FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION COMPRISING GLIPIZIDE
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to a stable controlled release pharmaceutical
composition comprising of an effective dose of glipizide or pharmaceutically
acceptable salt thereof in the form of complex with cyclodextrins or derivatives
thereof suitable for oral administration to a patient in need of treatment related
thereto.
The following specification particularly describes the invention and the manner
in which it is to be performed.
4. DESCRIPTION
The present invention relates to a stable controlled release pharmaceutical composition comprising of an effective dose of glipizide or pharmaceutically acceptable salt thereof in the form of complex with cyclodextrins or derivatives thereof suitable for oral administration to a patient in need of treatment related thereto.
Glipizide is an oral blood-glucose lowering drug that is used to manage hyperglycemia in patients with non-insulin dependent diabetes mellitus.
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Glipizide chemically is (1-cyclohexyl-3-[[p-[2-(5-methylpyrazinecarboxamido) ethyl]phenyl]sulfonyl]urea), of formula 1. Glipizide is generally a white, odorless compound. It is insoluble in water and alcohol, has a molecular weight of 445.55 and a pKa of 5.9. Glipizide stimulates insulin secretion from the beta cells of pancreatic-islet tissue, increases the concentration of insulin in the pancreatic vein, and may increase the number of insulin receptors. It is also indicated as an adjunct to diet for the control of hyperglycemia and its associated symptomatology in patients with type 2 diabetes formerly known as non-insulin-dependent diabetes mellitus (NIDDM) or maturity-onset diabetes, after an adequate trial of dietary therapy has proved unsatisfactory.

US Patent No 5,945,125 describes a process of manufacturing a controlled release tablet with a water swellable polymer, non-crosslinked polyethylene oxide, with an average molecular weight in the range of 900,000 to 5,000,000. The water swellable polymer is chosen such that the swelling rate of the polymer is equal to the dissolution rate of the swollen polymer.
US Patent No 6,875,793 discloses a method of treating diabetes comprising administering a sustained release dosage form for oral administration comprising a therapeutically effective amount of sulfonylurea suspended or dissolved in an alkaline aqueous medium; and, a controlled release matrix comprising a gelling agent, and an inert diluent; wherein: the ratio of gelling agent to inert diluent is from about 1:8 to about 8:1; and the gelling agent comprises a
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heteropolysaccharide and a homopolysaccharide in a ratio of from about 3:1 to about 1:3.
US Patent No 6,703,045 discloses a composition with an oral controlled release system useful for reducing serum glucose levels, said composition comprising: sulphonylurea at a concentration ranging from 5 to 20% by weight, polyethylene oxide polymer having a molecular weight of from 4 million to 8 million at a concentration ranging from 5 to 18% by weight, lubricant at a concentration ranging from 1 to 3% by weight, and dicalcium phosphate at a concentration of more than 50% by weight.
Diabetes mellitus is a metabolic disorder characterized by hyperglycemia, insulin resistance, and is often associated with other disorders such as obesity, hypertension, hyperlipidemia, as well as complications such as cardiovascular disease, retinopathy, neuropathy, and nephropathy. The disease is progressive in nature, and can often be controlled initially by diet alone, but generally requires treatment with drugs such as sulfonylureas e.g., glipizide. The use of sulfonylureas in treating type 2 diabetes is established as an effective means of controlling hypoglycemia. Sulfonylureas act by stimulating insulin release and are thus only effective with some residual pancreatic beta-cell activity.
However physical and chemical properties of glipizide do not easily lend the drug to formulation into a dosage form which provides glipizide at a controlled and known rate per unit time to produce the intended therapy. Extended release sulfonylurea formulations with improved dissolution properties, are therefore desirable additions to the medical treatment of diabetes, including type II diabetes.
In view of the above discussion, it will be appreciated that a need exists for dosage forms that can deliver a sulfonylurea in a controlled release to a patient in clinical need of blood-glucose lowering therapy, and methods of use thereof.
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The present invention now provides a controlled release dosage form for oral administration comprising of an effective dose of glipizide or pharmaceutical^ acceptable salt thereof along with cyclodextrins or derivatives thereof to a patient in need of treatment related thereto. The invention also uses controlled release coating agent to further coat the core comprising glipizide or pharmaceutically acceptable salt thereof.
In one of the aspects of the present invention there is provided a controlled release dosage form comprising glipizide or salt thereof wherein the glipizide is present in the form of complex with cyclodextrins or derivatives thereof along with pharmaceutically acceptable excipients.
Glipizide has poor aqueous solubility and slow dissolution rate which leads to irreproducible clinical response or therapeutic failure in some cases due to subtherapeutic plasma drug levels. Complexation of glipizide with cyclodextrins or derivatives thereof leads to great enhancement in dissolution rate, increased duration of action and improvement of therapeutic efficacy of the drug. Suitable cyclodextrin derivatives may be selected from hydroxypropyl-0-cyclodextrin, p-cyclodextrin, a-cyclodextrin, hydroxypropyl- a -cyclodextrin and the like.
In another aspect of the present invention there is provided a controlled release dosage form which comprises a core comprising glipizide or salt thereof in the form of complex with cyclodextrins or derivatives thereof along with other pharmaceutically acceptable excipients; the core is further coated with a pharmaceutically acceptable release controlling polymers.
The therapeutically effective amount of glipizide or salt thereof is included in this composition. The pharmaceutical compositions comprising the glipizide or salt thereof disclosed herein are administered orally. The term dosage form means at least one unit dosage form of the present invention. The composition can be
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employed in admixture with pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients can be diluent, filler, binder, lubricant, sweetener, polymers, wetting agent, coloring and flavoring agent, glidant and the like. Suitable diluents include pharmaceutically acceptable inert fillers, such as one or more of microcrystalline cellulose, lactose, dibasic calcium phosphate, mannitol, starch, sorbitol, sucrose, dextrose, maltodextrin and mixtures thereof. Suitable binders may include one or more of polyvinyl pyrrolidone, lactose, starches, gums, waxes, gelatin, polymers and mixtures thereof. Suitable lubricants include one or more of colloidal silicon dioxide, talc, stearic acid, magnesium stearate, magnesium silicate, polyethylene, sodium benzoate, sodium lauryl sulphate, fumaric acid, zinc stearate, paraffin, and mixtures thereof. Suitable glidants include, for example, one or more of talc or magnesium stearate and colloidal silicon dioxide. Suitable coloring and flavoring agents include those approved for use by the United States Food and Drug Administration (FDA) and are well known to those skilled in the art.
The pharmaceutically acceptable release controlling polymers include but is not limited to a hydroxyalkylcellulose (e.g., hydroxypropyl cellulose, hydroxypropylmethyl cellulose); polyalkylene oxide (e.g., poly(ethylene) oxide, poly(methylene oxide), poly(butylene oxide), and poly(hexylene oxide); poly(hydroxy alkyl methacrylate); poly(vinyl)alcohol, having a low acetal residue, which is cross-linked with glyoxal, formaldehyde or glutaraldehyde and having a degree of polymerization of from 200 to 30,000; a mixture of methyl cellulose, cross-linked agar and carboxymethyl cellulose; ethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, polymethyl methacrylate, polyethyl methacrylate, polybutyl methacrylate, polyisobutyl methacrylate, polyhexyl methacrylate, poly isodecyl methacrylate, polylauryl methacrylate, polyphenyl methacrylate, polymethyl acrylate, polyisopropyl acrylate, polyisobutyl acrylate, polyoctadecyl acrylate, polyethylene, polypropylene, polyethylene oxide,
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polyethylene terephthalate, polyvinyl isobutyl ether, polyvinyl acetate, polyvinyl chloride, polyurethane or a mixture thereof.
The core may optionally comprise absorption enhancer. The absorption enhancer can be any type of absorption enhancer commonly known in the art such as a surfactant, a chelating agent, a bile salt or mixtures thereof. Examples of some preferred absorption enhancers are surfactants such as sodium lauryl sulfate, polysorbate and the like, chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA) and the like, fatty acids such as capric acid, oleic acid and the like.
The dosage form can be prepared by direct compression, dry granulation or by wet granulation. The controlled release tablet may be prepared by wet granulation method and the process may comprise of mixing of B-cyclodextrin, calcium diphosphate dihydrate, hydroxypropyl cellulose and hydroxy ethyl cellulose using dry Saizona mixer; preparation of aqueous dispersion of dimethicone and sodium lauryl sulphate, addition of glipizide to this dispersion and preparation of granules using above blend, lubrication of granules, tablet compression followed by coating.
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 intended to be included within the scope of the present invention.
EXAMPLES
The composition of the batches is provided in Table 1.
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Table 1 - Composition of batches.

Sr. No. Ingredients Quantity / Tablet in mg
1. Glipizide 10.000
2. Sodium lauryl sulphate 15.000
3. Dimethicone 1.000
4. Beta- Cyclodextrin 181.840
5. Calcium hydrogen phosphate dihydrate 145.570
6. Hydroxtpropylcellulose (Klucel LF) 12.000
7. Hydroxyethylcellulose (Natrasol 250 M) 58.120
8. Stearic Acid 4.070
9. Colloidal silicon dioxide (Aerosil200) 2.000
10. Magnesium Stearate 0.400
11. Purified water q.s.
Total 430.000
Coating Formula -
Hypromellose 6 cps 14.300
Ethylcellulose 10 cps 8.300
Polyethylene glycol 4000 2.700
Methylene Chloride 0.150
Isopropyl Alcohol 0.100
Titanium Dioxide 2.700
Process -
1) G-cyclodextrin, calcium diphosphate dihydrate, hydroxypropyl cellulose and hydroxy ethyl cellulose were mixed properly using dry Saizona mixer.
2) Dimethicone and sodium lauryl sulphate were dispersed in purified water, to this mixture glipizide was added and stirred properly for half an hour.
3) Step 2 dispersion was added to step 1 and mixture was granulated keeping impeller on slow speed and chopper off.
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4) Granules were dried using fluidized bed drier at 60°C.
5) Stearic acid, colloidal silicon dioxide and magnesium stearate were added and mixed properly for 20 minutes.
6) Granules were compressed into tablets.
7) Further these tablets were coated with the coating solution.
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WE CLAIM:
1. A controlled release dosage form comprising glipizide or salt thereof wherein the glipizide is present in the form of complex with cyclodextrins or derivatives thereof along with pharmaceutically acceptable excipients.
2. A dosage form of claim 1, wherein the cyclodextrin is 0-cyclodextrin.
3. A controlled release dosage form which comprises a core comprising glipizide or salt thereof in the form of complex with cyclodextrins or derivatives thereof along with other pharmaceutically acceptable excipients; the core is further coated with a pharmaceutically acceptable release controlling polymers.
4. A dosage form of claim 1, wherein the composition is selected from a group consisting of a tablet, caplet, capsule and a granular form.
5. A dosage form of claim 3, wherein the pharmaceutically acceptable release controlling polymer is selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose; ethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, polymethyl methacrylate and the like.
6. A dosage form of claim 1, wherein the pharmaceutically acceptable excipients comprise one or more of diluents, binders, plasticizers, opacifiers, absorption enhancers, lubricants, diluents, opacifiers and colorants.
7. A dosage form of claim 1, wherein the diluent is selected from
pharmaceutically acceptable inert filler, such as one or more of microcrystalline
cellulose, lactose, dibasic calcium phosphate, mannitol, starch, sorbitol, sucrose,
maltodextrin and mixtures thereof.
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8. A dosage form of claim 1, wherein the binder is selected from one or more of polyvinyl pyrrolidone, lactose, starches, gums, waxes, gelatin and mixtures thereof.
9. A dosage form of claim 6, wherein the absorption enhancer is selected from surfactant, a chelating agent, a bile salt or mixtures thereof and the like.
10. A dosage form of claim 9, wherein the surfactant is sodium lauryl sulphate.
Dated this 28th day of June, 2006 For Wockhardt Limited
(Mandar Kodgule)
Authorized Signatory