed with glipizide of particle size 1-40)µm to form a mixed inclusion complex.
WO 03/043602A1 describes preparing a solid dispersion of drugs with poor solubility by dissolving the drug and a cyclodextrin in organic solvent, and removing the solvent by vacuum drying or spray drying to get the drug-cyclodextrin complex.
Most of these processes mentioned above involve the use of solvents. The use of organic solvents in particular, implicates additional precautions for safety considerations. Moreover, recovery of the complex form the solution would require additional processing steps.
US 5,007,966 discloses a method of forming a complex between a cyclodextrin and poorly soluble drug by forming a mixture of the poorly soluble drug and cyclodextrin with a moisture content between about 25% to 65% by weight; further mixing in a ball mill charged with a plurality of balls. The patent exemplifies the process by preparing complexes of cyclodextrin with liquid guest molecules and does not disclose any process for improving the solubility of a solid guest molecule. Further, this process has a limitation of presence of moisture in the cyclodextrin for achieving good results.
EP 371431 describes preparing supported drugs by a process which involves mixing the active substance and the support material like a cyclodextrin, co-grounding the mixture in a mill in which the grinding chamber is saturated with
one or more solvent vapours able to solubilize the active substance or to be absorbed on the surface of the support material.
We have now discovered a process of improving the aqueous solubility of a sulfonylurea which does not require use of solvents, basic excipients or high temperature. The process comprises co-pulverizing a dry mixture of the sulfonylurea and a cyclodextrin. The process is simple and can be carried out easily with commonly available equipments. The co-pulverized mixture when dissolved in water gives a clear solution. The improved solubility of the sulfonylurea may be due to complex formation with cyclodextrin. The co-pulverized mixture can be easily processed into solid dosage forms and even into liquid dosage forms as the pulverized mixture is completely water-soluble.
Summary of the Invention
In one general aspect, it relates to a process of improving the aqueous solubility of sulfonylurea wherein the process comprises co-pulverizing a dry mixture of sulfonylurea and a cyclodextrin.
In another general aspect, it relates to a process of improving the aqueous solubility of sulfonylurea wherein the process comprises co-pulverizing a dry mixture of sulfonylurea and cyclodextrin wherein the ratio of sulfonylurea to cyclodextrin is from about 1:1 to about 1:30 by weight.
Detailed Description of the Invention
Prior to co-pulverization, the particle size of sulfonyl urea as used herein may vary from about 0.1 µm to about 500µm. Like wise, the cyclodextrin may also have a particle size of about 0.µm to about 500µm. The initial smaller particle size of the materials prior to co-pulverization reduces the process duration. The
ratio of sulfonylurea to cyclodextrin may be from about 1:1 to about 1:30 by weight.
The sulfonylurea can be selected form glyburide, glipizide, glimepiride, chlorpropamide and tolbutamide.
The cyclodextrtins are cyclic oligosaccarides consisting of multiple (a-1,4)-linked a-D-glucopyranose units that display amphoteric properties of a lipophilic central cavity and a hydrophilic outer surface. Depending upon the number of gluopyranose units the cyclodextrins are classified as α, ß and y cyclodextrins. The synthetic derivatives of natural cyclodextrins are also available. Examples include hydroxypropyl-P-cyclodextrin, sulfobutylether-P-cyclodextrin, randomly methylated (3-cyclodextrins etc. These synthetic derivatives have improved solubility over the natural cyclodextrins. The cyclodextrin may be selected from α-, ß- and y-cyclodextrin and their derivatives. Particularly suitable are P-cyclodextrins such as hydroxypropyl-p-cyclodextrin and sulfobutylether P-cyclodextrin.
The co-pulverized mixture obtained by the process described herein can be used in the preparation of various pharmaceutical dosage forms like tablets, capsules, oral solutions, suspensions etc. For inclusion in solid dosage forms the co-pulverized mixture can be mixed with other commonly used excipients such as fillers, binders, disintegrants, glidants, lubricants and processed into a dosage form. The co-pulverized mixture can be dissolved in a pharmaceutically acceptable liquid along with other excipients to prepare a solution or suspension.
The pulverization may be carried out with commonly available equipments such as rotary mill, roller mill, mortar mill, ball mill. Particularly suitable is a ball mill. The ball mill has a cylindrical shell which is rotated on a horizontal axis. In the shell, the balls are placed which can be of porcelain or stainless steel. The balls serve as pulverizing medium. The shear forces are generated by the friction
between the balls and between the wall of the shell and the balls. The size reduction and complex formation are due to these shear forces.
In general, the process comprises premixing sulfonylurea and cyclodextrin in a blender. The blend is charged in a ball mill along with stainless steel balls and rotated at a speed sufficient to cause a sliding motion of the balls. The blend undergoes shearing forces of the balls and gets finely pulverized and mixed. During this process, the material sticking to the wall can be scraped. Generally, the ball mill can be operated from 1 hour to about 24 hours. The process can be followed in batches as well as continuously.
In one embodiment, the process comprises mixing sulfonylurea and hydroxypropyl-P-cyclodextrin in a weight ratio of about 1: 20 and charging in a ball mill with stainless steel balls; the ball mill is rotated for 18 to 24 hours with intermittent scraping of the material adhered to the wall. The material is removed from the mill and sifted to remove any aggregates.
The invention described herein is further illustrated by the following example but it should not be construed as limiting the scope of the invention.
EXAMPLE
Micronised glipizide and hydroxypropyl-ß-cyclodextrin in a weight ratio of 1:20 were blended in a blender for 10 minutes. The blend was sifted and placed in a ball mill and the mill was rotated for 24 hours with intermittent scraping of the material adhered to the wall of the mill. The material was removed from the mill and sifted.

WE CLAIM:
1. A process of improving the aqueous solubility of sulfonylurea wherein the process comprises co-pulverizing a dry mixture of sulfonylurea and a cyclodextrin.
2. The process according to claim 1 wherein the ratio of sulfonylurea to cyclodextrin is from about 1: 1 to about 1:30 by weight.
3. The process according to claim 2 wherein the ratio of sulfonylurea to cyclodextrin is about 1:20 by weight.
4. The process according to claim 1 wherein the co-pulverization is done for about 1 hour to about 24 hours.
5. The process according to claim 4 wherein the co-pulverization is done for about 18 hours to about 24 hours.
6. The process according to claim 1 wherein the sulfonylurea is selected from glyburide, glipizide, glimepiride, chlorpropamide and tolbutamide.
7. The process according to claim 6 wherein the sulfonylurea is glyburide.
8. The process according to claim 6 wherein the sulfonylurea is glipizide.
9. The process according to claim 1 wherein the cyclodextrin is selected form one or more of α-, ß-, and y- cyclodextrins.
10. The process according to claim 9 wherein the cyclodextrin is selected from P-cyclodextrin.
11. The process according to claim 10 wherein the 3-cyclodextrin is selected from hydroxypropyl-3-cyclodextrin and sulfobutylether-P-cyclodextrin.
12. The process according to claim 11 wherein the p-cyclodextrin is hydroxypropyl-P-cyclodextrin.
13. The process according to claim 1 wherein the co-pulverizing is done in rotary mill, roller mill, mortar mill and ball mill.
14. The process according to claim 13 wherein the co-pulverizing is done in ball mill.
15. A pharmaceutical composition comprising a co-pulverized mixture of sulfonylurea and cyclodextrin.
16. The pharmaceutical composition according to claim 15 wherein the composition is a tablet, capsule, solution or suspension.
17. A process of improving the aqueous solubility of sulfonylurea substantially as described and exemplified herein.