The present invention relates to an oral solid dosage form for the combination of biguanide and sulfonylurea wherein the dosage form provides extended-release of biguanide and immediate-release of sulfonylurea. The solid dosage form of the present invention is meant for once-a-day administration and maintains therapeutically effective plasma levels of both the drugs for upto 24 hours.
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 microvascular complications of retinopathy, neuropathy and nephropathy and the macrovascular complications of cardiovascular, cerebrovascular and peripheral vascular diseases. Initially, diet and exercise is the mainstay of treatment of type II diabetes. However, these are followed by administration of oral hypoglycemic agents. Current drugs used for managing type II diabetes and its precursor syndromes such as insulin resistance, include classes of compounds such as for example, biguanides and sulfonylureas, among others.
Biguanides, represented by metformin, phenformin and buformin, help in the control of blood glucose by decreasing hepatic glucose production and reducing intestinal absorption of glucose. Sulfonylureas, represented principally by 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 commercially available in the form of tablets of the individual drugs, as either immediate-release (IR) formulations or in some cases controlled-release (CR) formulations, to be 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 SU therapy (Gerich JE, 1990). Secondary failure with sulfonylureas is known to occur in approximately 5% to 10% of patients per year. Most sulfonylurea monotherapy patients (91.3%) typically progress to the addition of metformin (Brown, et
a/., 2004). Similarly, most metformin monotherapy patients (91.6%) require addition of a sulfonylurea.1
Biguanides, especially metformin, improve glucose tolerance but donot stimulate insulin secretion. Sulfonylureas lower blood glucose levels acutely by stimulating the release of insulin from the pancreas, an effect dependent upon 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.
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.
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.
For preparing 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 in a single dosage form and also in achieving content uniformity. Although combinations of two
1 Brown JB et al. (2004). The burden of treatment failure in type 2 diabetes. Diabetes Care. 27(7):
1535-40.
Gerich JE (1989). Oral hypoglycemic agents. N Engl. J Med. 321(18): 1231-1245.
antidiabetic agents are well known in the art and are convenient to formulate; a combination requiring 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.
It has previously been disclosed in our co-pending application published as WO 04/ 45622 discloses a dosage form that 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.
Summary of the Invention
It is one general aspect to provide an oral solid dosage form for the combination of biguanide and sulfonylurea wherein the dosage form provides extended-release of biguanide and immediate-release of sulfonylurea.
It is another general aspect to provide an oral solid dosage form comprising (a) an extended-release core comprising a biguanide, and (b) an immediate-release coating comprising a sulfonylurea over the core.
The immediate-release coating is applied as a non-aqueous solution of the sulfonylurea, owing to the poor solubility of the sulfonylurea in the 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 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 does not hold any relevance.
It is another aspect to provide an oral solid dosage form comprising: (a) an extended-release core comprising metformin;
(b) an immediate-release sulfonylurea containing coating applied to the core comprising glimepiride, film-forming polymer (s), solubilizers and plasticizer; wherein the immediate-release coating is applied to the core using a nonaqueous solvent.
In one of the embodiments, the core may be surrounded by a seal-coat.
It is yet another aspect to provide an oral solid dosage form for the combination of metformin and glimepiride wherein the dosage form when administered once daily under fed conditions exhibits area under the plasma concentration-time curve (AUC) for metformin and glimepiride comparable to that exhibited by separate simultaneously administered, commercially available, extended-release tablets of metformin (Glucophage XR™) and immediate-release tablet of glimepiride (Amaryl™).
It is yet another aspect to provide an oral solid dosage form for the combination of metformin and glimepiride wherein the dosage form when administered once daily under fed conditions exhibits mean maximum plasma concentration (Cmax) for metformin and glimepiride comparable to that exhibited by separate simultaneously administered commercially available, extended-release tablets of metformin (Glucophage XR™) and immediate-release tablet of glimepiride (Amaryl™).
It is yet another aspect to provide an oral solid dosage form for the combination of metformin and glimepiride, said dosage form comprising.
(a) an extended-release core comprising metformin;
(b) an immediate-release sulfonylurea coating containing film-forming polymer(s), solubilizers and plasticizer; wherein the immediate-release coating is applied to the core using a non-aqueous solvent; and
(c) optionally a non-functional film coat surrounding the sulfonylurea immediate-release coat;
wherein the dosage form exhibits a Tmax of metformin which occurs at time 2.5 hours to about 12 hours and exhibits a Tmax of glimepiride which occurs at a time 1 hour to about 6 hours after administration to a human patient.
A seal-coat may be applied to surround the core.
It is yet another aspect to provide a method of treatment of non-insulin dependent diabetes mellitus in a patient in need thereof, comprising 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.
Detailed Description
For many patients, the recommended regimens do not sufficiently control glycemia during long term treatment, leading to a requirement for combination therapy within several years following diagnosis (Howlett etal., 2003)2.
The selection of effective and well-tolerated treatments is the key step in the design of combination tablet, although there are also several other important considerations.
At present, FDC therapy represents a largely unexplored opportunity to improve the management of type 2 diabetes. It has been observed that administering glimepiride along with metformin in Type 2 diabetics resulted in superior glycemic control compared to glimepiride or metformin monotherapy (Charpentier et a/., 2001 )3.
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 (FDC) of glimepiride and metformin hydrochloride extended release could be beneficial
2 Howlett H et al. (2003). The development of an oral antidiabetic combination tablet:
design, evaluation and clinical benefits for patients with type diabetes. Current medical
research and opinion. 19(3): 218-225.
3 Charpentier G et al. (2001). Improved glycemic control by addition of glimepiride to
metformin monotherapy in type 2 diabetic patients. Diabet. Med. 18: 828-834.
in improving patient compliance, normalizing blood glucose levels and eventually preventing the long term complications of diabetes.
Biguanides that can be used in accordance with the present invention include, but are not limited to, metformin, phenformin, buformin and other pharmaceutically acceptable forms of the biguanide class. Particularly metformin may be used. Metformin as used herein may include base per se or a pharmaceutically acceptable salt may be hydrochloride, fumarate, hydrobromide, succinate or 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.
Metformin may constitute from about 20% to about 80% by weight of the dosage form.
Suitable sulfonylureas may include, but are not limited to, glipizide, glimepiride, glibonuride, glyburide, gliclazide, acetohexamide, chlorpropamide, tolazamide, tolbutamide and others, and their pharmaceutically acceptable forms including their salts, solvates, hydrates, polymorphs, complexes and other such products. Particularly, glimepiride may be used.
The daily effective dose of glimepiride may range from about 1 mg to about 8 mg once a day.
Glimepiride constitutes from about 0.05% to about 10% by weight of the dosage form.
As used herein, 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.
As used herein, the maximum plasma concentration (Cmax) 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 Cmax.
The biguanide may be incorporated in an extended-release core by dispersing in a rate-controlling polymer matrix, as described in our pending applications, published as WO 03/028704 and WO 03/039527. Alternatively the biguanide may be layered onto pharmaceutically acceptable inert cores or seeds in admixture with rate-controlling polymer or surrounded by rate-controlling polymers.
The term matrix, as used herein, refers to a uniform mixture of a biguanide, rate-controlling polymers and at least one pharmaceutically acceptable excipient.
The rate-controlling polymers may be hydrophilic, hydrophobic or combinations thereof. These rate-controlling polymers may constitute from about 5% to about 75% by weight of the dosage form.
Hydrophilic rate-controlling polymers may include one or more cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose hydroxymethyl cellulose, carboxy methyl cellulose, methyl cellulose, sodium carboxymethyl cellulose or combinations thereof; polyvinyl pyrrolidone, microcrystalline cellulose, polysaccharides, polyalkylene glycols, starch and starch derivatives; or mixtures thereof.
Hydrophobic polymers may be selected from 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 or mixtures thereof.
The pharmaceutically acceptable excipients may be selected from one or more of diluents, binders, lubricants, glidants, colorants or flavoring agents.
Suitable diluents may include one or more of microcrystalline cellulose, lactose, dibasic calcium phosphate, mannitol, starch, sorbitol, sucrose, dextrose, maltodextrin or mixtures thereof.
Suitable binders may be selected from one or more of polyvinyl pyrrolidone, hydroxyl propylcellulose, hydroxyl ethyl cellulose, hydroxyl propyl methylcellulose, gums, waxes, polyvinylalcohol or mixtures thereof.
Suitable lubricants may include 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 or mixtures thereof.
Suitable glidants may be selected from talc, silicon dioxide, colloidal silicon dioxide, tribasic calcium phosphate, powdered cellulose or magnesium trisilicate.
The core may be formulated by any pharmaceutical^ acceptable technique selected from dry granulation, wet granulation, compaction, fluidized bed granulation or 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 comprise one or more of
film-forming polymers or binders selected from 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 selected from one or more of purified water organic solvents or mixture thereof.
The coating formulation may also include plasticizers.
The seal-coat around the core may constitute from about 1 % to about 5% and particularly 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 comprises film-forming polymer(s), solubilizers, plasticizers and other conventional additives such as lubricants, fillers, antiadherents, opacifiers and colorants.
Suitable film-forming polymer(s) may be selected from one or more of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, vinyl acetate and N-vinylpyrrolidone copolymer, hydroxyalkyl celluloses, methylcelluloses, polyvinyl alcohol or mixtures thereof.
Suitable solubilizers may be selected from 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; or mixtures thereof.
Suitable plasticizers may include one or more of citric acid alkyl esters, glycerol esters, sucrose esters, sorbitan esters, polyethylene glycols, or mixtures thereof.
The immediate-release coating of sulfonylurea may be applied as a solution of the sulfonylurea in non-aqueous solvent.
Suitable non-aqueous solvents may be selected from 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; or mixtures thereof.
The immediate-release coating may be applied by any conventional technique such as pan coating, spray coating, centrifugal fluidized coating or 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.
The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention.
EXAMPLE 1
Metformin hydrochloride 250 mg and Glimepiride 1 mg tablets
(Table Removed)
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. Granules were prepared by roller compaction of the blend of step 2.
4. The granules were lubricated with remaining magnesium stearate and compressed into tablets.
5. A seal-coat solution was prepared by dissolving hydroxypropylmethyl 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, caprylocaproyi monoglyceride, polyethylene glycol, sodium lauryl sulphate hydroxypropyl methylcellulose and copovidone were added with 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 hydrochloride 500 mg and Glimepiride 1 mg tablets

(Table Removed)
Procedure: As followed in Example 1.
EXAMPLE 3
Metformin hydrochloride 500 mg and Glimepiride 2 mq tablets

(Table Removed)
Procedure: Similar to that followed in Example 1.
EXAMPLE 4
Metformin hydrochloride 500 mq and Glimepiride 2 mq tablets

(Table Removed)
Procedure: Similar to 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.

(Table Removed)
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.

(Table Removed)
Pharmacokinetic studies underfed 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 hydrochloride 500 mg (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, AUC0-t and AUCo-, were calculated using standard non-compartmental methods and are shown in Tables 3 and 4. The results as indicated by ratio of test to reference (T/R), are shown in
Tables 5 and 6. Figure 1 depicts the mean plasma concentration-time profile for metformin and Figure 2 depicts the mean plasma concentration-time profile for glimepiride.
Reference R: GLUCOPHAGE XR™ 500 mg (Bristol Myers Squibb) + AMARYL™
tablets, 2 mg (Aventis)
Test T: Metformin ER + Glimepiride IR tablets (Example 4 )
Table 3: Summary of pharmacokinetic parameters for metformin

(Table Removed)
Table 4: Summary of pharmacokinetic parameters for glimepiride

(Table Removed)
The results as indicated by ratio of test to reference, are shown in Tables 5 and 6.
Table 5: Summary of pharmacokinetic parameters for metformin

(Table Removed)
Table 6: Summary of pharmacokinetic parameters for qlimepiride
(Table Removed)

WE CLAIM:
1. An oral solid dosage form comprising (a) an extended-release core comprising a biguanide and (b) an immediate-release coating comprising a sulfonylurea over the core.
2. The dosage form of claim 1 wherein the biguanide is metformin, phenformin or buformin.
3. The dosage form of claim 1 wherein the sulfonylurea is glipizide, glimepiride, glibonuride, glyburide, gliclazide, acetohexamide, chlorpropamide, tolazamide or tolbutamide.
4. An oral solid dosage form comprising:

(a) an extended-release core comprising metformin;
(b) an immediate-release sulfonylurea containing coating applied to the core comprising glimepiride, film-forming polymer (s), solubilizers and plasticizer; wherein the immediate-release coating is applied to the core using a non-aqueous solvent.

5. The dosage form of claim 4 wherein metformin constitutes from about 20 % to about 80% by weight of the dosage form.
6. The dosage form of claim 4 wherein glimepiride constitutes from about 0.05 % to about 10 % by weight of the dosage form.
7. The dosage form of claim 4 wherein the extended-release core is prepared by dispersing metformin in a rate-controlling polymer matrix or by layering onto pharmaceutically acceptable inert cores in admixture with rate-controlling polymers.
8. The dosage form according to claim 7 wherein the rate controlling polymers are hydrophilic, hydrophobic or combinations thereof.
9. The dosage form according to claim 4 wherein the extended-release core further comprises pharmaceutically acceptable excipients that act in one or more capacities as diluents, binders, lubricants, glidants, colorants or flavoring agents.
10. The dosage form of claim 4 wherein the extended-release core is formulated as particles, pellets, beads, granules or tablets.
11 .The dosage form of claim 4 wherein the core is surrounded by a seal-coat.
12. The dosage form of claim 11 wherein the seal-coat includes film-forming polymers selected from one or more of hydroxypropyl methylcellulose, ethyl cellulose, cellulose acetate, poly vinyl alcohol- maleic anhydride copolymers, acrylic polymers and copolymers; or mixtures thereof.
13. The dosage form of claim 4 wherein the film-forming polymers of the immediate-release coating are selected from one or more of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, vinyl acetate and N-vinylpyrrolidone copolymer, hydroxyl alky! celluloses, methylcellulose, polyvinyl alcohol or mixtures thereof.
14.The dosage form of claim 4 wherein the solubilizers are selected from 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; or mixtures thereof.
15. The dosage form of claim 4 wherein the plasticizers are selected from one or more of citric acid alkyl esters, glycerol esters, sucrose esters, sorbitan esters, polyethylene glycols, or mixtures thereof.
16. The dosage form of claim 4 wherein the non-aqueous solvents are selected from 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; or mixtures thereof.
17. An oral solid dosage form for the combination of metformin and glimepiride wherein the dosage form when administered once daily under fed conditions exhibits area under the plasma concentration-time curve for metformin and glimepiride comparable to that exhibited by separate simultaneously administered, commercially available, extended-release tablets of metformin (GLUCOPHAGE XR™) and immediate-release tablet of glimepiride (AMARYL™).
18. An oral solid dosage form for the combination of metformin and glimepiride wherein the dosage form when administered once daily under fed conditions exhibits mean maximum plasma concentration (Cmax) for metformin and glimepiride comparable to that exhibited by separate simultaneously administered, commercially available, extended-release tablets of metformin (GLUCOPHAGE XR™) and immediate-release tablet of glimepiride (AMARYL™).
19. An oral solid dosage form for the combination of metformin and glimepiride, said dosage form comprising.

(a) an extended-release core comprising metformin;
(b) an immediate-release sulfonylurea containing film-forming polymer(s), solubilizers and plasticizer;
wherein the immediate-release coating is applied to the core using a nonaqueous solvent; and wherein the dosage form exhibits a Tmax of metformin which occurs at time 2.5 hours to about 12 hours and exhibits a Tmax of glimepiride which occurs at a time 1 hour to about 6 hours after administration to a human patient.
20. The dosage form of claim 19 wherein the core is surrounded by a seal-core.
21. A method of treatment of non-insulin dependent diabetes mellitus in a patient in need thereof, comprising 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.
22. The method of claim 21 wherein the dosage form further comprises one or more of glitazones, insulin, alpha-glucosidase inhibitors, meglitinides, fibrates, statins, squalene synthesis inhibitors and angiotensin-converting enzyme inhibitors.
23. The method of claim 21 further comprising concurrently or sequentially administering one or more of glitazones, insulin, alpha-glucosidase inhibitors, meglitinides, fibrates, statins, squalene synthesis inhibitors and angiotensin-converting enzyme inhibitors.