Title of Invention

A CONTROLLED RELEASE ANTIDIABETIC FORMULATION COMPRISING GLICLAZIDE

Abstract The present invention relates to a novel drug release system for sulfonylureas wherein the active ingredient is homogeneously dispersed throughout a rate controlling polymer mixture matrix and the rate of the drug is thus controlled by its diffusion through the polymer matrix. The present invention also relates to controlled release formulation for sulfonylureas and more particularly Gliclazide, which replaces the use of glucose syrup (maltodextrin) by a more pharmaceutically acceptable binding agent such as Polyvinylpyrrolidone. The use of two different grades of Hydropropylmethyl Cellulose i. e. 4000 cps and 15,000 cps gives the desired extended release irrespective of pH of the dissolution medium.
Full Text FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
[See section 10, rule 13]
"A CONTROLLED RELEASE ANTIDIABETIC FORMULATION"
(a) IPCA LABORATORIES LIMITED
(b) 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India
(c) Indian Company incorporated under the Companies Act 1956
The following specification describes the nature of this invention and the manner in which it is to be performed:


Related Application :
Related application for "A Process for preparation of Controlled Release Antidiabetic Formulation" with application no. 1155/MUM/2002 is disclosed and reported herein.
Technical Field of invention :
The present invention relates to a controlled release antidiabetic formulation comprising a novel drug release system wherein a pharmaceutically active ingredient such as sulfonyl urea is homogeneously dispersed throughout a rate- controlling matrix and the rate of drug release is controlled by its diffusion through the polymer matrix.
Background & Prior Art:
Gliclazide is a hypoglycemic agent of the sulphonylurea group used for the control of blood glucose level in people with type II diabetes. Gliclazide is used when diet, exercise and weight reduction have not been found to be effective towards controlling blood sugar. Gliclazide increases the amount of insulin released by the pancreas and helps the body to use insulin more effectively.
The initial development of Gliclazide led to the mairketing of different formulations of 80 mg tablets worldwide. Although these formulations differ substantially in their pharmacokinetic performance in vivo, there was no evidence that they were different in their efficiency and safety in type II diabetic patients, thereby suggesting that gliclazide does not exert its effect in a dose-dependent manner by virtue of threshold plasma drug concentration. Formulations of Gliclazide are prescribed in the dose range of 80-320 mg/day, tablets taken once to 3 times a day. Individual dose requirements vary between patients, which reflect the inter-individual variability in pharmacokinetic characteristics in addition to differences in diabetes severity. Administration of Gliclazide in such types i.e. conventional dosage forms often result in extreme fluctuation of drug concentration in systemic circulation and tissue compartments.
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It is often impossible to predict or determine whether a particular sustained release formulation will provide the desired release profile for a relatively insoluble drug and hence it is necessary to carry out considerable experimentation to obtain sustained release formulations having the desired bioavailability when ingested particularly for drugs like Gliclazide, which is poorly soluble in water.
Uniformity and predictability of the therapeutic level of sulfonylureas and resulting blood sugar levels are considered to be desired in the management of diabetic patients and particularly for the management of type II patients. It is usually desirable from the standpoint of pharmacodynamics, to maintain the drug concentration in the ailing tissue cells at a constant level and within a therapeutically effective dose range as long as the treatment requires. However, the availability of the drug molecules to the cells is governed by a sequence of pharmacokinetic process release, absorption dilution and elimination. These processes could, in some cases, result in the inefficient bioavailability of the drug to the target tissue cells. Very often doses far in excess of those required in the cells have to be administered in order to achieve the necessary therapeutically effective concentration. Unfortunately this massive dosing frequency leads to resistance and elicits undesirable immunological and toxicological effects in non- target tissues. The bioavailability to a target tissue can be maximized and the adverse side effects in non-target tissues can be minimized by applying the principles of controlled drug administration.
A number of controlled release formulations of sulfonylureas have been described in various patents such as Osmotic pump devices US Pat 4,803, 076, 5,091,190, and 5,024,848.
Enteric coated with additional sustained release coating formulations of sulfonylureas are reported in US Pat 6,056,977, WO 9918932. Drug polymer mixture in hot state i.e. using thermoforming extrusion process is described in US Pat 6,319,520. All these inventions based on complex manufacturing processes are time-consuming with
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attendant high cost. The processes discussed in these patents are not commercially viable and are not satisfactory for therapeutic development. They also do not meet the minimum requirements of economic exploitation as well as predicable and uniform treatment regimen.
The prior art also describes a number of patents that disclose the use of Gliclazide in combination with other antidiabetic agents such as in US Pat 6,475,521. However there is only one patent on Gliclazide formulations as such. International application WO 0018373 describes a Gliclazide formulation wherein glucose syrup (maltodextrin) is used as binder. As disclosed above, Gliclazide is a hypoglycemic agent for management of type II diabetes and use of glucose syrup or maltodextrin in an antidiabetic preparation is not only not advisable but is also not ethical, especially because the patient often does not get informed about the nature of excipients used in a formulation.
A highly critical problem, facing the pharmaceutical industry is to formulate a bioavailable oral sustained release dosage form of an insoluble sulfonylurea related to the ability of the dosage form to release the drug over the desired period of time to such an extent that the sulfonylurea content of the dosage form will be effectively bioavailable. To increase the bioavailability of sulfonylurea with the inclusion of solubilising agent would not be considered desirable in sustained release oral dosage form, where the goal is to slow down the release of drug over an extended period of time.
Thus there is a need to develop a simple, stable and more economical controlled release drug delivery to release sulfonylureas which significantly reduces the frequency of drug dosing, maintains a steady drug concentration in blood circulation and minimizes the incidence and severity of adverse side effects.
Thus the current invention is designed to overcome the abovementioned problems in formulation of controlled release dosage forms of relatively insoluble sulphonylureas.
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Objectives
An object of the present invention is to design a simple, stable and economical
controlled release drug delivery to release sulfonylureas.
Another object is to reduce the frequency of drug dosing.
A further objective is to maintain a steady drug concentration in blood circulation.
Another objective is to minimize the incidence and severity of adverse side effect.
Summary of the Invention :
The present invention discloses a controlled release antidiabetic formulation comprising a novel drug release system wherein a pharmaceutically active ingredient such as sulfonyl urea, preferably gliclazide is homogeneously dispersed throughout a rate-controlling matrix and the rate of drug release is controlled by its diffusion through the polymer matrix.
In the present invention, the drug reservoir compound is homogeneously dispersed as discrete crystals in a matrix environment formed by the cross linking of linear polymer chain. The rate of release of the drug is controlled by first dissolution in the surrounding polymer and then diffusion through the polymer matrix.
In the present invention the use of combination of two specific Hydroxypropylmethyl Cellulose polymers helps in releasing the drug effectively over a specific period of time independent of pH effect.
The present invention also avoids use of glucose syrup (maltodextrin) as binding agent and uses a more acceptable binding agent such as polyvinylpyrrolidone.
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Detailed Description of the Invention :
The present invention discloses a controlled release antidiabetic formulation comprising a novel drug release system wherein the sulfonyl urea is homogeneously dispersed throughout a rate- controlling matrix and the rate of drug release is controlled by its diffusion through the polymer matrix.
The said controlled release antidiabetic formulation comprises an active ingredient such as sulfonyl urea in the range 15-35 % of total mass of the dosage form, preferably 25.8 % of the total mass of the dosage form; a combination of two or more release retardant polymers of about 5 to 15% of total mass of the dosage form; diluent about 40-60% of total mass of the dosage form; binding agent 2-15% of total mass of the dosage form; preferably 2-8%; lubricant about 0.5 - 1% of total mass of the dosage form; and glidant about 0.2 - 0.4 % in an aqueous vehicle q.s.
The said sulfonyl urea is Gliclazide
The combination of two or more release retardant polymers is selected from cellulosic polymers having different viscosity. The preferred polymers used are Hydroxypropyl methyl cellulose with different viscosities. The said Hydroxypropylmethyl Cellulose is well known controlled release excipient and is capable of producing a controller swelling bioerodible matrix, in an extended release dosage form. In controlled release formulation the most practical approach is choosing the correct ratios and viscosity grades of Hydroxypropyl methyl cellulose. Two different grades of Hydroxypropyl methyl cellulose are granulated together to fine adjust the dissolution rate. The said polymers are Hydropropyl methyl cellulose - 4000 cps and Hydroxypropyl methyl cellulose - 15000 cps. The said binder is polyvinylpyrrolidone of grades varying from 10 -120, preferably with K value of 30 or grade 30. Povidone USP: a non-release controlling excipient. Polyvinylpyrrolidone is a water soluble granulating agent, added as an aqueous binder for the release controlling excipients. The said lubricant is magnesium stearate. Further Magnesium Stearate prevents powder from sticking to the
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tablet tooling, thus reducing the friction between the dye wall and the tablet as it is being ejected. The said glidant is Silicon Dioxide which is non-release controlling excipient. Glidant promotes granulate flow by reduction of the inter particulate friction. The said aqueous vehicle is Purified Water which is used as a granulating fluid in the manufacture of granulating agent. The water poses no environmental problems or health hazards to the workers and alleviates the necessity of solvent recovering systems.
The said controlled release antidiabetic formulation may be in the dosage from of tablet or hard gelatin capsules. The said tablet may be designed as capsule shaped tablet.
The process of formulation involves following steps:
(a) dispersing the active ingredient in the range of 15-35 %, preferably 25.8 % in about 5-15 % of polymer matrix by blending a therapeutic dose of finely ground drug particles into mixer with combination of two modified release retardant polymers i.e. Hydroxypropyl methyl cellulose 4000 cps and Hydroxypropyl methyl cellulose 15000 cps wherein 40 - 60 % diluents is added to above mixture with mixing;
(b) preparing 2-10 % of the binder solution and adding the said solution slowly into drug polymer mixture prepared as in step (a);
(c) blending the mixture uniformly till uniform distribution and mixing the polymers in drug to form a matrix with aid of the said binding agent;

d) allowing the polymer to swell and grow in thickness of drug depleted gel layer and to form the envelope around the drug;
e) drying the wet granules and rasping through sieve of 20 mesh and loading these granules into planetary mixer;
f) adding 0.5 - 1 % of lubricants and 0.2-0.4 % of glidants to this mixture and mixing for 2 to 5 minutes; and
g) transferring the lubricated granules to a compression machine and compressing the granules into tablets.
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The process as described helps the drug molecules to elute out of cellulose matrix by first dissolution in the surrounding polymer and then diffusion through the polymer structure. When this polymer layer becomes depleted the drug solids in the next layer then begin to dissolute and elute. Thus the goal of release of drug in controlled manner can be achieved with such type of proportionate matrix design.
In a preferred embodiment of the present invention, the said formulation comprises about 15 to 35 %, preferably 25.8% of active ingredient and about 5 - 15% of release retardant polymer A & B with around 40 to 60% of the diluent and 2 to 10% of binding agent.
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the invention.
Example 1
40 g of lactose and 30 g of Gliclazide was passed through 40 mesh and mixed in planetary mixer for 10 mins. 4 g of Polyvinylpyrrolidone (PVP) (K-30) was dissolved in water by dispersion. This solution of PVP was then added to the dry mixture slowly till a wet mass was formed. The wet mass was passed through 8 mesh and the granules were dried at 50 to 55°C. The following lubricants 30 g of Hydroxypropylmethyl cellulose, 5 g of Silicon Dioxide were sifted through 60 mesh and mixed with dry granules of Gliclazide in planetary mixer for 10 mins. Finally they were lubricated with 0.4 g of Magnesium Stearate for 2 mins. and the blend was compressed into capsule shaped tablets, each containing 30 mg of Gliclazide. When these tablets were subjected to invitro dissolution, following results were obtained.
Time in Hrs. % Gliclazide Release
2 Hrs. 20%
4 Hrs. 33%
8 Hrs. 48%
12 Hrs 76%
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Example 2
30 g of Lactose, 30 g of Starch, 10 g of Hydroxypropyl methyl cellulose (4000 cps.), 10
g of Hydroxypropyl methyl cellulose (15 cps) was passed through 40 mesh and 30 g of
Gliclazide was passed through 60 mesh and mixed in planetary mixer for 10 mins. 5 g
of polyvinyl pyrrolidone(K-30) was dissolved in water by dispersion. The polyvinyl
pyrrolidone solution was then added slowly into dry mixture till desired wet mass was
formed. The wet mass was passed through 8 mesh and the granules were dried at 50-55°
C. The silicon dioxide was sifted through 40 mesh and mixed with the dry granules and
finally lubricated with 0.4 g of Magnesium Stearate for 2 mins. and the blend was
compressed into capsule shaped tablets, each containing 30 mg of Gliclazide. When
these tablets were subjected to invitro dissolution, following results were obtained.
Time in Hrs. % Gliclazide Release
2 Hrs. 24%
4 Hrs. 40%
8 Hrs. 80%
12 Hrs 92%
Example 3
75 g of Dicalcium Phosphate Dihydrate granules, 5 g Polyvinylpyrrolidone (K-30), 10 g of Hydroxypropylmethyl Cellulose (4000 cps), 10 g of Hydroxypropylmethyl Cellulose (15000 cps), 0.4 g of colloidal Silicon Dioxide, 0.6 g of Talc and 30 g of Gliclazide was passed through 40 mesh and mixed in a planetary mixer for 15 minutes. 0.8 g of Magnesium Stearate was passed through 40 mesh and mixed with above dry blend for 2 mins. and this dry blend was compressed into capsule shaped tablets, each containing 30 mg of Gliclazide. When these tablets were subjected to in vitro dissolution, following results were obtained.
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Time in Hrs. % Gliclazide Release
2 Hrs. 21%
4 Hrs. 36%
8 Hrs. 58%
12 Hrs 71%
Example 4
51g of Dicalcium Phosphate Dihydrate granule, 3 g of Polyvinylpyrrolidone (K-30), 25 g of Hydroxypropylmethyl Cellulose (15000 cps), 0.4 g of Colloidal Silicon Dioxide, 30 g of Microcrystalline Cellulose (pH 10) and 30 g of Gliclazide were passed through 40 mesh and mixed in a planetary mixer for 15 minutes. 0.8 g of Magnesium Stearate was passed through 40 mesh and mixed with above dry blend for 2 mins. and this dry blend was compressed into capsule shaped tablets, each containing 30 mg of Gliclazide. When these tablets were subjected to invitro dissolution, following results were obtained.
Time in Hrs. % Gliclazide Release
2 Hrs. 22%
4 Hrs. 42%
8 Hrs. 59%
12 Hrs 73%
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We Claim,
1. A controlled release antidiabetic formulation wherein the said formulation comprises an active ingredient such as sulfonyl urea in the range of 15-35 % of the total mass of dosage form; one or more release retardant polymers in concentrations of 5 to 15 % of the total mass of dosage form; binding agent preparing 2-15 % of the total mass of dosage form; diluents 40 - 60 % of the total mass of dosage form; lubricant in concentration of 0.5 to 1.0 % of the total mass of dosage form; glidant in concentration of 0.2 - 0.4 % of the total mass of the dosage form; and an aqueous vehicle q. s.
2. The formulation as claimed in claim 1, wherein the said sulfonylurea is gliclazide.
3. The formulation as claimed in claim 1, wherein the said one or more release retardant polymers are selected from cellulosic polymers with different viscosities.
4. The formulation as claimed in claims 1 and 3, wherein the said cellulosic polymers are Hydroxypropyl methyl cellulose - 4000 cps and Hydroxylpropyl methyl cellulose 15000 cps.
5. The formulation as claimed in claim 1, wherein the said binder used is polyvinylpyrrolidone of grades varying from 10-120, preferably with K value of 30 or grade 30.
6. The formulation as claimed in claim 1, wherein the said lubricant is Magnesium Stearate.
7. The formulation as claimed in claim 1, wherein the said glidant is colloidal Silicon Dioxide.
8. The formulation as claimed in claims 1 to 7, wherein the said formulation is in the form of granules; which may be compressed into tablets, preferably capsule shaped tablets.
9. The formulation as claimed in claims 1 to 7, wherein the said formulation is in the form of granules; which may be filled into hard gelatin capsules
10. The formulation as claimed in claims 1 to 9, wherein the drug reservoir compartment has a homogeneous dispersion of a drug or a combination of drugs as
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discrete crystals in the matrix environment formed by the cross-linking of linear polymer chains.
11. The formulation as claimed in claims 1 to 9, wherein the active ingredient is homogeneously dispersed throughout a rate controlling matrix and the rate of the drug is controlled by its diffusion through the polymer matrix.
12. A controlled release anti diabetic formulation as substantially described herein with reference to foregoing examples 1 to 4.
Dated this the 16th day of August 2004
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Abstract:
The present invention relates to a novel drug release system for sulfonylureas wherein the active ingredient is homogeneously dispersed throughout a rate controlling polymer mixture matrix and the rate of the drug is thus controlled by its diffusion through the polymer matrix. The present invention also relates to controlled release formulation for sulfonylureas and more particularly Gliclazide, which replaces the use of glucose syrup (maltodextrin) by a more pharmaceutically acceptable binding agent such as Polyvinylpyrrolidone. The use of two different grades of Hydropropylmethyl Cellulose i. e. 4000 cps and 15,000 cps gives the desired extended release irrespective of pH of the dissolution medium.

Documents:

890-MUM-2004-ABSTRACT(9-7-2009).pdf

890-MUM-2004-ABSTRACT(GRANTED)-(9-6-2011).pdf

890-mum-2004-abstract.doc

890-mum-2004-abstract.pdf

890-MUM-2004-CANCELLED PAGES(17-3-2011).pdf

890-MUM-2004-CLAIMS(9-7-2009).pdf

890-MUM-2004-CLAIMS(AMENDED)-(17-3-2011).pdf

890-MUM-2004-CLAIMS(GRANTED)-(9-6-2011).pdf

890-MUM-2004-CLAIMS(MARKED COPY)-(17-3-2011).pdf

890-mum-2004-claims.doc

890-mum-2004-claims.pdf

890-MUM-2004-CORRESPONDENCE(28-12-2005).pdf

890-MUM-2004-CORRESPONDENCE(IPO)-(10-6-2011).pdf

890-mum-2004-correspondence-received-031106.pdf

890-mum-2004-correspondence-received-200207.pdf

890-mum-2004-correspondence-received.pdf

890-mum-2004-descripiton (complete).pdf

890-MUM-2004-DESCRIPTION(COMPLETE)-(9-7-2009).pdf

890-MUM-2004-DESCRIPTION(GRANTED)-(9-6-2011).pdf

890-MUM-2004-FORM 1(16-8-2004).pdf

890-MUM-2004-FORM 1(9-7-2009).pdf

890-MUM-2004-FORM 18(28-12-2005).pdf

890-mum-2004-form 2(9-7-2009).pdf

890-MUM-2004-FORM 2(GRANTED)-(9-6-2011).pdf

890-MUM-2004-FORM 2(TITLE PAGE)-(9-7-2009).pdf

890-MUM-2004-FORM 2(TITLE PAGE)-(COMPLETE)-(16-8-2004).pdf

890-MUM-2004-FORM 2(TITLE PAGE)-(GRANTED)-(9-6-2011).pdf

890-MUM-2004-FORM 3(16-8-2004).pdf

890-MUM-2004-FORM 3(9-7-2009).pdf

890-mum-2004-form-1.pdf

890-mum-2004-form-18.pdf

890-mum-2004-form-2.doc

890-mum-2004-form-2.pdf

890-mum-2004-form-26.pdf

890-mum-2004-form-3.pdf

890-MUM-2004-REPLY TO EXAMINATION REPORT(15-4-2010).pdf

890-MUM-2004-REPLY TO EXAMINATION REPORT(9-7-2009).pdf

890-MUM-2004-REPLY TO HEARING(17-3-2011).pdf


Patent Number 248023
Indian Patent Application Number 890/MUM/2004
PG Journal Number 24/2011
Publication Date 17-Jun-2011
Grant Date 09-Jun-2011
Date of Filing 16-Aug-2004
Name of Patentee IPCA LABORATORIES LIMITED
Applicant Address 48, KANDIVLI INDUSTRIAL ESTATE, MUMBAI
Inventors:
# Inventor's Name Inventor's Address
1 THEMBALATH RAMACHANDRAN 6/35, PRAKASH CO. HOUSING SOCIETY, RELIEF ROAD, SANTACRUZ (WEST), MUMBAI-400054
2 BANSAL YATISH KUMAR FLAT NO. 5, SIRAS VILLA, PLOT NO. 40, SAI BABA PARK, EVERSHNE NAGAR, MALAD (WEST), MUMBAI - 400 064.
3 TAWADE VAISHALI MANISH B-2, 14th FORJETT TERRACE, FORJETT HILL ROAD, OPP. BHATIYA HOSPITAL, GRANT ROAD, MUMBAI - 400 036,
4 JADHAV VIVEK FLAT NO. 2, R. R. SABAGI CO-OP. HOUSING SOCIETY, 10, RAMBAGH, ANDHERI (W), MUMBAI - 400 058.
5 Bansal, Yatish Kumar Flat No.5, Siras Villa, Plot No. 40, Sai Baba Park, Evershine Nagar, Malad (West) Mumbai 400 064
PCT International Classification Number A61K 9/20, A61K 9/22, A61K 31/426
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA