The present invention relates to a procen for prepariy a formulation comprising a matrix of
plynanide and a matrix of sulfonylon
pharmaceutical composition for oral administration of combination of antidiabetic agents wherein one is present in an extended release form and the other In an immediate release form.
• 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 or injections of exogenous insulin.
Sulfonylureas are a group of drugs that induce hypoglycemia by stimulating insulin release from the pancreas. Suitable sulfonylureas include acetohexamide, glibenclamide (glyburide), glipizide, gliclazide, glimepiride, tolazamide and tolbutamide. Glyburide is available as tablets of 1.25 mg, 2.5 mg and 5 mg strengths for oral administration and is administered twice a day. Glipizide tablets are available in 5 and 10 mg tablets. Similarly, glimepiride is available as 1, 2 and 4 mg tablets to be administered once daily.
BIguanldes are another group of drugs that have been widely used as antidiabetics. They act by increasing insulin activity in peripheral tissues, reducing hepatic glucose output due to inhibition of gluconeogenesis and reducing the absorption of glucose from the intestine. Metformin, phenformin, buformin, etc. belong to this group. Metformin has been widely prescribed for lowering blood glucose in patients with non-insulin-dependent diabetes (NIDDM), marketed in 500, 850 or 1000 mg strengths. However, being a short acting drug, metformin requires twice-daily or three-times-a-day dosing (500 - 850 mg tab 2-3x/day or 1000 mg bid with meals).
Unlike the sulfonylureas, biguanides do not induce release of insulin from the pancreas. Its effects are mediated by increasing insulin activity in peripheral tissues, reducing hepatic glucose output due to inhibition of gluconeogenesis and reducing the absorption of glucose from the intestine.
These agents are often given in combination with drugs that increase the output of insulin from the pancreas, such as the sulfonylureas, which sometimes result in greater efficacy and/or the ability to
use lowel" doses of the drugs, with an improved side effect profile. Adverse events associated with
the administration of biguanides are anorexia, nausea, vomiting and diarrhea, etc. The adverse events may be partially avoided by either reducing the initial and / or maintenance dose using an extended-release dosage form. Another advantage of an extended-release dosage form is a reduction in the frequency of administration. Findings suggest that extended-release dosage form of a biguanide may improve the quality of therapy in patients with NIDDM1
Studies have shown that a combination of insulin secretion enhancers and insulin sensitivity enhancer has a remarkable effect on glycemic control. The different mechanism of action in targeting hyperglycemia are complimentary and capable of providing remedy for both the deficiency in insulin secretion and insulin sensitivity conditions2.
The combination therapy therefore plays an important therapeutic role, since it allows obtaining an effective metabolic control in NIDDM patients in whom the therapy with only sulfonylureas or only biguanides becomes ineffective with time.
Although extended-release formulations of biguanide alone, as well as biguanide (conventional) in combination with sulfonylureas are well known now, but no such formulation is available which can provide the combined benefits of biguanide once daily and sulfonylureas in once per day dosage form. This combination administered in a single dosage form for once daily administration will not only improve patient compliance but also save time and cost for preparing two different dosage forms.
In the present invention we have found that a combination of a sulfonylurea as immediate release form and a biguanide as extended release form, administered once daily provide equivalent efficacy when compared to an extended release biguanide and sulfonylurea in separate dosage forms administered together.' Kadhe, G. and Arasan, R.E., 'Advances in Drug Delivery of Oral Hypoglycemic agents', Current Science, Vol. 83, No. 12, December 2002
Physicians Desk Reference, The Complete Drug Reference, Anniversary, (Denniston, P.L. ed.), Mosby-Year book, Inc., USA (54* edition).
Therefore, the present invention is related to a novel pharmaceutical composition for oral
administration, comprising a combination of a biguanide and a sulfonylurea, wherein the biguanide is present as extended release form and the sulfonylurea is present as immediate release form in a single dosage form.
The invention provides a dosage form containing both sulfonylurea and biguanide. The sulfonylurea is contained in an immediate-release form, so that it is released substantially immediately upon ingestion (i.e. upon swallowing). Generally at least 80% of the sulfonylurea is released from the dosage form within an hour after administration. The biguanide, by contrast, releases in a sustained fashion, at least about 75% of the drug contained in the dosage form releasing over a period of 4 to 36 hours, preferably about 8 to 24 hours. The term "about" as used above and elsewhere herein means plus or minus 10% for each of the numerical limits.
Biguanide as employed herein is intended to include metformin, phenformin, buformin and the like. Biguanides constitute from about 40 to about 60% w/w of the matrix providing extended release of the biguanide. Particularly the biguanide is metformin.
Sulfonylurea as employed herein is intended to include acetohexamide, glibenclamide (glyburide), glipizide, gliclazide, glimepiride, tolazamide, tolbutamide and the like. Sulfonylureas constitute from about 1 to about 5% by weight of the immediate release matrix. Particularly, the sulfonylurea is glimepiride.
The pharmaceutical compositions of the present invention can be administered orally in the form of tablets such as coated tablets or bilayered tablets; or in form of capsules containing pellets, beads, granules, multiparticulates, tablets or powder.
A sulfonylurea can be incorporated into the matrix as an immediate release component in a variety of ways. For example, it can be incorporated into an exterior coating for a tablet from which it releases substantially immediately upon ingestion. Such a coating can similarly be applied to each of the particles comprising a multiparticulate i.e. granules, beads. If the dosage form is to be a capsule, sulfonylurea can be contained In a single pellet inside the capsule from which it releases substantially immediately once the capsule shell dissolves. Alternatively, the sulfonylurea can be contained in several smaller pellets or be present as immediate release particles or as immediate release layer over the extended release cores or beads. The coating composition may comprise water-soluble polymers such as polyvinyl pyrrolidone, hydroxypropyl cellulose, polyvinyl alcohol,
hydroxypropyl methylcellulose and the like. The polymers constitute from about 40 to about 60%
by weight of the immediate release matrix. The polymer may be applied as a solution in an organic solvent or as an aqueous dispersion. The solvent may be selected from water; alcohols like ethyl alcohols or isopropyl alcohol; ketones like acetone, or ethylmethyl ketone; chlorinated hydrocarbons like dichloromethane and trichloroethane. The coating composition may also comprise wetting agents, plasticizers, opacifiers, colorants and other conventional pharmaceutically acceptable excipients. These excipients constitute from about 30 to about 50% by weight of the immediate release matrix. Any conventional coating equipment may be employed to facilitate coating such as centrifugal fluidized bed coating apparatus, pan coating apparatus, or fluidlzed bed granulating coating apparatus.
Due to poor dispersibility in solvents, the coating composition comprising the sulfonylurea may also include a wetting agent. Suitable wetting agents for use in conjunction with the present invention include hydrophilic and hydrophobic surfactants. Hydrophilic surfactants may be selected from the group consisting of hydrophilic non-ionic surfactants, hydrophilic ionic surfactants, and combinations thereof. Hydrophobic surfactant may be selected from the group consisting of alcohols; polyoxyethylene alkylethers; fatty acids; glycerol fatty acid monoesters; glycerol fatty acid diesters; acetylated glycerol fatty acid monoesters; acetylated glycerol fatty acid diesters, lower alcohol fatty acid esters; polyethylene glycol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; lactic acid derivatives of monoglycerides; lactic acid derivatives of diglycerides; propylene glycol diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers, polyethyleneglycols as esters or ethers, polyethoxylated castor oil; polyethoxylated hydrogenated castor oil, polyethoxylated fatty acid from castor oil or polyethoxylated fatty acid from castor oil or polyethoxylated fatty acid from hydrogenated castor oil.
The biguanide may be incorporated in an extended release core by dispersing in a rate controlling polymer matrix; or biguanide may be layered onto pharmaceutically acceptable inert cores or seeds, which is surrounded by rate controlling polymer layer.
The term matrix, as used herein, refers to a uniform mixture of a biguanide, rate-controlling
polymers and optionally other excipients. The rate-controlling polymers may be hydrophilic,
hydrophobic or a combination thereof. The rate-controlling polymers are uniformly dispersed
throughout the matrix to achieve uniform drug release. Hydrophilic polymers of the present
invention include cellulose derivatives such as hydroxypropylcellulose, hydroxypropyl
methylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose,
methylcellulose, sodium carboxymethylcellulose or combinations thereof. The hydrophobic polymers may be selected from poly (ethylene) oxide, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, poly (alkyl) methacrylate, and copolymers of acrylic or methacrylic acid esters, waxes, shellac and hydrogenated vegetable oils. The rate controlling polymers constitute from about 10 to about 30% by weight of the extended release matrix.
In addition to the active and rate-controlling polymers, the matrix of the present invention may contain other pharmaceutically acceptable excipients, which act in one or more capacities as diluents, binders, lubricants, glidants, colorants or flavoring agents. These excipients constitute from about 10 to about 30% by weight of the extended release matrix. The matrix may be made by any pharmaceutically acceptable technique that achieves uniform blending, e.g. dry blending, wet granulation, compaction and fluid bed granulation.
Suitable diluents include pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, dibasic calcium phosphate, mannitol, starch, sorbitol, sucrose, dextrose, maltodextrin or mixtures thereof.
Suitable binders may be selected from polyvinyl pyrrolidone, lactose, starches, gums, waxes, gelatin, polymers or mixtures thereof.
Suitable lubricants include colloidal silicon dioxide, talc, stearic acid, magnesium stearate, magnesium silicate, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, fumaric acid, zinc stearate, paraffin, or mixtures thereof.
Suitable glidants may be selected from talc and colloidal silicon dioxide.
The matrix formed can be compressed to form the tablets.
Beads or pellets can be prepared using techniques like extrusion-spheronization, drug layering, granulation and the like. The inert core or seeds may be water soluble like sucrose, lactose, maltodextrin and the like or water insoluble like microcrystalline cellulose, partially pregelatinized starch, dicalcium phosphate and the like. Biguanide and rate controlling polymer can be coated as single layer or as separate layers on to these inert cores; or granulated with the inert cores; or mixed with inert cores and extruded and spheronized to form the pellets.
The coating can be applied to the inert/active core using a conventional coating pan or a spray
coater, or a rotating perforated pan or an automated system, a fluidized bed process or any other suitably automated coating equipment.
The extended-release core containing biguanide may optionally be coated to seal the core. The coated active cores may be dried under conditions effective for drying e.g. in an oven or in a fluidized bed dryer.
Finally beads/pellets comprising extended release and immediate release portions can be filled into capsules or compressed to form the tablets.
Accordingly the invention relates to a process for preparing a pharmaceutical composition for the combination of biguanide and sulfonylurea as described herein, said process comprising:
a.dispersing said biguanide in a matrix as described herein, which provides extended
release of the biguanide, wherein the matrix comprises a uniform mixture of:
i. from about 40 to about 60% by weight of biguanide depending upon the weight of
the matrix, ii. from about 10 to about 30% by weight of rate-controlling polymers selected from
amongst hydrophilic and hydrophobic polymers or combination thereof, and iii. from about 10 to about 30% by weight of other pharmaceutically acceptable
excipients selected from amongst diluents, lubricants, binders, glidants, coloring
and flavoring agents;
b.dispersing said sulfonyl urea in a matrix as described herein, which provides immediate
release of the sulfonyl urea, wherein the matrix comprises:
i. from about 1 to about 5 % by weight of sulfonylurea,
ii. from about 30 to about 50% by weight of pharmaceutically acceptable excipients
selected from amongst wetting agents, plasticizers, opacifiers and colorants; and iii optionally from about 40 to about 60% by weight of water soluble polymers; and
c.compinig-the biguanide matrix and the sulfonyl urea matrix into distinct layers with
respect to each other, in a know conventionl manner.
The present invention is further illustrated by the following examples. Those skilled in the art will find It apparent that various modifications and variations can be made to the formulations of this invention.
EXAMPLE 1

(Table Removed)
Procedure:
1. Metformin hydrochloride was milled through 1 mm screen and mixed with microcrystalline cellulose and sodium carboxymethyl cellulose. The blend was sieved through No. 44 mesh, transferred to Rapid mixer granulator and wet granulated with purified water. The granules were dried in Fluid bed dryer, sized through multimill and sifted through No. 30 mesh.
2. Hydroxypropyl methylcellulose was separately sifted through No.30 mesh and mixed with granules in a low shear mixer. The blend was then mixed with magnesium stearate and compressed into tablets.
3. A coating dispersion was prepared by dispersing all ingredients of seal coat in water. The tablets were coated with this dispersion till weight build up of 2% w/w.
4. To prepare the active coat, caprylocaproyl monoglyceride was dissolved in purified water. To this solution, glimepiride was added with stirring to form dispersion. The other ingredients of the active coat were added with stirring to this dispersion and the resulting dispersion was then coated upon the tablets obtained from step 3, using spray-coating, up to a weight build up of 5% w/w.
EXAMPLE 2

(Table Removed)
Procedure:
1 Metformin hydrochloride was milled through 1 mm screen and mixed with microcrystalline cellulose and sodium carboxymethyl cellulose. The blend was sieved through No. 44 mesh.
2. Hydroxypropyl methylcellulose was separately sifted through No.30 mesh and mixed with the blend in a low shear mixer. The blend was then mixed with magnesium stearate and compressed into tablets.
3. A coating dispersion was prepared by dispersing all ingredients of seal coat in water. The tablets were coated with this dispersion till weight build up of 2 w/w%.
4. To prepare the active coat, caprylocaproyl monoglyceride was dissolved in purified water. To this solution, glimepiride was added with stirring to form dispersion. The other ingredients of the active coat were added with stirring to this dispersion and the resulting dispersion was then coated upon the tablets obtained from step 3, using spray-coating, up to a weight build up of 5% w/w.
EXAMPLE 3

(Table Removed)
Procedure:
1. Metformin hydrochloride was milled through 1 mm screen and mixed with microcrystalline cellulose and sodium carboxymethyl cellulose. The blend was sieved through No. 44 mesh.
2. Hydroxypropyl methylcellulose was separately sifted through No.30 mesh and mixed with the blend of step 1 in a low shear mixer. The blend was then mixed with magnesium stearate and passed through roller compactor and then milled again to form granules. These granules are then compressed into tablets.
3. A coating dispersion was prepared by dispersing all ingredients of seal coat in water. The tablets were coated with this dispersion till weight build up of 2% w/w.
4. To prepare the active coat, caprylocaproyl monoglyceride was dissolved in purified water. To this solution, glimepiride was added with stirring to form dispersion. The other ingredients of the active coat were added with stirring to this dispersion and the resulting dispersion was then coated upon the tablets obtained from step 3, using spray-coating, up to a weight build up of 5% w/w.
A comparative dissolution profile of metformin hydrochloride in innovator's marketed tablets (Glucophage XR 500 mg) and tablet formulation made in accordance with the Example 3 was
obtained. The dissolution was carried out in USP Apparatus Type I (basket) at a speed of 100
rpm. The medium was 900ml phosphate buffer, pH 6.8. The data obtained is disclosed in Table 1.
Table 1: Comparative in vitro dissolution profile of metformin hydrochloride in Glucophage XR 500 mg vs tablets made in accordance with Examples.

(Table Removed)
From the results, it is clearly evident that both the formulations have substantially similar dissolution profiles.
A comparative dissolution profile of glimepiride in innovator's marketed tablets (Amaryl 2 mg) and tablet formulation made in accordance with the Example 3 was obtained. The dissolution was carried out in USP Apparatus Type I at a speed of 100 rpm. The medium was 900ml phosphate buffer, pH 8. The data obtained is disclosed in Table 2.
Table 2: Comparative in vitro dissolution profile of glimepiride in Amaryl 2 mg tablets vs tablets made in accordance with Example 3.

(Table Removed)
From the results, it is clearly evident that more than 95% of the drug is released in 15 minutes and both formulations show substantially similar dissolution profiles.

WE CLAIM:
1. A process for preparing a, formulation comprising a matrix of biguanide and
matrix Siilfonylurea as described herein, said process comprising:
a. dispersing said biguanide in a matrix as described herein, which provides extended
release of the biguanide, wherein the matrix comprises a uniform mixture of:
i. from 40 to 60% by weight of biguanide depending upon the weight of the
matrix, ii. from 10 to 30% by weight of rate-controlling polymers selected from
amongst hydrophilic and hydrophobic polymers or combination thereof, and iii. from 10 to 30% by weight of other conventional pharmaceutically
acceptable excipients selected from amongst diluents, lubricants, binders, glidants,
coloring and flavoring agents;
b. dispersing said sulfonyl urea in a matrix as described herein, which provides immediate
release of the sulfonyl urea, wherein the matrix comprises:
I. from 1 to 5% by weight of sulfonylurea depending upon the weight of the
matrix , ii. from 30 to 50% by weight of conventional pharmaceutically acceptable
excipients selected from amongst wetting agents, plasticizers, opacifiers and
colorants; and iii. optionally from 40 to 60% by weight of water soluble polymers; and
c. comprising the [biguanide matrix and the sulfonyl urea matrix into distinct layers with
respect to each othe was a know comprising manner
2. The process according to claim 1 wherein the biguanide is selected from amongst metformin,
phenformin and buformin.
3. The process according to claim 1 wherein the sulfonyl urea is selected from amongst
acetohexamide, glibenclamide (glyburide), glipizide, gliclazide, glimepiride, tolazamide and
tolbutamide.
4. The process according to claim 1 wherein the biguanide is prelluaphy released over a period of 8to 24
hours
5. The process according to claim 1 wherein th^^armaceutical composition is formulated into a
dosage form selected from coated taW^Lbilayered tablets or capsules containing pellets,
beads, granules, multJparticulates>tabl^;ior powder.
6. A process for preparing a pAi3jaii^c0^s^usi^jXimpf^^^&f\ fe5f-ihe--€omteinafeaB:-el.a biguanide and A
t:> sulfonylurea as exemplified and described herein.