FIELD OF THE INVENTION
The present invention relates to multilayered antidiabetic pharmaceutical compositions comprising at least two antidiabetic agents each selected from same or different classes of antidiabetic agents, at least one release rate controlling polymer(s) that predominantly controls the release of at least one antidiabetic active agent(s) and optionally one or more pharmaceutically acceptable excipient(s). Particularly the multilayered antidiabetic pharmaceutical compositions comprise three layers wherein the first layer comprises an antidiabetic agent selected from a group comprising sulfonylureas, insulin sensitizers and alpha glucosidase inhibitors optionally alongwith one or more pharmaceutically acceptable excipient(s) in the immediate release form; a second layer entirely covering the first layer comprising an antidiabetic agent which is a biguanide, at least one release rate controlling polymer(s) and optionally one or more pharmaceutically acceptable excipient(s) in the sustained release form; and a third layer comprising an antidiabetic agent selected from a group comprising sulfonylureas, insulin sensitizers and alpha glucosidase inhibitors optionally alongwith one or more pharmaceutically acceptable excipient(s) in the immediate release form such that the said third layer is a coated or compressed on to the second layer. The present invention also describes process for preparation of such compositions and method of using such compositions.
BACKGROUND OF THE INVENTION
Diabetes mellitus is a mammalian condition in which the amount of glucose in the blood plasma is abnormally high. This condition can be life-threatening and high glucose levels in the blood plasma (hyperglycemia) can lead to a number of chronic diabetes syndromes, for example, atherosclerosis, microangiopathy, kidney disorders or failure, cardiac disease, diabetic retinopathy and other ocular disorders, including blindness. There are two forms of the disease. In the form of this disease known as Type II, non-insulin dependent diabetes mellitus (NIDDM) or adult-onset (as opposed to juvenile diabetes or Type I), the pancreas often continues to secrete normal amounts of insulin. However, this insulin is ineffective in preventing the symptoms of diabetes which include cardiovascular risk factors such as hyperglycemia, impaired carbohydrate (particularly glucose) metabolism, glycosuria, decreased insulin sensitivity, centralized obesity hypertriglyceridemia, low HDL levels, elevated blood pressure and various cardiovascular effects attending these risk factors. These symptoms, if left untreated, often lead to severe complications, including premature atherosclerosis, retinopathy, nephropathy, and neuropathy. Insulin resistance is believed to be a precursor to overt NIDDM and strategies directed toward ameliorating insulin resistance can provide unique benefits to patients with NIDDM.
Current drugs used for managing Type II diabetes and its precursor syndromes, such as insulin resistance, primarily fall within five classes of compounds namely biguanides, thiazolidinediones, sulfonylureas, benzoic acid derivatives and alpha-glucosidase inhibitors. The biguanides, e.g., metformin, are believed to prevent excessive hepatic gluconeogenesis. The thiazolidinediones are believed to act by increasing the rate of peripheral glucose disposal. The sulfonylureas, e.g., glimepiride, the benzoic acid derivatives, e.g. repaglinide, and the alpha-glucosidase inhibitors, e.g. acarbose inhibits enzymes (glycoside hydrolases) needed to digest carbohydrates: specifically alpha-glucosidase enzymes in the brush border of the small intestines and pancreatic alpha-amylase. Among biguanides useful as diabetic therapeutic agents, metformin has proven particularly successful. Metformin is an anti-diabetic agent that acts by reducing glucose production by the liver and by decreasing intestinal absorption of glucose. It is also believed to improve the insulin sensitivity of tissues elsewhere in the body (increases peripheral glucose uptake and utilization). Metformin improves glucose tolerance in impaired glucose tolerant (IGT) subjects and NIDDM subjects, lowering both basal and postprandial plasma glucose. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects.
However, about 75% of patients with Type 2 Diabetes who are treated with sulphonylureas aren't able to adjust their glucose levels to desired levels and require supplementing the treatment with a second oral agent. Also, most of the patients who are treated with a single-drug such as sulphonylurea require, after some years, an additional drug to help with the control therapy and attain glycemic control. The causes of this loss of effectiveness have not yet been determined. One possible explanation is that a gradual deterioration of the pancreas prevents it from maintaining an insulin excretion rate for an extended period of time, which is exacerbated by the constant and long-term stimulation caused by the therapy with sulphonylurea. However, Metformin therapy, whose activity is not based in the stimulation of beta-cells, also shows a lack of response after some time of prolonged use, which would contradict the explanation given to the loss of response of sulphonylureas.
Several studies have disclosed that a combination therapy of sulphonylureas and Metformin is more effective than the monotherapy with any of these two drugs. Further, the probability of hypoglycemic events is increased when a combination of sulfonyl urea and biguanide is prescribed. It has been widely proven that the hypoglycemic action of Metformin is completely additive to the one of sulphonylureas (de Fronzo R A, Goodman A M Yn. Engl. J. Med. 333,541 (1995)). It has been also reported that when the monotherapy with sulphonylureas doesn't attain the desired level it should not
be discontinued to be substituted with monotherapy of Metformin because this will diminish the blood glucose level below the levels observed with monotherapy of sulphonylureas (Rosenstock J, Samols E., Muchmore D B, Sheneider J. Diabetes Care, 19, 1194 (1996); Gasber A J, Duncan T G, Goodman A M, Mills D J, Rohtf J L, Amer. J. Med. 103, 491 (1997)).
Intensive insulin or treatments that produce insulin, such as sulfonylureas, increase the risk of hypoglycemia (or insulin shock), which occurs if blood glucose levels fall below normal (Ref: 6-UKPDS Group. UK Prospective Diabetes Study 33: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet, 352, 837-853, 1998). Hypoglycemia may also be caused by insufficient intake of food, exercise, or alcohol intake. Usually the condition is manageable, but occasionally, it can be severe or even life threatening, particularly if the patient fails to recognize the symptoms. Mild symptoms usually occur at moderately low and easily correctable levels of blood glucose; they include sweating, trembling, hunger, and rapid heartbeat. Severely low blood glucose levels can precipitate neurologic symptoms-confusion, weakness, disorientation, combativeness, and in rare and worst cases, coma, seizure, and death. Patients who experience repeated episodes of hypoglycemia may become insensitive to symptoms; even a single recent episode of hypoglycemia may make it more difficult to detect the next episode. By rigorously avoiding low blood glucose, such patients can regain the ability to sense the symptoms. Experts have been concerned that the increased incidence of hypoglycemia accompanying strict blood glucose control could cause mental deterioration over time. This observation is attributed to the unusual and interesting feature of the brain that, while like other organs systems in its reliance on blood glucose concentration for function, the brain differs from other organs in that it does not need insulin to utilize glucose. Boyle et al. (1995) (9) have reported that hypoglycemia is likely to lead to a reversible, maladaptive central nervous system tolerance to subnormal plasma glucose concentrations.
The Diabetes Control and Complications Trial (DCCT)(10), a ten-year study completed in mid-1993, demonstrated that tight or "intensive" control of blood glucose levels—i.e., frequent self-monitoring of glucose levels and maintenance of these levels as close as possible to those in nondiabetics-significantly reduces diabetes-associated complications, such as retinopathy, nephropathy and neuropathy. The DCCT (11) showed that the frequency of health complications was 40-75% lower for persons in the intensive control group than for those in the conventional treatment group. It has since become a central doctrine of diabetic management that the intensive control of hyperglycemia is critical to effective retardation or delay in the appearance or
progression of the late complications of the disease. However, it was found in the DCCT that patients in the intensive treatment group more often suffered from seizures or coma or required another person's assistance to recover from hypoglycemia than did patients treated less intensively. The chief adverse complication associated with intensive therapy was 3-fold increase in the incidence of severe hypoglycemia, defined as the need for assistance from others, as compared to diabetics undertaking conventional therapy. Thus, the danger in maintaining artificially a patient's blood glucose within the narrow, normal range-the essence of intensive control prescribed according to the DCCT—is that such regimens can induce recurrent low blood-glucose levels, raising the threat of seizure or a coma with little or no warning. Lewin in 1996(12) has recognized that tight control of the blood glucose levels poses a difficult dilemma. Specifically, while tight control of blood glucose levels appears to be required to control hyperglycemia-associated pathology, in practice the patient often overcorreets, thereby inducing repeated episodes of hypoglycemia, giving rise to hypoglycemia unawareness. In order to provide a long term solution to Type II sufferers, a comprehensive treatment must be provided to assist them in maintaining healthy or near normal blood sugar levels. Boyle et al. have also found that, because the body, and especially the brain, adapts to lower blood sugar levels, there is little margin between the blood glucose level at which hypoglycemic signs become perceptible and the level at which dangerous cognitive impairment occurs. Accordingly, patients who use rigorous treatment regimens to maintain near-normal plasma glucose levels are at increased risk for seizures and comas. It is difficult to achieve the tightest level of glycemic control (to minimize microvascular and other complications while at the same time avoiding even a slight degree of hypoglycemia to avoid central nervous system tolerance to subnormal glucose levels.
Glimepiride (AMARYL®) is an oral blood-glucose-lowering drug of the sulfonylurea class. Glimepiride is a white to yellowish-white, crystalline, odorless to practically odorless powder formulated into tablets of 1-mg, 2-mg, and 4-mg strengths for oral administration. Glimepiride, like most of the sulfonylurea drugs, is capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Patients with impaired renal function may be more sensitive to the glucose-lowering effect of glimepiride. A starting dose of 1 mg once daily followed by appropriate dose titration is recommended in such patients. Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents. Hypoglycemia is more likely to occur
when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used. Combined use of glimepiride with metformin may increase the potential for hypoglycemia.
Antidiabetic pharmaceutical compositions comprising various classes of diabetic agents are disclosed in several patent publications. Currently, Laboratories Silanes S.A. de C.V. has a product line called Glimetal.RTM. (Metformin HC1 1,000 mg-Glimepiride 4 mg or 2 mg and Metformin HC1 500 mg--Glimepiride 1 mg) that provides a viable alternative for improved control and prevention of type 2 diabetes.
US Pat. No. 6,682,759 discloses an oral tablet containing a system of immediate-release of a drug including glimepiride and another drug including metformin hydrochloride, with extended release. According to the procedure revealed in this document, glimepiride is formulated in a coating surrounding the core of metformin. US20030187074 discloses a release system consisting of a two-layered pharmaceutical form, one with a biguanide including metformin hydrochloride of controlled release depending on the pH environment, and the other layer of sulphonylurea such as glimepiride. US20070264331 claims a stable pharmaceutical composition in the form of a tablet comprising a core or matrix containing an extended-release biguanide; further comprising an insulating layer or coating comprising a hydrophobic polymer, and further comprising a coating containing an immediate-release sulphonylurea. W09929314 discloses a combination of metformin (2:1) salts alongwith sulfonylureas such as glimepiride. WO0132158 describes an antidiabetic formulation comprising a low dose combination of metformin and at least one other antidiabetic agent such as glimepiride employed in substantially higher daily dosages as prescribed in generally accepted medical practice for first line therapy in treating diabetes. WO 200412700 claims a dosage form of combination of high dose high solubility active ingredient such as metformin hydrochloride as modified release and low dose active ingredient such as glibenclamide as immediate release suitable for swallowing. WO 200326637 claims a dosage form for the treatment of diabetes mellitus and conditions associated with it, comprising a compressible controlled release core composition comprising metformin or its pharmaceutically acceptable salt, two or more swellable polymers wherein at least one polymer is an anionic polymer, one or more pharmaceutically acceptable excipient(s) that improve the compressibility of the core composition, and optionally, a coat comprising one or more water insoluble polymer(s) surrounding the core; further comprising an immediate release long-acting sulfonylurea such as glibenclamide. WO200294285 claims a single-daily-dose antidiabetic oral
pharmaceutical form comprising a biguanide and at least another active principle such as glibenclamide, wherein either of them is in the form of prolonged release compositions.
WO2004045622 (Ranbaxy Lab Ltd.) claims a solid pharmaceutical dosage form for oral administration, the dosage form comprising an extended release layer comprising a biguanide; and an immediate release layer comprising a sulfonylurea. The composition is in the form of a matrix comprising a mixture of the biguanide and one or more rate controlling polymers or the biguanide layered onto a pharmaceutically inert core or seed, along with an immediate release outer layer comprising a sulfonylurea.
US20040081697 describes a pharmaceutical composition which comprises an insulin sensitiser and another antidiabetic agent and a pharmaceutically acceptable carrier therefor, wherein the composition is arranged to provide a modified release of at least one of the insulin sensitiser and the other antidiabetic agent. US 20030219482 claims a pharmaceutical composition for the once-a-day administration of drugs for the treatment of non-insulin dependent diabetes mellitus in humans, the composition comprising a core comprising a multiparticulate polyphasic system comprising a first particulate phase comprising a biguanide or pharmaceutically acceptable salt of the biguanide, a binding agent and a first hydrophilic water-swellable polymer; a second particulate phase comprising a sulfonylurea or pharmaceutically acceptable salt of the sulfonylurea, a wetting agent, a cyclodextrin polymer and a second hydrophilic water-swellable polymer; and a third phase comprising a third hydrophilic water-swellable polymer; and a coating on the core, wherein the coating has a rupture time of not more than about 1 hour. US 20040039031 discloses antidiabetic medicinal products consisting of a combination of an antidiabetic biguanide and an antidiabetic sulfonamide, at low doses, in combination or as a mixture with one or more inert, pharmaceutically acceptable excipients. US Pat. No. 6,099,862 claims a controlled release pharmaceutical tablet containing antihyperglycemic drug preferably biguanides and a hypoglycemic drug preferably sulfonylureas that does not contain an expanding or gelling polymer layer and comprising a core containing the antihyperglycemic drug and the hypoglycemic drug, a semipermeable coating membrane surrounding the core and at least one passageway in the membrane to allow the drugs to be released from the core
However none of the prior art documents described hereinabove disclose multilayered antidiabetic pharmaceutical compositions which are highly safe and effective and are easy to formulate as described in the present invention. A review of the prior art reveals that there still exists an unmet
medical need for development of pharmaceutical compositions to provide diabetes treatment regimens that could alleviate the drawbacks associated with the prior art compositions that have so far plagued effective patient management. The present invention provides safe and effective compositions for the management of diabetes which are particularly devoid of the associated side effects and therefore provides a significant advancement in the said field.
SUMMARY OF THE INVENTION
It is an objective of the present invention to provide multilayered antidiabetic pharmaceutical compositions comprising at least two antidiabetic agents each selected from same or different classes of anti diabetic agents, at least one release rate controlling polymer(s) that predominantly controls the release of at least one antidiabetic active agent(s) and optionally one or more pharmaceutically acceptable excipient(s).
In accordance with the present invention, the term "multilayered antidiabetic pharmaceutical composition" as used herein refers to a composition wherein the dosage form can have at least two or more layers such as bilayered tablet or trilayered tablet wherein one layer is exactly adjacent to the next layer and completely surrounded by the next layer. For example, a bilayered coated tablet-in-tablet dosage form wherein first layer is in the form of a compressed tablet surrounded by a second layer compressed on to the first layer, and a third layer in the form of a coating such as film coating over the second layer, wherein all the three layer comprises at least one antidiabetic agent.
Alternatively the composition can be a trilayered tablet-in-tablet dosage form wherein first layer is in the form of a compressed tablet surrounded by a second layer compressed on to the first layer, and a third layer compressed on to the second layer, optionally further comprising a coating such as film coating over the third layer wherein the coat may or may not comprise an antidiabetic active agent. The multilayered antidiabetic pharmaceutical composition can also be in the form of an inlay tablet or tablet-in-tablet or combinations thereof.
It is a preferred objective of the present invention to provide multilayered antidiabetic pharmaceutical compositions comprising three layers wherein the first layer comprises an antidiabetic agent selected from a group comprising sulfonylureas, insulin sensitizers and alpha glucosidase inhibitors optionally alongwith one or more pharmaceutically acceptable excipient(s) in the immediate release form; a second layer entirely covering the first layer comprising an antidiabetic agent which is a biguanide, at least one release rate controlling polymer(s) and
optionally one or more pharmaceutically acceptable excipient(s) in the sustained release form; and a third layer comprising an antidiabetic agent selected from a group comprising sulfonylureas, insulin sensitizers and alpha glucosidase inhibitors optionally alongwith one or more pharmaceutically acceptable excipient(s) in the immediate release form.
It is an objective of the present invention to provide multilayercd antidiabetic pharmaceutical compositions comprising three layers wherein the first layer comprises an antidiabetic agent selected from a group comprising sulfonylureas, insulin sensitizers and alpha glucosidase inhibitors optionally alongwith one or more pharmaceutically acceptable excipient(s) in the immediate release form; a second layer entirely covering the first layer comprising an antidiabetic agent which is a biguanide, at least one release rate controlling polymer(s) and optionally one or more pharmaceutically acceptable excipient(s) in the sustained release form; and a third layer which is in the form of a coating provided on the second layer wherein said coating comprises an antidiabetic agent selected from a group comprising sulfonylureas, insulin sensitizers and alpha glucosidase inhibitors alongwith with a film former and optionally one or more pharmaceutically acceptable excipient(s) which provides an immediate release of the antidiabetic agent.
It is a particularly preferred objective of the present invention to provide multilayercd antidiabetic pharmaceutical compositions comprising three layers wherein the first layer comprises a sulfonylureas specifically glimepiride or its salts, esters, prodrugs, isomers, solvates, hydrates, or derivatives, optionally alongwith one or more pharmaceutically acceptable excipient(s) in the immediate release form; a second layer entirely covering the first layer comprising metformin or its salts, esters, prodrugs, isomers, solvates, hydrates, or derivatives, at least one release rate controlling polymer(s) and optionally one or more pharmaceutically acceptable excipient(s) in the sustained release form; and a third layer which is in the form of a coating provided on the second layer wherein said coating comprises a sulfonylureas specifically glimepiride or its salts, esters, prodrugs, isomers, solvates, hydrates, or derivatives, alongwith with a film former and optionally one or more pharmaceutically acceptable excipient(s) which provides an immediate release of the antidiabetic agent.
It is also an objective of the present invention to provide a dosage form composition which comprises glimepiride in two distinct fractions, wherein the said dosage form provides an immediate release of first antidiabetic active agent glimepiride from the first layer; a sustained release of the second antidiabetic active agent metformin from the second layer; and again an immediate release of first antidiabetic active agent glimepiride from the third layer, such that the
gap or lag or difference between the release of first and second pulse of the first antidiabetic active glimepiride is atleast 3 hours and wherein the said dosage form provides a safe and effective management of diabetes for an extended period of time such as from 8-24 hours.
It is yet another objective of the present invention to provide process for preparation of such multilayered antidiabetic pharmaceutical compositions.
It is still another objective of the present invention to provide a method of using such composition which comprises administering to a subject in need thereof an effective amount of the composition.
It is the objective of the present invention to provide antidiabetic pharmaceutical compositions for safe and effective use in the management of diabetes especially in the treatment of mild-to-moderate-to-severely diabetic patients by providing glycemic control to minimize microvascular and other complications.
The compositions of the present invention provide effective prophylactic or therapeutic concentrations of antidiabetic active agent(s) for extended periods of time.
DETAILED DESCRIPTION OF THE INVENTION
The present invention satisfies the existing unmet medical need for development of pharmaceutical compositions to provide diabetes treatment regimens that could alleviate the drawbacks associated with the prior art compositions that have so far plagued effective patient management.
The present invention describes multilayered antidiabetic pharmaceutical compositions comprising at least two antidiabetic agents each selected from same or different classes of anti diabetic agents, at least one release rate controlling polymer(s) that predominantly controls the release of at least one antidiabetic active agent(s) and optionally one or more pharmaceutically acceptable excipient(s). The antidiabetic pharmaceutical compositions provides for a safe and effective use in the management of diabetes especially in the treatment of mild-to-moderate-to-severely diabetic patients by providing the tightest level of glycemic control to minimize microvascular and other complications while at the same time avoiding even a slight degree of hypoglycemia to avoid central nervous system tolerance to subnormal glucose levels. The compositions are able to maintain near-normal plasma glucose levels and alleviate or substantially reduce the risk for hypoglycemia induced seizures and comas for extended period of time.
In accordance with the present invention, the term "multilayered antidiabetic pharmaceutical composition" as used herein refers to a composition wherein the dosage form can have at least two or more layers such as bilayered tablet or trilayered tablet wherein one layer is exactly adjacent to the next layer and completely surrounded by the next layer. For example, a bilayered coated tablet-in-tablet dosage form wherein first layer is in the form of a compressed tablet surrounded by a second layer compressed on to the first layer, and a third layer in the form of a coating such as film coating over the second layer third layer, wherein all the three layer comprises at least one antidiabetic agent. Alternatively the composition can be a trilayered tablet-in-tablet dosage form wherein first layer is in the form of a compressed tablet surrounded by a second layer compressed on to the first layer, and a third layer compressed on to the second layer, optionally further comprising a coating such as film coating over the third layer wherein the coat may or may not comprise an antidiabetic active agent. The multilayered antidiabetic pharmaceutical composition can also be in the form of an inlay tablet or tablet-in-tablet or combinations thereof.
In an embodiment, the present invention provides multilayered antidiabetic pharmaceutical compositions comprising three layers wherein the first layer comprises an antidiabetic agent selected from a group comprising sulfonylureas, insulin sensitizers and alpha glucosidase inhibitors optionally alongwith one or more pharmaceutically acceptable excipient(s) in the immediate release form; a second layer entirely covering the first layer comprising an antidiabetic agent which is a biguanide, at least one release rate controlling polymer(s) and optionally one or more pharmaceutically acceptable excipient(s) in the sustained release form; and a third layer comprising an antidiabetie agent selected from a group comprising sulfonylureas, insulin sensitizers and alpha glucosidase inhibitors optionally alongwith one or more pharmaceutically acceptable excipient(s) in the immediate release form.
In another embodiment, the present invention provides multilayered antidiabetic pharmaceutical compositions comprising three layers wherein the first layer comprises an antidiabetic agent selected from a group comprising sulfonylureas, insulin sensitizers and alpha glucosidase inhibitors optionally alongwith one or more pharmaceutically acceptable excipient(s) in the immediate release form; a second layer entirely covering the first layer comprising an antidiabetic agent which is a biguanide, at least one release rate controlling polymer(s) and optionally one or more pharmaceutically acceptable excipient(s) in the sustained release form; and a third layer which is in the form of a coating provided on the second layer wherein said coating comprises an antidiabetic agent selected from a group comprising sulfonylureas, insulin sensitizers and alpha glucosidase
inhibitors alongwith with a film former and optionally one or more pharmaceutically acceptable excipient(s) which provides an immediate release of the antidiabetic agent.
In an embodiment, the multilayered antidiabetic pharmaceutical compositions according to the present invention are designed to contain higher amounts of an active compound and are prepared in such a manner as to affect an immediate release of the first pulse of the first antidiabetic active agent followed by a sustained release of the second antidiabetic active agent and further followed by immediate release of the second pulse of the first antidiabetic active agent. The antidiabetic pharmaceutical compositions of the present invention provide a less frequent dosing of the medicament as is required by only a sustained release dosage form, increases the resultant patient regime compliance, provides a sustained drug blood level response and effectively controls the blood sugar levels without any side effect. By providing a slow and steady release of a medicament over time, absorbed drug concentration spikes are mitigated or eliminated by affecting a smoother and more sustained blood level response. The compositions comprise a biguanide active agent in an amount of about 250 mg to about 2500 mg alongwith a sulfonylurea active agent in an amount of 0.1 mg to about 100 mg, and are useful for once-a-day treatment of diabetes. The compositions of the present invention can also be made for twice-a-day or thrice-a-day administration. The compositions of the present invention result in a uniform and constant dissolution of the biguanide active agent (metformin) from the pharmaceutical formulation and are thus effective for an extended period of time. Further, such a formulation is simple to make and the manufacturing process is reproducible.
In another embodiment, the multilayered antidiabetic pharmaceutical compositions are able to provide efficient blood glucose control as compared to once a day glimepiride and sustained release metformin hydrochloride administered alone.
In an embodiment, the biguanide according to the present invention is selected from but not limited to a group comprising metformin, fenformin and buformin, and their pharmaceutically acceptable salts, esters, amides, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, used either alone or in combination thereof.
In an embodiment, the sulfonylurea useful according to the present invention is selected from but not limited to a group comprising glipizide, glimepiride, glibornuride, glyburide, glisoxepide, gliclazide, acetohexamide, chlorpropamide, tolazamide and tolbutamide, or combinations thereof
In an embodiment, the insulin sensitizer according to the present invention is selected from but not limited to a group comprising thiazolidinediones such as pioglitazonc, rosiglitazone or troglitazone, and meglitinides such as repaglinide and nateglinide, and their pharmaceutically acceptable salts, esters, amides, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, used either alone or in combination thereof.
In a preferred embodiment, the present invention provides multilayered antidiabetic pharmaceutical compositions comprising three layers wherein the first layer comprises a sulfonylureas specifically glimepiride or its salts, esters, prodrugs, isomers, solvates, hydrates, or derivatives, optionally alongwith one or more pharmaceutically acceptable excipient(s) in the immediate release form; a second layer entirely covering the first layer comprising metformin or its salts, esters, prodrugs, isomers, solvates, hydrates, or derivatives, at least one release rate controlling polymer(s) and optionally one or more pharmaceutically acceptable excipient(s) in the sustained release form; and a third layer which is in the form of a coating provided on the second layer wherein said coating comprises a sulfonylureas specifically glimepiride or its salts, esters, prodrugs, isomers, solvates, hydrates, or derivatives, alongwith with a film former and optionally one or more pharmaceutically acceptable excipient(s) which provides an immediate release of the antidiabetic agent.
In yet another embodiment, multilayered antidiabetic pharmaceutical compositions may be prepared in the manner wherein the combination of an immediate release active agent with a extended/sustained/controlled release active agent can be formulated as an inlay tablet and the like.
In an embodiment, inlay tablet is a compressed solid oral dosage form which has a small tablet placed within a large tablet, such that the three sides of small tablet are within a large tablet and only one surface of the small tablet gets exposed. This particular dosage form provides advantage to the formulator in formulating a multiple drug fixed dose compositions; particularly wherein the release of at least one active needs to be modified and other actives are present for immediate release from the compositions. The extended/sustained/controlled release portion can be present as a smaller tablet placed within a larger tablet containing the immediate release portion of the composition, or the immediate release portion can be present as a smaller tablet placed within a larger tablet containing the modified release portion of the composition.
In a preferred embodiment, the present invention provides multilayered antidiabetic
pharmaceutical compositions wherein the said system releases the active agent(s) predominantly by erosion mechanism or combination of erosion and diffusion mechanisms, and which provides therapeutic concentrations of active agent(s) for extended periods of time. In an embodiment, the objective of the present invention is to provide a dosage form composition which comprises glimepiride in two distinct fractions, wherein the said dosage form provides an immediate release of first antidiabetic active agent glimepiride from the first layer; a sustained release of the second antidiabetic active agent metformin from the second layer; and again an immediate release of first antidiabetic active agent glimepiride from the third layer, such that the gap or lag or difference between the release of first and second pulse of the first antidiabetic active glimepiride is atleast 3 hours and wherein the said dosage form provides a safe and effective management of diabetes for an extended period of time such as from 8 hours to 24 hours.
In another embodiment, the release controlling polymer(s) of the present invention comprises a polymeric material selected from but not limited to the group comprising pH dependent polymers; pH independent polymers; swellable polymers; non-swellable polymers; hydrophilic polymers; hydrophobic polymers and/or one or more other hydrophobic materials; ionic polymers such as sodium alginate, carbomer, calcium carboxymethylcellulose or sodium carboxymethylcellulose (Cekol 50000); non-ionic polymers such as hydroxypropyl methylcellulose; synthetic or natural polysaccharide selected from the group comprising alkylcelluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitrocelluloses, dextrin, agar, carrageenan, pectin, furcellaran, starch and starch derivative, and mixtures thereof. The polymeric material used in the present invention is selected from but not limited to a group comprising cellulosic polymer, methacrylate polymer, methacrylate copolymer such as Eudragit® EPO, Eudragit® El00, Eudragit® El2,5 and the like or mixtures thereof, Polyvinylpyrollidone (PVP), alginate, polyvinylpyrrolidone-polyvinyl acetate (PVP-PVA) copolymer, ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(alkyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(alkyl acrylate), poly(octadecyl acrylate), poly(ethylene), poly(alkylene), poly(alkylene oxide), poly(alkylene terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride) and polyurethane or a mixture thereof used either alone or in combination thereof. In a further embodiment, the dosage form additionally comprises a gum selected from but not limited to a group comprising xanthan gum, guar gum, gum arabic, carrageenan gum, karaya gum, locust bean gum, acacia gum, tragacanth gum, agar and the like or mixtures thereof.
In a further embodiment, the release controlling polymer(s) useful in the present invention is preferably selected from but not limited to a group comprising carbopol; cellulosic polymers such as sodium carboxymethyl cellulose, hydroxypropyl cellulose (Klucel HXF), hydroxypropyl methyl cellulose (Methocel KlOO CR), hydroxyethyl cellulose, methyl cellulose; copolymers of methyl vinyl ether and maleic anhydride such as Gantrez.®; enteric polymers; sodium hyaluronate; gums; alginates; polycarbophil; polyethylene oxide; starch; dextran; chitosan; and the like or mixtures thereof.
In an embodiment of the present invention, the pH independent polymer is selected from but not
limited to a group comprising alkyl celluloses such as methyl cellulose, hydroxyalkyl alkyl
celluloses such as hydroxypropyl methyl cellulose (HPMC, Methocel®), hydroxy alkyl celluloses
such as hydroxypropyl cellulose (HPC, Klucel®) and hydroxy ethyl cellulose (HEC, Natrosol®),
polyethylene glycols (PEG®, Lutrol®), copolymers of ethylene oxide with propylene oxide
(Poloxamer®), gelatin, polyvinylpyrrolidones (PVP, Kollidon®), vinylpyrrolidones, vinyl acetates,
polyvinylimidazoles, polyvinylpyridine N-oxides, copolymers of vinylpyrrolidone with long-
chained alpha.-olefins, copolymers of vinylpyrrolidone with vinylimidazole,
poly(vinylpyrrolidone/dimethylaminoethyl methacrylates), copolymers of
vinylpyrrolidone/dimethylaminopropyl methacry lam ides, copolymers of vinylpyrrolidone/ dimethylaminopropyl acrylamides, quaternised copolymers of vinylpyrrolidones and dimethylaminoethyl methacrylates, terpolymers of vinylcaprolactam/vinylpyrrolidone/ dimethylaminoethyl methacrylates, copolymers of vinylpyrrolidone and methacrylamidopropyl-trimethylammonium chloride, terpolymers of caprolactam/vinylpyrrolidone/dimethylaminoethyl methacrylates, copolymers of styrene and acrylic acid, polycarboxylic acids, polyacryiamides, polyvinyl alcohols (PVA, Mowiol®), optionally hydrolysed polyvinyl acetate, copolymers of ethyl acrylate with methacrylate and methacrylic acid, copolymers of maleic acid with unsaturated hydrocarbons and mixed polymerisation products of the said polymers, polysaccharide gums, both natural and modified (semi-synthetic), including but not limited to xanthan gum, veegum, agar, guar gum, locust bean gum, gum arabic, okra gum, alginie acid, other alginates (e.g. sodium alginate, propyleneglycol alginate), benitonite, arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin, and the like, or mixtures thereof.
In another embodiment of the present invention, the release rate controlling polymer(s) is present in an amount of not less than about 1.5% preferably not less than about 3% by weight of the composition. In another embodiment, the release rate modifying system comprises pH independent
rate controlling polymer(s) in an amount of not less than about 2% by weight of the composition. In an embodiment, the release rate controlling polymer is a cellulosic polymer and optionally used in combination with one or more other rate controlling agent.
In another embodiment, the multilayered antidiabetic pharmaceutical compositions of the present invention is intended to reduce the adverse effects or side effects of the active agent(s) such as hypoglycemia by controlling the peak plasma concentration (Cmax) of one or both the antidiabetic active agents. Also the steady state concentrations of the active agent(s) do not exhibit substantial fluctuations. The reduced incidence of side effects is thus intended to improve patient compliance with the therapy.
In another preferred embodiment, multilayered antidiabetic pharmaceutical compositions delivers glimepiride in two substantially distinct pulses, wherein one pulse is released in vivo almost immediately after ingestion and a second pulse is released after a gap of at least 3 hours, preferably after 5 hours. The total daily dose of glimepiride is therefore divided into two fractions for release separately so as to avoid a high concentration of the sulfonylurea at any given point of time which can synergize or potentiate or add to the effect of metformin to cause hypoglycemia during the therapy for an extended period of time. In an embodiment, the dosage form compositions according to the present invention are designed in the following manner:
i) A coating or a compressed layer of glimepiride that is released almost immediately (first
pulse) after the tablet is exposed to medium either in-vivo or vitro, ii) A layer of metformin beneath the coating or compressed layer (containing the immediate
release tablet of glimepiride) that provides a sustained release of metformin for an extended
period of time, and iii) A inner tablet of glimepiride that disintegrates to provide an immediate release of the drug
(second pulse) once the sustained release layer of metformin hydrochloride has been
substantially eroded allowing the passage of in vivo fluids.
In an embodiment according to the present invention, the sustained release layer i.e. described above as (ii) comprising the biguanide is formulated using a hydrophilic swelling polymer such as hydroxypropyl methylcellulose (HPMC) as the release rate controlling polymer. When the said layer is exposed to aqueous fluids in vivo, the said release rate controlling polymer swells forming a gel or a gel-like mass which prevents the entry of the fluid into the inner tablet as
described in (iii) for at least 3-5 hours. Subsequently the said gel or gel-like mass erodes gradually thus leading to the contact of the in vivo fluids with the inner layer (iii) and its disintegration to release the second pulse of the sulfonylurea.
In an embodiment, the composition of the present invention comprises one or more pharmaceutically acceptable excipients selected from but not limited to a group comprising diluents; disintegrants; binders; fillers; bulking agent; organic acid(s); colorants; stabilizers; preservatives; lubricants; glidants; chelating agents; vehicles; bulking agents; stabilizers; preservatives; hydrophilic polymers; solubility enhancing agents such as glycerine, various grades of polyethylene oxides, transcutol and glycofurol; tonicity adjusting agents; local anesthetics; pH adjusting agents; antioxidants; osmotic agents; chelating agents; viscosifying agents; acids; sugar alcohol; reducing sugars; non-reducing sugars and the like used either alone or in combination thereof. Certain excipients used in the present composition can serve more than one purpose. Suitable binders include for example starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose, pregelatinised starch, hydroxypropylcellulose, or mixtures thereof. The disintegrants useful in the present invention include but not limited to a group comprising croscarmellose sodium (e.g. Primellose®), sodium starch glycollate, cross-linked sodium carboxymethyl cellulose (e.g. Ac-di-sol®), Solutab®, Vivasol®, starches, pregelatinized starch, celluloses, cross-linked carboxymethylcellulose, crospovidone, clays, alginates, gums and the like used either alone or in combination thereof. The diluents or fillers useful in the present invention are selected from but not limited to a group comprising lactose, lactose anhydrous (Pharmatose® DCL 21) starch, mannitol, sorbitol, dextrose, microcrystalline cellulose (Avicel 102), dibasic calcium phosphate, sucrose-based diluents, confectioner's sugar, monobasic calcium sulfate monohydrate, calcium sulfate, calcium lactate, dextrose, dextran, dextrates, inositol, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, cellulose powder, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, glycine, or bentonites, and the like, or mixtures thereof. The lubricants useful in the present invention are selected from but not limited to a group comprising talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, glyceryl behenate, waxes and the like used either alone or in combination thereof. The anti-adherents or glidants are selected from but not limited to a group comprising talc, corn starch, DL-leucine, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, colloidal silicon dioxide, and the like, or mixtures thereof. In an embodiment of the present invention, the composition may additionally comprise a conventionally known antioxidant such as ascorbyl palmirate, butyl hydroxy anisole, butyl hydroxy toluene, propyl gallate, a-tocopherol, and the like or mixtures thereof. In another
embodiment, the dosage form of the present invention additionally comprises at least one surfactant selected from a group comprising anionic surfactants, cationic surfactants, non-ionic surfactants, zwitterionic surfactants or mixtures thereof.
In an embodiment of the present invention is provided a process for the preparation of such multilayered antidiabetic pharmaceutical compositions according to the present invention. In an embodiment, the preparation of such composition comprises the following steps: i) treating the sulfonylurea with one or more pharmaceutically acceptable excipient(s) and
compressing it into a tablet, ii) treating the biguanide with a release rate controlling polymer(s) and optionally with one or
more pharmaceutically acceptable excipient(s), and compressing the material thus obtained
on to the tablet of step (i) to obtain a bilayered tablet, iii) treating the sulfonylurea with one or more pharmaceutically acceptable excipient(s) and
compressing the material thus obtained on to the tablet of step (ii) to obtain a trilayered tablet, iv) optionally coating the tablet obtained in step (iii).
In another embodiment, the preparation of such composition comprises the following steps:
i) treating the sulfonylurea with one or more pharmaceutically acceptable excipient(s) and
compressing it into a tablet, ii) treating the biguanide with a release rate controlling polymer(s) and optionally with one or
more pharmaceutically acceptable excipient(s), and compressing the material thus obtained
on to the tablet of step (i) to obtain a bilayered tablet, iii) preparing a coating composition comprising sulfonylurea alongwith a film former and
optionally one or more pharmaceutically acceptable excipient(s), and iv) coating the tablet of step (ii) with the coating material of step (iii).
In a further embodiment, the composition of the present invention is preferably formulated as a solid dosage form such as layered tablets or layered minitablets filled into capsules. The tablets can be prepared by either wet granulation, direct compression, or by dry compression (slugging). The granulation technique is either aqueous or non-aqueous. The non-aqueous solvent used is selected from a group comprising acetone, ethanol, isopropyl alcohol or methylene chloride. In an embodiment, the compositions of the present invention are in the form of compressed tablets, moulded tablets, mini-tablets, compacts, pellets, granules or the like. In another embodiment, the composition of the present invention has a better controlled release profile which may not induce occurrence of hypoglycemic shock in patients suffering from diabetes.
In yet another embodiment of the present invention is provided a method of using such sustained release compositions which comprises administering to a subject in need thereof an effective amount of the composition. In a further embodiment, the composition of the present invention may be useful for the management such as prophylaxis, amelioration or treatment of diabetes for extended time period.
The examples given below serve to illustrate embodiments of the present invention. However they do not intend to limit the scope of present invention in any manner whatsoever.
Example - 1
A) Glimepiride Tablet:
S. No. Ingredients Quantity / tab (mg)
1. Glimepiride 1
2. Microcrystalline Cellulose (Avicel 102) 40.5
3. Polyvinyl pyrrolidone K-30 2.5
4. Sodium Starch Glycolate 5
5. Magnesium Stearate 1 Procedure:
i) All the ingredients were weighed & passed through #40 except magnesium stearate.
ii) All the ingredients of step (i) were mixed together for 10 min except magnesium stearate.
iii) Magnesium stearate was passed through #60 and was added to the blend of step (ii) &
mixed for 5 min. iv) The blend of step (iii) was compressed into tablets.
B) Metformin Outer Layer
S. No. Ingredients Quantity / tab (mg)
1. Metformin hydrochloride 500
2. Microcrystalline Cellulose (Avicel 102) 10
3. Polyvinyl pyrrolidone K-90 40
4. Sodium carboxymethyl cellulose (Cekol 50000) 80
5. Cetosteryl Alcohol 10
6. Magnesium Stearate 5
7. Hydroxypropyl cellulose (Klucel EXF) 9 Procedure:
i) Metformin, microcrystalline cellulose, polyvinyl pyrrolidone K-30 & sodium carboxymethyl cellulose (Cekol 50000) were weighed, mixed well and passed through #60.
ii) The blend of step (i) was granulated with water.
iii) The soft mass of step (ii) was passed through #10 & was dried for 10 min.
iv) The semidried granules of step (iii) were passed through ii 16 followed by #24 and were dried
completely. v) The granules of step (iv) were mixed with 40 passed cetosteryl alcohol and magnesium
stearate and were mixed for 10 min. vi) The blend of step (v) was compressed with the tablets of (A).
C) Coating Composition
S. No. Ingredients Quantity / tab (mg)
1. Glimepiride 1
2. Opadry Yellow 19
3. Ethanol: Dichloromethane Q.S Procedure:
i) The required amount of ethanol and dichloromethane were stirred with the help of a
mechanical stirrer, ii) Opadry yellow and glimepiride were passed through #200 and were mixed, iii) The required amount of step (ii) was stirred with the material of step (i) for 30 mins to obtain the
coating solution, iv) The tablets of (B) were coated with the coating solution of step (iii).
Dissolution Profile:
Dissolution Parameters: The dissolution study was carried out using USP Apparatus Type-Ill at 15 DPM using 250 ml pH 7.8 phosphate buffer as the dissolution media. The data is provided in table-1 and the graph is shown in figures-1 & 2 respectively.
Table-1: Drug release data for Metformin & Glimepiride

(Table Removed)
Example - 2
A) Glimepiride Tablet:
S. No. Ingredients Quantity / tab (mg)
1. Glimepiride 1
2. Pregelatinized Starch 40.5
3. Polyvinyl pyrrolidone K-30 2.5
4. Sodium Starch Glycolate 5
5. Magnesium Stearate 1 Procedure:
i) All the ingredients were weighed and passed through #40 except magnesium stearate ii) All the ingredients of step (i) were mixed except magnesium stearate for 10 min. iii) Magnesium stearate (#60) was added to the blend of step (ii) and was mixed for 5 min iv) The blend of step (iii) was compressed into tablets.
B) Metformin Hydrochloride Tablet
S. No. Ingredients Quantity / tab (mg)
1. Metformin Hydrochloride 500
2. Microcrystalline Cellulose (Avicel 102) 10
3. Polyvinyl pyrrolidone K-90 40
4. Sodium carboxymethyl cellulose (Cekol 50000) 80
5. Cetosteryl Alcohol 10
6. Magnesium Stearate 5
7. Hydroxypropyl Methyl cellulose (Methocel Kl00 CR) 90 Procedure:
i) Metformin, microcrystalline cellulose, polyvinyl pyrrolidone K-30 & sodium carboxymethyl cellulose (Cekol 50000) were weighed, mixed well and passed through #60.
ii) The blend of step (i) was granulated with water.
iii) The soft mass of step (ii) was passed through #10 & was dried for 10 min.
iv) The semidried granules of step (iii) were passed through # 16 followed by #24 and were dried completely.
v) The granules of step (iv) were mixed with 40 passed cetosteryl alcohol and magnesium
stearate and were mixed for 10 min. vi) The blend of step (v) was compressed with the tablets of (A).
C) Coating Composition
S. No. Ingredients Quantity / tab (nig)
1. Glimepiride 1
2. Opadry Yellow 19
3. Ethanol: dichloromethane Q.S Procedure:
i) The required amount of ethanol and dichloromethane were stirred with the help of a
mechanical stirrer, ii) Opadry yellow and glimepiride were passed through #200 and were mixed, iii) The required amount of step (ii) was stirred with the material of step (i) for 30 mins to obtain the
coating solution, iv) The tablets of (B) were coated with the coating solution of step (iii).
Dissolution profile
Dissolution parameters: The dissolution study was carried out using USP Apparatus Type-Ill at 15 DPM using 250 ml pH 7.8 phosphate buffer as the dissolution media. The data is provided in table-2 and the graph is shown in figures-1 & 2 respectively.
Table-2
(Table Removed)

We claim:
1. Multilayered antidiabetic pharmaceutical compositions comprising at least two active agents each selected from same or different classes of anti diabetic agents, at least one release rate controlling polymer(s) that predominantly pontrols the release of at least one antidiabetic active agent(s) and optionally one or more pharmaceutically acceptable excipient(s).
2. The compositions according to claim 1, wherein the antidiabetic agent is selected from a group comprising sulfonylureas, insulin sensitizers and a1pha glucosidase inhibitors.
3. The compositions according to claim 2, comprising three layers wherein the first layer comprises an antidiabetic agent selected from a group comprising sulfonylureas, insulin sensitizers and alpha glucosidase inhibitors optionally alongwith one or more pharmaceutically acceptable excipient(s) in the immediate release form; a second layer entirely covering the first layer comprising an antidiabetic agent which is a biguanide, at least one release rate controlling polymer(s) and optionally one or more pharmaceutically acceptable excipient(s) in the sustained release form; and a third layer comprising an antidiabetic agent selected from a group comprising sulfonylureas, insulin sensitizers and alpha glucosidase inhibitors optionally alongwith one or more pharmaceutically acceptable excipient(s) in the immediate release form.
4. The compositions according to claim 1, wherein the third layer is in the form of a coating provided on the second layer, wherein said coating comprises an antidiabetic agent selected from a group comprising sulfonylureas, insulin sensitizers and alpha glucosidase inhibitors alongwith a film former and optionally one or rnore pharmaceutically acceptable excipient(s) which provides an immediate release of the antidiabetic agent.
5. The compositions according to claim 3, wherein the composition comprises biguanide selected from a group comprising metformin, fenformin, buformin and their pharmaceutically acceptable salts, esters, amides, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixturels thereof, used either alone or in combination thereof.
6. The compositions according to claim 1 or 3, wherein the composition comprising sulfonylurea is selected from a group comprising glipizide, glimepiride, glibornuride, glyburide, glisoxepide, gliclazide, acetohexamide, chlorpropamide, tolazamide and tolbutamide or combinations thereof.
7. The compositions according to claim 1 or 3, wherein tie composition comprising insulin sensitizer selected from to a group comprising thiazolidinediones such as pioglitazone, rosiglitazone or troglitazone and meglitinides such as repaglinide and nateglinide and their pharmaceutically acceptable salts, esters, amides, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof, used either alone or in combination thereof.
8. The compositions according to claim 1, wherein the first layer comprises sulfonylureas specifically glimepiride or its salts, esters, prodrugs, isomers, solvates, hydrates or derivatives, optionally alongwith one or more pharmaceutically acceptable excipient(s) in the immediate release form; a second layer entirely covering the first layer comprising metformin or its salts, esters, prodrugs, isomers, solvates, hydrates or derivatives, at least one release rate controlling polymer(s) and optionally one or more pharmaceutically acceptable excipient(s) in the sustained release form and a third layer which is in the form of a coating provided on the second layer wherein said coating comprises sulfonylureas specifically glimepiride or its salts, esters, prodrugs, isomers, solvates, hydrates or derivatives, alongwith with a film former and optionally one or more pharmaceutically acceptable excipient(s) which provides an immediate release of the antidiabetic agent.
9. The compositions according to claim 3, wherein the composition provides a dosage form composition which comprises glimepiride in two distinct fractions, wherein the said dosage form provides an immediate release of first antidiabetic active agent glimepiride from the first layer; a sustained release of the second antidiabetic active agent metformin from the second layer; and again an immediate release of first antidiabetic active agent glimepiride from the third layer.
10. The compositions according to any one of the preceding claims , wherein the composition comprises a polymeric material selected from the group comprising pH dependent polymers; pH independent polymers; swellable polymers; non-swellablc polymers; hydrophilic polymers; hydrophobic polymers and/or one or more other hydrophobic materials; ionic polymers, non-ionic polymers, synthetic or natural polysaccharide selected from the group comprising alkylcelluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitrocelluloses, dextrin, agar, carrageenan, pectin, furcellaran, starch and starch derivative and mixtures thereof.
11. The compositions according to any one of the preceding claim, wherein the composition comprising the polymeric material is selected from to a group comprising cellulosic
polymer, methacrylate polymer, methacrylate copolymer or mixtures thereof, Polyvinylpyrollidone (PVP). alginate, polyvinylpyrrolidone-polyvinyl acetate (PVP-PVA) copolymer, ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(alkyl methacrylate). poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phcnyl methacrylate), poty(alkyl acrylate), poly(octadecyl acrylate), poly(ethylene), poly(alkylene), poly(alkylene oxide). poly(alkylene terephthalate), poiy(vinyl isobutyl ether). poly(vinyl acetate), polyvinyl chloride) and polyurethane or a mixture thereof used either alone or in combination thereof.
12. The compositions according to claim 11, wherein the composition comprises a gum selected from a group comprising xanthan gum, guar gum, gum arabic, carrageenan gum, karaya gum, locust bean gum, acacia gum, tragacanth gum, agar or mixtures thereof.
13. The compositions according to claim 10, .wherein the composition comprises the release controlling polymer(s) preferably selected from a group comprising carbopol; cellulosic polymers; copolymers of methyl vinyl ether and maleic anhydride; enteric polymers; sodium hyaluronate; gums; alginates; polycarbophil; polyethylene oxide; starch; dextran; chitosan; or mixtures thereof.
14. The compositions according to claim 10, wherein the composition comprises the pH independent polymer is selected from a group comprising alkyl celluloses, hydroxyalkyl alkyl celluloses, hydroxy alkyl celluloses and hydroxy ethyl cellulose (HEC, Natrosol®), polyethylene glycols (PEG®, Lutrol®), copolymers of ethylene oxide with propylene oxide (Poloxamer®), gelatin, polyvinylpyrrolidones (PVP. Kollidon®), vinylpyrrolidones, vinyl acetates, polyvmylimidazoles. polyvinylpyridine N-oxides. copolymers of vinylpyrrolidone with long-chained alpha.-olefins, copolymers of vinylpyrrolidone with vinylimidazole, poIy(vinylpyrro!idone/dimethylaminoethyl methacrylates), copolymers of vinylpyrrolidone/dimethytaminopropyl methacrylamides, copolymers of vinyipyrrolidone/ dirnethylaminopropyl aerylam ides, quaternised copolymers of vinylpyrrolidones and dimethylaminoethy! methacrylates, terpolymers of vinylcaproiactam/vinylpyrrolidone/ dimethylaminoethyl methacrylates, copolymers of vinylpyrrolidone and methacrylamidopropyl-trimethylammonium chloride, terpolymers of caproiactam/vinylpyrrolidone/dimethylaminoethyl methacrylates, copolymers of styrene and acrylic acid, polycarboxylic acids, polyacrylamides, polyvinyl alcohols (PVA,
Mowiol®), optionally hydrolysed polyvinyl acetate, copolymers of ethyl acrylate with methacrylate and methacrylic acid, copolymers of maleic acid with unsaturated hydrocarbons and mixed polymerisation products of the said polymers, polysaccharide gums, both natural and modified (semi-synthetic), including xanthan gum, veegum, agar, guar gum, locust bean gum, gum arabic, okra gum, alginic acid, other alginates (e.g. sodium alginate, propyleneglycol alginate), benitonite, arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin or mixtures thereof.
15. The compositions according any one of the preceding claim, wherein the composition comprises the release rate controlling polymer(s) is present in an amount of not less than about 1.5% preferably not less than about 3% by weight of the composition.
16. The compositions according any one of the preceding claim, wherein the composition comprises the release rate controlling system comprises pH independent rate controlling polymer(s) in an amount of not less than about 2% by weight of the composition.
17. The compositions according any to claim 10, wherein the release rate controlling polymer is a cellulosic polymer and optionally used in combination with one or more other rate controlling agent.
18. The compositions according any to claim 1, wherein the composition, delivers glimepiride in two substantially distinct pulses, wherein one pulse is released in vivo almost immediately after ingestion and a second pulse is released after a gap of at least 3 hours, preferably after 5 hours and the total daily dose of glimepiride is therefore divided into two fractions for release separately so as to avoid a high concentration of the sulfonylurea at any given point of time which can synergize or potentiate or add to the effect of metformin to cause hypoglycemia during the therapy for an extended period of time.
19. The compositions according any to claim 1, wherein the composition is designed in the following manner:
i) A coating or a compressed layer of glimepiride that is released almost immediately (first pulse) after the tablet is exposed to medium either in-vivo or vitro,
ii) A layer of metformin beneath the coating or compressed layer (containing the immediate release tablet of glimepiride) that provides a sustained release of metformin for an extended period of time and
iii) A inner tablet of glimepiride that disintegrates to provide an immediate release of
the drug (second pulse) once the sustained release layer of metformin hydrochloride has been substantially eroded allowing the passage of in vivo fluids.
The compositions according to claim I, wherein the composition comprises one or more pharmaceutically acceptable excipients selected from a group comprising diluents; disintegrants; binders; fillers; bulking agent; organic acid(s); colorants; stabilizers; preservatives; lubricants; glidants; chelating agents; vehicles; bulking agents; stabilizers; preservatives; hydrophilic polymers; solubility enhancing agents; tonicity adjusting agents; local anesthetics; pH adjusting agents; antioxidants; osmotic agents; chelating agents; viscosifying agents; acids; sugar alcohol; reducing sugars; non-reducing sugars used either alone or in combination thereof.
A process of preparation of the composition as claimed in claim 1, wherein the composition comprises of the following steps:
i) treating the sulfonylurea with one or more pharmaceutically acceptable excipient(s) and compressing it into a tablet,
ii) treating the biguanide with a release rate controlling polymer(s) and optionally with one or more pharmaceutically acceptable excipient(s) and compressing the material thus obtained on to the tablet of step (i) to obtain a bilayered tablet,
iii) treating the sulfonylurea with one or more pharmaceutically acceptable excipient(s) and compressing the material thus obtained on to the tablet of step (ii) to obtain a trilayered tablet,
iv) optionally coating the tablet obtained in step (iii).
A process of preparation of the composition as claimed in claim 1. wherein the composition comprises of the following steps:
i) treating the sulfonylurea with one or more pharmaceutically acceptable excipient(s) and compressing it into a tablet,
ii) treating the biguanide with a release rate controlling polymer(s) and optionally with one or more pharmaceutically acceptable excipient(s) and compressing the material thus obtained on to the tablet of step (i) to obtain a bilayered tablet,
iii) preparing a coating composition comprising sulfonylurea alongwith a film former and optionally one or more pharmaceutically acceptable excipient(s) and
iv) coating the tablet of step (ii) with the coating material of step (iii).
23. The compositions according any to any one of the preceding claim, wherein the composition is preferably formulated as a solid dosage form such as layered tablets or layered mini tablets filled into capsules, wherein the tablets can be prepared by either wet granulation, direct compression or by dry compression (slugging) and the granulation technique is either aqueous or non-aqueous.
24. The compositions according to any one of the preceding claim, wherein the composition are in the form of compressed tablets, molded tablets, mini-tablets, compacts, pellets, granules or the like.
25. The pharmaceutical compositions and process for the preparation of multilayered antidiabetic compositions substantially as herein described and illustrated by examples.