PHARMACEUTICAL COMPOSITIONS OF A BIGUANIDE AND A SULFONYLUREA
Technical Field of the Invention
The present invention relates to an oral solid dosage form that includes a combination of a biguanide and a sulfonylurea, wherein the dosage form provides an extended-release phase of the biguanide and an immediate-release coating containing the sulfonylurea. Also provided is a process for the preparation of the oral solid dosage form and method of its we.
Background of the Invention
Diabetes mellitus of type II is a progressive metabolic disorder with diverse pathologic manifestations and is often associated with lipid metabolism and glycometabolic disorders. The long-term effects of diabetes result from its vascular complications: the micro vascular complications of retinopathy, neuropathy and nephropathy and the macrovascular complications of cardiovascular, cerebrovascular and peripheral vascular diseases, Initially, diet regulation and exercise are the preliminary course of treatment for type II diabetes; however, these are generally followed by the administration of oral hypoglycemic agents, The current drugs used for managing type II diabetes and its precursor syndromes, such as insulin resistance, include biguanides and sulfonylureas, among others.
Biguanides, which include metformin, phenformin and buformin, help control the blood glucose level by decreasing hepatic glucose production arid reducing the intestinal absorption of glucose, Sulfonylureas, which include glipizide, glimepiride, glyburide, glibonuride, glisoxepide, gliclazide acetohexamide, chlorpropamide, tolazamide, and tolbutamide, among others, help in controlling or managing NIDDM by stimulating the release of insulin from the pancreas.
Biguanides and sulfonylureas are individually commercially available in the form of tablets as either oral immediate-release (IR) formulations or controlled-release (CR) formulations. These are typically administered orally to patients in need thereof, in protocols calling for the single administration of the individual ingredient.
Approximately 20% to 25% percent of patients with type 2 diabetes demonstrate primary failure to sulfonylurea therapy. Gerich JE (1989), "Oral hypoglycemic agents," N.

Engl. J. Med. 321(18):1231-1245. Secondary failure with sulfonylureas is known to occur in approximately 5% to 10% of the patients per year. Most sulfonylurea monotherapy patients (91.3%) typically progress to the addition of metformm. Brown JB et a!., "The burden of treatment failure in type 2 diabetes", Diabetes Care, 27(7): 1535-40 (2004). Similarly, most metformin monotherapy patients (91.6%) eventually require the addition of a sulfonylurea.
Biguanides, particularly metformin, improve glucose tolerance but do not stimulate insulin secretion. Sulfonylureas lower blood glucose levels acutely by stimulating the release of insulin from the pancreas, an effect that is dependent upon properly functioning beta cells in the pancreatic islets. A combination therapy of a biguanide and sulfonylurea has a synergistic effect on glucose control, since both agents act by different, but complementary, mechanisms.
This combination therapy plays an important therapeutic role, since it allows an effective metabolic control in NIDDM patients in whom the therapy with only sulfonylureas or only biguanides has become ineffective.
The use of combinations of metformin (a biguanide) and a sulfonylurea has been demonstrated to be synergistic in clinical trials when compared with the use of the individual agents separately. Physician's Desk Reference 2000, page 832. The monograph also advocates the use of combinations of metformin and sulfonylureas for patients not controlled on metformin alone. Several references pertain to pharmaceutical compositions having combinations of biguanides and sulfonylureas providing for controlled or immediate-release of both of the drugs.
In order to formulate a single dosage form for the combination of a biguanide and a sulfonylurea, the biguanide, which has a shorter half-life, needs to be administered in a controlled or extended-release form; whereas the sulfonylurea, particularly glimepiride, which has a longer half-life, needs to be administered in immediate-release form. Further, a large disparity between the doses of the two agents and differences in their solubility and permeability profiles pose difficulties in their formulation into a single dosage form. Although combinations of two antidiabetic agents are well known in the art and are convenient to formulate, a combination requiring an extended-release of a high dose, water-soluble active, i.e., biguanide, and immediate-release of low-dose, water-insoluble or

sparingly soluble active, i.e. sulfonylurea is difficult to achieve using a simple and cost-effective process.
WO 04/ 45622 discloses a dosage form which includes one layer or a core from which one high-dose, water-soluble active is released on a prolonged basis and a coating or layer from which low-dose, water-insoluble active is released on an immediate-release basis can be prepared in a manner that provides a high degree of uniformity. This application is incorporated herein in its entirety by reference.
At present, fixed dose combination ("FDC") therapy represents a largely unexplored opportunity to improve the management of type 2 diabetes. It has been observed that administering glirnepiride along with metformin in Type 2 diabetics resulted in superior glycemic control compared to glimepiride or metformin monotherapy. Charpentier G et al, "Improved glycemic control by addition of glimepiride to metformin monotherapy in type 2 diabetic patients", Diabet. Med. 18: 828-834 (2001).
Summary of the Invention
Since glimepiride tablets and metformin hydrochloride extended release tablets are available for use as once daily doses, the regular use of a fixed dose combination of glimepiride and metformin hydrochloride extended release could be beneficial in improving patient compliance, normalizing blood glucose levels and eventually preventing the long term complications of diabetes.
In one general aspect there is provided an oral solid dosage form which includes an extended-release core comprising a biguanide and an immediate-release coating comprising a sulfonylurea over the core.
Embodiments of the pharmaceutical compositions may include one or more of the following features. For example, the biguanide may be metformin, phenformin or bufonnin.
The sulfonylurea may include glipizide, glimepiride, glibonuride, glyburide, gliclazide, acetohexamide, chlorpropamide, tolazamide or tolbutamide.
In another general aspect there is provided an oral solid dosage form which includes an extended-release core comprising metformin and an immediate-release sulfonylurea containing coating applied to the core comprising glimepiride, one or more film-forming

polymer (s), one or more solubilizers and one or more plasticizers; wherein the immediate-release coating is applied to the core using a non-aqueous solvent.
Embodiments of the pharmaceutical compositions may include one or more of the following features. For example, the metformin may be present at a concentration of from about 20 % to about 80% by weight of the dosage form and the glimepiride may be present at a concentration from about 0.05 % to about 10 % by weight of the dosage form.
The extended-release core may be prepared by dispersing metformin with one or more rate-controlling polymer to form a matrix or by layering onto pharmaceutically acceptable inert cores in an admixture with one or more rate-controlling polymers. The one or more rate controlling polymers may include hydrophilic polymers, hydrophobic polymers, random-blcok copolymers, mixtures and blends thereof.
The extended-release core further may include one or more pharmaceutically acceptable excipients. The one or more pharmaceutically acceptable excipients may include one or more of diluents, binders, lubricants, glidants, colorants and flavoring agents. The extended-release core may be formulated as particles, pellets, beads, granules or tablets. The core may be surrounded by a seal-coat. The seal-coat may include one or more film-forming polymers. The one or more film-forming polymers may be one or more of hydroxypropyl methyl cellulose, ethyl cellulose, cellulose acetate, poly vinyl alcohol- maleic anhydride copolymers, acrylic polymers and copolymers and mixtures thereof.
The one or more film-forming polymers may also be one or more of polyviny! pyrrolidone, vinyl acetate and N-vinylpyrrolidone copolymer, hydroxyl alkyl celluloses, rnethylcellulose, polyvinyl alcohol and mixtures thereof.
The one or more solubilizers may be one or more of polyethylene glycols, polyethoxyiated fatty acids, medium chain glycerides, polyglycolyzed glycerides, diethylene glycol mono ethyl ether, cyclodextrin, polyoxyethylene, sorbitan fatty acid esters, sodium lauryl sulphate and mixtures thereof.
The one or more plasticizers may be one or more of citric acid alkyl esters, glycerol esters, sucrose esters, sorbitan esters, polyethylene glycols and mixtures thereof.
The non-aqueous solvents maybe one or more of alcohols, ketones, chlorinated hydrocarbons and mixtures thereof. The alcohols may be one or both of ethyl alcohol and isopropyl alcohol. The ketones may be one or both of acetone and ethyl methyl ketone. The

chlorinated hydrocarbons may be dichloroethane, dichloromethane, trichloroethane and mixtures thereof.
In another general aspect there is provided an oral solid dosage form which includes a combination of metformin and glimepiride. The dosage form, when administered once daily under fed conditions, exhibits an area under the plasma concentration-time curve for metformin and glimepiride comparable to that exhibited by separate simultaneously administered, commercially available, extended-release tablet of metformin (GLUCOPHAGE XR™) and an immediate-release tablet of glimepiride (AMARYL™),
In another general aspect there is provided an oral solid dosage form which includes a combination of metformin and glimepiride. The dosage form, when administered once daily under fed conditions, exhibits mean maximum plasma concentrations (Cmax) for metformin and glimepiride comparable to that exhibited by separate simultaneously administered, commercially available, extended-release tablet of metformin (GLUCOPHAGE XR™) and an immediate-release tablet of glimepiride (AMARYL™), respectively.
In yet another general aspect there is provided an oral solid dosage form, which includes an extended-release core comprising metformin and an immediate-release sulfonylurea coating comprising one or more film-forming polymer(s), one or more solubilizers and one or more plasticizers. The immediate-release coating is applied to the core using a non-aqueous solvent. Additionally, the dosage form exhibits a Tmax of metformin which occurs at a time about 2.5 hours to about 12 hours administration to a human patient and exhibits a Tmax of glimepiride which occurs at a time about 1 hour to about 6 hours after administration to a human patient.
Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the core may be surrounded by a seal-core.
In another general aspect there is provided a method of treating non-insulin dependent diabetes mellitus in a patient in need thereof. The method includes administering an oral solid dosage form comprising an extended-release core of metformin and an immediate-release coating of glimepiride over the core.
Embodiments of the method may include one or more of the following features. For example, the dosage form may further include one or more of glitazones, insulin, alpha-

glucosidase inhibitors, meglitinides, fibrates, statins, squalene synthesis inhibitors and angiotensin-converting enzyme inhibitors.
The method may further include concurrently or sequentially administering one or more of glitazones, insulin, alpha-glucosidase inhibitors, meglitinides, fibrates, statins, squalene synthesis inhibitors and angiotensin-converting enzyme inhibitors.
Detailed Description of the Invention
The inventors have developed an oral solid dosage form which includes a combination of biguanide and sulfonylurea. The dosage form provides an extended-release core which includes a biguanide and an immediate-release coating which includes a sulfonylurea over the core,
Suitable biguanides include one or more of metformin, phenformin, buformin and other pharraaceutically acceptable forms of the biguanide class. For example, metformin may be used. The metformin include free base or a pharmaceutically acceptable salt thereof. Suitable pharmaceutically acceptable salts of metformin include hydrochloride, fumarate, hydrobromide, succinate and embonate. The daily effective dose of metformin may range from about 500 mg to about 2550 mg; particularly, the dose is a single dose of 250 mg to about 1000 mg. The metformin in the present dosage form may be present at a concentration of about 20% to about 80% by weight of the dosage form.
Suitable sulfonylureas may include one or more of glipizide, glimepiride, glibonuride, glyburide, gliclazide, acetohexamide, chlorpropamide, tolazamide, and tolbutamide. Also included are pharmaceutically acceptable forms of sulfonylureas including their salts, solvates, hydrates, polymorphs, complexes and other such products. For example, glimepiride may be used. The daily effective dose of glimepiride may range from about 1 mg to about 8 mg once a day. In the present dosage form, the glimepiride may be present from about 0.05% to about 10% by weight of the dosage form.
The area under the plasma concentration-time curve (AUC) for the test is said to be comparable to that of the reference when the test/reference (T/R) ratio of the geometric means based on log transformed data fall within 70% to about 143% for area under the plasma
concentration time curve.

The maximum plasma concentration (Cmax) for the test is said to be comparable to that of the reference when the tesfreference (T/R) ratio of the geometric means based on log-transformed data fall within 70 to about 143% for Cmax.
The biguanide may be incorporated into an extended-release core by dispersing in a rate-controlling polymer matrix, as described in WO 03/028704 and WO 03/039527. Alternatively, the biguanide may be layered onto pharmaceutically acceptable inert cores or seeds in admixture with, or surrounded by, one or more rate-controlling polymers.
The matrix may be a uniform mixture of a biguanide, one or more rate-controlling polymers and one or more pharmaceutically acceptable excipient.
Suitable rate-controlling polymers may be hydrophilic, hydrophobic or mixtures thereof. These rate-controlling polymers may be present at a concentration of from about 5% to about 75% by weight of the dosage form,
Suitable hydrophilic rate-controlling polymers may include one or more of cellulose derivatives, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose hydroxymethyl cellulose, carboxy methyl cellulose, methyl cellulose, sodium carboxymethyl cellulose and mixtures thereof; polyvinyl pyrrolidone, microcrystalline cellulose, polysaccharides, polyalkylene glycols, starch and starch derivatives; and mixtures thereof.
Suitable hydrophobic polymers may be include one or more of ethyl cellulose* cellulose acetate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, copolymers of acrylic or methacrylic acid esters, waxes, shellac, hydrogenated vegetable oil
and mixtures thereof.
Suitable pharmaceutically acceptable excipients include one or more of diluents, binders, lubricants, glidants, colorants and flavoring agents.
Suitable diluents may include 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, hydroxyl propyicellulose, hydroxyl ethyl cellulose, hydroxyl propyl methylcellulose, gums, waxes, polyvinylalcohol and mixtures thereof.
Suitable lubricants may include one or more of silicon dioxide, colloidal silicon dioxide, talc, stearic acid, magnesium stearate, magnesium trisilicate, sodium benzoate, polyethylene glycol, sodium lauryl sulphate, fumaric acid, zinc stearate, paraffin, glyceryl
behenate and mixtures thereof.
Suitable glidants may include one or more of talc, silicon dioxide, colloidal silicon dioxide, tribasic calcium phosphate, powdered cellulose and magnesium trisilicate.
The core may be formulated by any pharmaceutically acceptable technique including dry granulation, wet granulation, compaction, fluidized bed granulation and extrusion-
spheronization.
The core may be compressed to form tablets or alternatively, formulated as plurality of discrete or aggregated particles, pellets, beads or granules. These pellets, beads, particles or granules may be filled into capsules.
The extended-release core may be coated to seal the core. The coating layer may include any conventional coating formulation and may include one or more of film-forming polymers or binders. Suitable film-forming polymers and binders include one or more of hydroxypropyl methylcellulose, ethyl cellulose, cellulose acetate, polyvinyl alcohol-maleic anhydride copolymers, acrylic polymers and copolymers; or mixtures thereof. These polymers may be applied using solvents including one or more of purified water organic solvents or mixture thereof. In addition, the coating formulation may also include plasticizers, The seal-coat around the core may be present at a concentration of from about 1% to about 5% and particularly from about 1.5% to about 3% by weight of the dosage form.
The immediate-release coating comprising sulfonylurea is applied directly onto the core or over the seal-coated core. The immediate-release coating includes one or more film-forming polymer(s), one or more solubilizers, one or more plasticizers and one or more additional pharmaceutically acceptable excipients including fillers, antiadherents, opacifiers
and colorants.

Suitable film-forming polymer(s) may include one or more of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, vinyl acetate and N-vinylpyrrolidone copolymer, hydroxyalkyl celluloses, methylcelluloses, polyvinyl alcohol and mixtures thereof.
Suitable solubilizers may include one or more of polyethylene glycols, polyethoxylated fatty acids, medium chain glycerides, polyglycolyzed glycerides, diethylene glycol mono ethyl ether,, cyclodextrin, polyoxyethylene, sorbitan fatty acid esters, sodium lauryl sulphate and mixtures thereof.
Suitable plasticizers may include one or more of citric acid alkyl esters, glycerol esters, sucrose esters, sorbitan esters, polyethylene glycols, and mixtures thereof.
The immediate-release coating of sulfonylurea may be applied as a solution of the sulfonylurea in non-aqueous solvent due to the poor solubility of the sulfonylurea in an
aqueous medium.
Layering with a non-aqueous sulfonylurea-solution is preferred over aqueous or non-aqueous suspension since on drying the suspension may form irregular deposits from which the low dose active is released non-uniformly. Further, to achieve substantial content uniformity, the suspension requires the presence of additional excipients, such as suspending agents that are not required with preparing a solution. Moreover, solutions are easier to handle as compared to suspensions and the particle size of the active before going into solution holds less relevance.
Suitable non-aqueous solvents include one or more of alcohols, such as ethyl alcohol or isopropyl alcohol; ketones, such as acetone or ethyl methyl ketone; chlorinated hydrocarbons, such as dichloroethane, dichloromethane or trichloroethane; and mixtures thereof.
The immediate-release coating may be applied by any conventional technique including pan coating, spray coating, centrifugal fluidized coating and fluidized bed coating.
Alternatively, the immediate-release coating may be applied by press-coating^ dry compression or deposition over the extended-release core or seal-coated extended-release core. An outer protective coating layer comprising conventional coating formulations may be applied additionally over the immediate-release coating.

The coated cores may be dried under conditions effective for drying, such as in an oven or by means of fluidized bed dryer.
Tn another embodiment there is provided a method of treating non-insulin dependent diabetes mellitus in a patient in need thereof. The method includes administering an oral solid dosage form comprising:
(a) an extended-release core comprising metformin and (b) an immediate-release
coating comprising glimepiride over the core.
The dosage form may further include one or more of glitazones, insulin, alpha-glucosidase inhibitors, meglitinides, fibrates, statins, squalene synthesis inhibitors and angiotensin-converting enzyme inhibitors.
In addition, one or more of glitazones, insulin, alpha-glucosidase inhibitors, meglitinides, fibrates, statins, squalene synthesis inhibitors and angiotensin-converting enzyme inhibitors may be concurrently or sequentially administered.
The following non-limiting examples illustrate the process for making the oral dosage form disclosed in various embodiments of the specification.

EXAMPLE 1 Metforrain hvdrochloride 250 me and Glimepiride 1 mg tablets

INGREDIENTS nig/ tablet
METFORMIN CORE Metformin Hydrochloride 250

Hydroxypropyl methylcellulose 184

Sodium Carboxymethyl Cellulose 18

Microcrystalline Cellulose 30

Purified Water qs

Magnesium Stearate 3
SEAL-COAT Hydroxypropyl methylcellulose 8.75

Polyethylene glycol 1.25

Purified Water qs
GLIMEPIRIDE COAT Glimepiride 1

Hydroxypropyl methylcellulose 13

Copovidone 19.5

Polyethylene glycol 2.5

Caprylocaporyl Macrogolglycerides 4

Sodium lauryl sulphate 1

Isopropyl alcohol qs

Methylene chloride qs
FILM-COAT Hydroxypropyl methylcellulose 4.5

Lactose 4

Polyethylene glycol 1

Color 0.5

Purified Water qs
Procedure:
1. Metformin hydrochloride was mixed with microcrystalline cellulose and purified water
was added to the blend.

2. Sodium carboxymethyl cellulose, hydroxypropyl methylcellulose and a part of
magnesium stearate were mixed with blend of step 1.
3. Gra mil es were prepared by roller compaction of the blend of step 2.
4. The granules were lubricated with the remaining magnesium stearate and compressed into
tablets.
5. A seal-coat solution was prepared by dissolving hydroxypropylruethyl cellulose and
polyethylene glycol in water, which was subsequently used to coat the core tablets of
Step-4.
6. To prepare the active coat, glimepiride was dispersed in methylene chloride followed by
the addition of isopropyl alcohol to obtain a clear solution.
7. To this solution, caprylocaproyl monoglyceride., polyethylene glycol, sodium lauryl
sulphate hydroxypropyl methylcellulose and copovidone were added under constant
stirring till a clear solution was obtained.
8. The resulting solution was then coated upon the tablets obtained from step 5, using spray-
coating.
9. The tablets of Step-8 were given an overcoat using the final-coat dispersion.

EXAMPLE 2 Metformin hvdrochloride 500 my and Glimepiride 1 mg tablets

INGREDIENTS mg per tablet
Metformin Hydrochloride 500
Hydroxypropyl methylcellulose 368
METFORMIN Sodium Carboxymethyl Cellulose 36
CORE Microcrystalline Cellulose 60
Purified Water qs
Magnesium Stearate 6
Hydroxypropyl methylcellulose 17.5
SEAL-COAT Polyethylene glycol 2.5
Purified Water qs
Glimepiride 1
Hydroxypropyl methylcellulose 26
Copovidone 39
GLIMEPIRIDE Polyethylene glycol 5
COAT Caprylocaporyl Macrogolglycerides 8
Sodium lauryl sulphate 2
Isopropyl alcohol qs
Methylene chloride qs
Hydroxypropyl methylcellulose 9
Lactose 9
FILM-COAT Polyethylene glycol 7

Purified Water qs
Procedure: As followed in Example 1.

EXAMPLE 3 Metformin hvdrochloride 500 me and Glimepiride 2 me tablets

INGREDIENTS Mg/ tablet
CORE Metformin Hydrochloride 500

Hydroxypropyl methylcellulose 368

Sodium Carboxymethyl Cellulose 36

Macrocrystalline Cellulose 60

Purified Water qs

Magnesium Stearate 6
SEAL-COAT Hydroxypropyl methylcellulose 17.5

Polyethylene glycol 2.5

Purified Water qs

ACTIVE Glimepiride 2

Hydroxypropyl methylcellulose 26

Copovidone 39

Polyethylene glycol 5
COAT Caprylocaporyl Macrogolglycerides 8

Sodium lauryl sulphate 2

Isopropyl alcohol qs

Methylene chloride qs
FILM- Hydroxypropyl methylcellulose 9

Lactose 8

Polyethylene glycol 2
COAT

Color 1

Purified Water qs
Procedure: As followed in Example 1.

EXAMPLE 4 Metformin hvdrochloride 500 me aad Glimepiride 2 ing tablets

INGREDIENTS Mg/ tablet
Metformin Hydrochloride 500
Hydroxypropyl methylcellulose 368
Sodium Carboxymethyi Cellulose 36
CORE Microcrystalline Cellulose 60
Purified Water qs
Magnesium Stearate 6
Hydroxypropyl methylcellulose 17.5
SEAL- Polyethylene glycol 25

COAT Purified Water qs
Glimepiride 2
Hydroxypropyl methylcellulose 26
Copovidone 39
Polyethylene glycol 5
ACTIVE Caprylocaporyl Macrogolglycerides g

COAT Silicon dioxide 10

Sodium lauryl sulphate 2
Isopropyl alcohol qs
Methylene chloride qs
FILM- Opadry 90

COAT [
j Purified Water qs
Procedure: As followed in Example 1.

Tables 1 and 2 provide the in-vitro release profiles of metformin and glimepiride respectively from the tablets prepared by the composition and process of Example 4 in phosphate buffers pH 6.8 and 7.8, respectively (900 mL), USP 2 at 75 rpm.
Table 1: Release profile of metformin from tablets prepared as per Example 4 in simulated intestinal fluid (Phosphate buffer pH 6.8), 900 mL, USP 2 at 75 rpm.

Time (hrs) Percent release of metformin (%)
0.5 19
1.0 31
2.0 45
4.0 63
6.0 76
8.0 89
10.0 97
12.0 103
Table 2: Release profile of glimepiride from tablets prepared as per Example 4 in Phosphate buffer pH 7.8,900 mL, USP 2 at 75 rpm.

Time (min) Percent release of glimepiride (%)
10 35
20 65 1*
30 78
45 88
60 94

Pharmacokinetie studies under fed conditions;
A single fixed dose combination of Metformin ER 500 mg and Glimepiride ER 2 mg tablet of Example 4 was compared with simultaneously, separately administered, extended-release metformin kydrochloride 500 mg tablets (GLUCOPHAGE XR™ tablets; Bristol Myers Squibb) and Glimepiride 2 mg tablets (AMARYL™ tablets; Aventis) under fed conditions.
Values for pharmacokinetic parameters, including observed Tmax, Cmax, AUC