FIELD OF THE INVENTION
The present invention relates to multilayered antidiabetic pharmaceutical compositions comprising a combination of atleast two antidiabetic agents, or their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as active agents, optionally with one or more pharmaceutically acceptable excipient(s), whereby the antidiabetic agents are present in fixed dose combination in therapeutically effective amounts. Preferably the antidiabetic agents are metformin and acarbose. The compositions of the present invention are formulated in such a manner that the drug release profile from the composition of the present invention may delay diabetic complications through improvement of metabolic control. The present invention also provides process for the preparation of such compositions and method of using such compositions for treating metabolic disorders, more especially diabetes and in particular type 2 diabetes mellitus (DM), or a disease or condition associated with diabetes comprising administering a fixed dose combination comprising metformin and acarbose optionally with one or more pharmaceutically acceptable excipient(s).
BACKGROUND OF THE INVENTION
Diabetes mellitus, often simply diabetes is a syndrome characterized by disordered metabolism and inappropriately high blood sugar (hyperglycemia) resulting from either low levels of the hormone insulin or from abnormal resistance to insulin's effects coupled with inadequate levels of insulin secretion to compensate. The characteristic symptoms are excessive urine production (polyuria), excessive thirst and increased fluid intake (polydipsia), and blurred vision.
There are two forms of diabetes mellitus: type 1 and type 2, which have different causes and population distributions. While, ultimately, all forms are due to the inability of beta cells of the pancreas to produce sufficient insulin to prevent hyperglycemia, the causes are different. Type 1 diabetes is usually due to autoimmune destruction of the pancreatic beta cells. Type 2 diabetes is a metabolic disorder characterized by insulin resistance in target tissues. Further, it results from complex interactions of multiple factors and is characterized by 2 major defects: decreased secretion of insulin by the pancreas and resistance to the action of insulin in various tissues (muscle, liver and adipose), which results in impaired glucose uptake. It is a major health issue associated with excess mortality and morbidity. The condition is increasing in epidemic proportions in both developed and developing nations, with the global population predicted to rise from 118 million in 1995 to 220 million in 2010. Individuals with type 2 DM are at a significantly higher risk for coronary heart disease, peripheral vascular disease and stroke, as well as microvascular complications affecting various organs such as eyes, kidneys and nerves. The economic impact of
diabetes is substantial: in developed countries, it accounts for 10% or more of the total health care budget on its management or that of its associated complications. The epidemic is thought to be in part related to the rising levels of obesity and fat accumulation as a result of a positive calorific balance.
The precise molecular mechanism of insulin resistance is not clearly understood, but deficits in the postinsulin receptor intracellular signaling pathways are believed to play a major role. Insulin resistance, which is usually present before the onset of diabetes, is determined by a number of factors, including genetics, age, and obesity and, later in the disease, hyperglycemia itself. Excessive visceral adiposity, dyslipidemia and hypertension often accompany insulin resistance. Other findings may include impaired fibrinolysis, increased platelet aggregation, vascular inflammation, endothelial dysfunction and premature atherosclerosis. The inability to suppress hepatic glucose production is a major contributor to the fasting hyperglycemia seen in diabetes.
Individuals who have developed type-2 DM are thought to proceed through a phase of impaired glucose tolerance, with defects in the action or secretion of insulin thought to be the two major abnormalities leading to the development of glucose intolerance and DM. As tissue resistance to insulin progressively increases, insulin secretion by pancreatic beta cells progressively rises as it attempts to compensate for this resistance. Glucose tolerance remains normal as long as the beta cells can compensate for insulin resistance. Eventually, beta cell failure tends to be slowly progressive over time and leads to a progressively rising glucose levels. Initially, impaired glucose tolerance (IGT) develops, resulting in postprandial hyperglycemia and subsequently type-2 DM, when glucose levels reach a critical point at which the risk of microvascular complications ensues. The risk of progressing from IGT to type 2 DM is variable, depending on the type of population studied, ethnicity, obesity and other cardiovascular risk factors present. IGT is associated with a 6-10-fold increase in overall risk of progression to type 2 DM compared to individuals without IGT, averaging around 6% per annum. Individuals with IGT also have a significantly increased risk of cardiovascular disease and death. Although these individuals do have a greater frequency of cardiovascular risk factors, including hypertension, dyslipidaemia and obesity, this does not entirely explain the increased risk.
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, lower plasma glucose primarily by stimulating insulin secretion. The alpha-glucosidase inhibitors, e.g. acarbose inhibit enzymes (glycoside hydrolases) needed to digest carbohydrates specifically alpha-glucosidase enzymes in the brush border of the small intestines and pancreatic alpha-amylase. In diabetic patients, the short-term effect of these drugs therapies is to decrease current blood glucose levels; the long term effect is a small reduction in HbAlc level. 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.
The generally accepted aims in the treatment of diabetes are to provide relief from symptoms, improvement of the quality of life and prevention of both acute (hyperosmolar coma and ketoacidosis) and chronic complications (e.g. diabetic neuropathy, diabetic nephropathy and premature atherosclerosis). Type-2 diabetes is characterized by both increased peripheral insulin resistance and abnormal insulin secretion. At least two abnormalities of insulin secretion are recognized: in the first phase insulin is both delayed and inadequate in the face of elevated circulating glucose levels and in the second phase insulin secretion is lost. Several metabolic, hormonal, and pharmacological entities are known to stimulate insulin secretion including glucose, amino-acids and gastrointestinal peptides. The Diabetes Control and Complications Trial (DCCT) performed in Type-2 DM subjects has established that lowering of blood glucose is associated with decreases in the onset and progression of diabetic microvascular complications (Diabetes.Control and Complications Trial Research Group; N. Engl. J. Med. 1993, 329, 977-986). Therefore, one therapeutic focus is on optimizing and potentially normalizing glycemic control in subjects with type-2 diabetes. Presently available oral agents fail to meet this therapeutic challenge in some patient subgroups, result sometimes in side-effects or are fraught with other problems.
Several studies have disclosed that a combination therapy of acarbose and metformin is more effective than the monotherapy with any of these two drugs. It has been widely proven that the antihyperglycaemic action of Metformin is completely additive to acarbose (A.J.Scheen, Diabetes and Metabolism (Paris), 1998, 24, 311-320) to be verified. Further, it has been also reported that acarbose in combination with metformin thus has the potential to delay diabetes complications
through improvement of metabolic control (Patrick Phillips et al; Diabetes Care 26:269-273, 2003). It is also reported that the complementary mode of action of metformin with acarbose led to their use as combination therapy. The addition of acarbose to the therapeutic regimen in patients inadequately controlled with metformin diet lowered HbAlc, fasting and postpradial glucose as well as plasma insulin concentrations (Gaal et al, Diabetologia (2003), 46 [Suppl 1]: M44-M50). Addition of acarbose to patients with type-2 diabetes who are inadequately controlled with metformin and diet is safe and generally well tolerated and that it significantly lowers HbAlc and fasting and postprandial glucose and insulin levels (Rosenstock J et al.; Diabetes care 21:2050-2055).
Metformin hydrochloride (GLUCOPHAGE®) (N,N -dimethylimidodicarbonimidic diamide hydrochloride) is a white crystalline powder with a molecular formula of C4H11N5HCI and a molecular weight of 165.62. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The main use for metformin is in the treatment of diabetes mellitus type 2, especially when this accompanies obesity and insulin resistance. Metformin is the only anti-diabetic drug that has been proven to reduce the cardiovascular complications of diabetes, as shown in a large study of overweight patients with diabetes. Unlike the other most-commonly prescribed class of oral diabetes drugs, the sulfonylureas, metformin (taken alone) does not induce hypoglycemia. Metformin also modestly reduces LDL and triglyceride levels. The exact mechanism of action of metformin is uncertain, despite its known therapeutic benefits. It appears to act mainly by reducing hepatic gluconeogenesis, but it also decreases absorption of glucose from the gastrointestinal tract and increases insulin sensitivity by increasing peripheral utilization of glucose. Evidence suggests that increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors since metformin is not effective in patients who no longer have any residual insulin production. The 'average' person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one third.
PRECOSE® (acarbose tablets) is an oral alpha-glucosidase inhibitor for use in the management of type 2 diabetes mellitus. Acarbose is an oligosaccharide which is obtained from fermentation processes of a microorganism, Actinoplanes utahensis, and is chemically known as 0-4,6-dideoxy-4-[[(lS,4R,5S,6S)-4,5,6-trihydroxy-3-( hydroxymethyl)-2-cyclohexen-l-yl] amino]-a -D-glucopyranosyl-(l->4)-0-a -D-glucopyranosyl-(l->4)-D-glucose. It is a white to off-white powder with a molecular weight of 645.6. Acarbose is soluble in water and has a pKa of 5.1. PRECOSE®
is available as 25 mg, 50 mg, and 100 mg tablets for oral use. PRECOSE®, as monotherapy, is indicated as an adjunct to diet to lower blood glucose in patients with type 2 diabetes mellitus whose hyperglycemia cannot be managed on diet alone. PRECOSE® may also be used in combination with a sulfonylurea when diet plus either PRECOSE® or a sulfonylurea do not result in adequate glycemic control. Also, PRECOSE® may be used in combination with insulin or metformin. The effect of PRECOSE® to enhance glycemic control is additive to that of sulfonylureas, insulin, or metformin when used in combination, presumably because its mechanism of action is different. In contrast to sulfonylureas, PRECOSE® does not enhance insulin secretion. The antihyperglycemic action of acarbose results from a competitive, reversible inhibition of pancreatic alpha-amylase complex starches to oligosaccharides, in the lumen of the small intestine, while the membrane-bound intestinal and membrane-bound intestinal alpha-glucoside hydrolase enzymes. Pancreatic alpha-amylase hydrolyzes complex starches to oligosaccharides in the lumen of the small intestine, while the membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In diabetic patients, this enzyme inhibition results in a delayed glucose absorption and a lowering of postprandial hyperglycemia. In addition, PRECOSE® diminishes the insulinotropic and weight-increasing effects of sulfonylureas. Acarbose has no inhibitory activity against lactase and consequently would not be expected to induce lactose intolerance.
WO200040233 discloses a pharmaceutical composition with improved effect and tolerability for the treatment of type II diabetes mellitus. Said composition contains a combination of metformin and/or its pharmaceutically acceptable salts and glimepiride and/or acarbose and optionally poly-(dimethyl)-siloxane as active components. WO2007043853 discloses a composition comprising a combination of different types of antidiabetic substances. The composition is characterized in that the aforementioned combination or association consists of two or three antidiabetic substances that are selected from the group containing: sulfonylureas, meglitinides, biguanides or inhibitors of alpha-glucoside with thiazolidinediones for the treatment of type 2 diabetes mellitus in formulations.
Although the prior art literature discloses the additive combination of antidiabetic agents such as metformin and acarbose for the treatment of diabetes; there still exists an unmet need for an improved and safe form of administration of drugs for diabetes management. Also there is a need to provide pharmaceutical compositions comprising the abovesaid antidiabetic agents in combination which could alleviate the drawbacks associated with the prior art compositions that have so far
plagued effective patient management. The inventors of the present invention with considerable expense of intellectual effort have done extensive research and conducted several experiments to alleviate the drawbacks existing in present art to develop a fixed dose combination comprising metformin and acarbose optionally with one or more pharmaceutically acceptable excipient(s). The present invention also 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
The present invention relates to multilayered antidiabetic pharmaceutical compositions comprising a combination of atleast two antidiabetic agents, or their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof as active agents, optionally in association with one or more pharmaceutically acceptable excipient(s), whereby the antidiabetic agents are present in fixed dose combination in therapeutically effective amounts.
It is an objective of the present invention to provide multilayered antidiabetic pharmaceutical compositions comprising a combination of atleast two antidiabetic agents, or their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof, 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).
It is an objective of the present invention to provide multilayered pharmaceutical compositions comprising a combination of atleast two antidiabetic agents, or their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof, at least one release rate controlling polymer(s) or enteric polymer that predominantly controls or delays the release of one antidiabetic agent and optionally one or more pharmaceutically acceptable excipient(s).
It is an objective of the present invention to provide multilayered antidiabetic pharmaceutical compositions 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 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 an objective of the present invention to provide multilayered pharmaceutical compositions comprising atleast three layers wherein the first layer comprises one antidiabetic agent alongwith at least one release rate controlling polymer(s) or enteric polymer(s) optionally alongwith one or more pharmaceutically acceptable excipient(s) in the extended or sustained or prolonged or delayed release form; a second layer entirely covering the first layer comprising atleast one hydrophilic swellable polymer(s) and optionally one or more pharmaceutically acceptable excipient(s); and a third layer comprising at least one antidiabetic agent which is same or different from the first antidiabetic agent, 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.
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 which is an alpha glucosidase inhibitor 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 which is an alpha glucosidase inhibitor optionally alongwith one or more pharmaceutically acceptable excipient(s) in the immediate release form.
It is an objective of the present invention to provide multilayered antidiabetic pharmaceutical compositions comprising three layers wherein the first layer comprises an antidiabetic agent which is an alpha glucosidase inhibitor 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 which is an alpha glucosidase inhibitor 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 multilayered antidiabetic pharmaceutical compositions comprising three layers wherein the first layer comprises acarbose 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 acarbose 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 acarbose in two distinct fractions, wherein the said dosage form provides an immediate release of first antidiabetic active agent acarbose 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 acarbose from the third layer.
It is also an objective of the present invention to provide a dosage form composition which comprises antidiabetic agent in two distinct fractions, wherein the said dosage form provides extended or sustained or prolonged or delayed release of first fraction of the antidiabetic agent from the first (innermost) layer; a second inert polymeric layer covering the first layer, and an immediate release of the antidiabetic agent from the third layer (outermost), such that the gap or lag or interval or delay or difference between the release of first and second pulse of the active agent from the first (innermost) and third (outermost) layer is atleast 3 hours after oral administration and wherein the said dosage form provides a sustained release of the first (innermost) layer 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 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.
The compositions of the present invention provide effective prophylactic or therapeutic concentrations of active agent(s) for extended period 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 a combination of atleast two antidiabetic agents, or their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof, at least one release rate controlling polymer(s) or enteric polymer(s) that predominantly controls or delays the release of at least one antidiabetic 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.
In an embodiment, the present invention provides the present invention describes multilayered antidiabetic pharmaceutical compositions comprising a combination of atleast two antidiabetic agents, or their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof, 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 another embodiment, the present invention provides multilayered pharmaceutical compositions comprising a combination of atleast two antidiabetic agents, or their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof, at least enteric polymer(s) that predominantly delays the release of at least one antidiabetic agent(s) and optionally one or more pharmaceutically acceptable excipient(s).
In an embodiment, the present invention provides multilayered antidiabetic pharmaceutical compositions wherein the dosage form can have at least two or more layers such as bi layered 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 or layered coating over the third layer wherein the coat may or may not comprise an antidiabetic agent. The multilayered antidiabetic pharmaceutical composition can also be in the form of an inlay tablet or tablet-in-tablet or combinations thereof.
In yet another embodiment, the present invention provides multilayered pharmaceutical compositions comprising atleast three layers wherein the first layer comprises one antidiabetic agent alongwith at least one release rate controlling polymer(s) or enteric polymer(s) optionally alongwith one or more pharmaceutically acceptable excipient(s) in the extended or sustained or prolonged or delayed release form; a second layer entirely covering the first layer comprising atleast one hydrophilic swellable polymer(s) and optionally one or more pharmaceutically acceptable excipient(s); and a third layer comprising at least one antidiabetic agent which is same or different from the first antidiabetic agent, 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.
In an embodiment, the present invention provides multilayered antidiabetic pharmaceutical compositions comprising three layers wherein the first layer comprises an antidiabetic agent which is an alpha glucosidase inhibitor 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 which is an alpha glucosidase inhibitor 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 which is an alpha glucosidase inhibitor 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 which is an alpha glucosidase inhibitor alongwith with a film former and optionally one or more pharmaceutically acceptable excipient(s) which provides an immediate release of the antidiabetic agent.
In a preferred embodiment, the present invention provides multilayered antidiabetic pharmaceutical compositions comprising three layers wherein the first layer comprises acarbose 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 acarbose 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 another embodiment, the present invention provides a dosage form composition which comprises acarbose in two distinct fractions, wherein the said dosage form provides an immediate release of first antidiabetic active agent acarbose 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 acarbose from the third layer.
In another embodiment, the present invention provides a dosage form composition which comprises antidiabetic agent in two distinct fractions, wherein the said dosage form provide extended or sustained or prolonged or delayed release of first fraction of antidiabetic agent from the first (innermost) layer; a second inert polymeric layer covering the first layer, and an immediate release of the antidiabetic agent from the third layer (outermost), such that the gap or lag or interval or delay or difference between the release of first and second pulse of the active agent from the first (innermost) and third (outermost) layer is atleast 3 hours after oral administration and wherein the said dosage form provides a sustained release of the first (innermost) layer for an extended period of time such as from 8-24 hours.
In an embodiment, the present invention provide a dosage form composition wherein the said dosage form provide immediate release of first fraction of antidiabetic agent from the first (innermost) layer and sustained or prolonged or delayed release of second fraction of antidiabetic agent from the outermost layer.
In a preferred embodiment, the present invention provide a dosage form composition wherein the said dosage form provide immediate release of first fraction of alpha glucosidase inhibitor from the first (innermost) layer and sustained or prolonged or delayed release of second fraction of biguanide from the outermost layer.
In an embodiment, the multilayered pharmaceutical compositions according to the present invention are designed in such a manner so as to affect an immediate release of the first pulse of the antidiabetic agent followed by extended or sustained or prolonged or delayed release of the antidiabetic agent which is same or different from the first antidiabetic agent. The pharmaceutical compositions of the present invention provide a less frequent dosing of the medicament as is required by only a sustained release dosage form, increase the resultant patient compliance and provides a more sustained drug blood level response without any side effect(s). The compositions comprise a biguanide active agent in an amount of about 250 mg to about 2500 mg alongwith an alpha glucosidase inhibitor 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 be made for once-a-day or twice-a-day administration or thrice-a-day administration. The compositions of the present invention result in a uniform and constant dissolution of the active agent 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 pharmaceutical compositions are able to provide efficient blood therapeutic levels of the antidiabetic agent for extended duration. Also the first pulse of the antidiabetic agent released almost immediately upon in vivo administration helps to provide immediate relief against a disease/disorder and the subsequent sustained release of the second pulse of the antidiabetic agent after a lag time of about 3-5 hours provides a treatment for an extended duration of time besides ensuring that there is no substantial build-up of toxic levels of active agent in the blood at any point of time.
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 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 another embodiment, the release rate 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; 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), polyvinyl
isobutyl ether), polyvinyl acetate), polyvinyl 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, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methyl cellulose; copolymers of methyl vinyl ether and maleic anhydride such as Gantrez®; enteric polymers; sodium hyaluronate; gums; alginates; polycarbophil; polyethylene oxide (PEO); 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 methacrylamides, 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, 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 but not limited to xanthan gum, veegurh, 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, and the like, or mixtures thereof.
In an embodiment of the present invention, the hydrophobic polymers is selected from but not limited to a group comprising glyceryl behenate such as Compritol® ATO888, Compritol® HD AT05, and the like; hydrogenated vegetable oil such as hydrogenated castor oil e.g. Lubritab® and the like; and glyceryl palmitostearate such as Precirol® AT05 and the like; waxes such as carnuba wax, beeswax, and the like; fatty substances such as one or more triglycerides; or mixtures thereof.
The release rate controlling material(s) useful in the present invention preferably comprises a polymeric material selected from but not limited to the group comprising pH dependent polymers such as alginates, carbomers, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate or methacrylic acid polymers 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 or dependent or mixtures thereof as 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(s).
In an embodiment, the enteric polymer used to make the delayed release fraction comprising metformin is preferably a polyacrylate or a polymethacrylate or methacrylic acid copolymer such as Eudragit® L-100, Eudragit® L-100 55, Eudragit® S100, Eudragit® L100, and the like or mixtures thereof.
In a further embodiment, a film coating is applied on the multilayered tablet according to the present invention which may be a protective seal coat which is applied by means of a conventional polymeric film coating solution. For example, a composition of Opadry® Yellow and sodium chloride (90%-10% to 10%-90%) which is applied from a water based system may be used to coat the tablets of the invention. Opadry® yellow contains hydroxypropylmethyl cellulose; titanium dioxide; polyethylene glycol 4000; polysorbate 80; D&C yellow No. 10 aluminum lake; and FD&C red #40 aluminum lake. These coatings may also contain a minor amount e.g. 2-5% of a water swellable polymer such as hydroxypropylmethyl cellulose or a polyethylene oxide (PEO) polymer having a molecular weight of 200,000 to 1,000,000 (wt.av.). Other Opadry® coating products such as Opadry® Clear or Opadry® with various pigment lakes may also be used in the invention to
change the appearance of the tablets. Other aqueous film-forming polymers may also be employed in place of hydroxypropyl methylcellulose. These coatings may be applied in the form of a suspension by using a perforated coating pan.
In a preferred embodiment, multilayered antidiabetic pharmaceutical compositions delivers acarbose 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. 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 acarbose 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 acarbose) that provides a sustained release of metformin for an extended period
of time, and iii) An inner tablet of acarbose 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 biguanide.
In another preferred embodiment, the dosage form compositions according to the present invention
are designed in the following manner:
i) A coating or a compressed layer of antidiabetic agent that is released almost immediately (first
pulse) after the oral dosage form is exposed to medium either in-vivo or in vitro, ii) An intermediate inert polymeric layer comprising at least one hydrophilic swellable polymer,
and iii) An inner tablet of antidiabetic agent same or different from the first antidiabetic agent that
provides a delayed or sustained release of the active agent (second pulse).
In an embodiment according to the present invention, the second (intermediate) inert or placebo layer comprises at least one hydrophilic swellable polymer(s) as the release rate controlling polymer. The inert or placebo layer on exposure to aqueous fluids in vivo swells the release rate controlling polymer forming a gel or a gel-like mass which prevents the entry of the fluid into the innermost layer comprising the active agent in an immediate release form 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 and its disintegration to release the second pulse of the antidiabetic agent same or different from the first antidiabetic agent released from the outermost layer.
In an embodiment, the composition of the present invention comprises one or more pharmaceutically acceptable excipient(s) 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 (PEO), 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, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, 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 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, tablet in tablets, compacts, pellets, granules or the like.
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 alpha glucosidase inhibitor 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 alpha glucosidase inhibitor with one or more pharmaceutically acceptable
excipient(s) and compressing the material thus obtained on to the tablet of step (ii) to obtain
a tri layered 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 alpha glucosidase inhibitor 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 alpha glucosidase inhibitor 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 yet another embodiment, the preparation of such composition comprises the following steps:
i) treating the alpha glucosidase inhibitor 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 tablet in tablet, iii) optionally coating the tablet in tablet of step (ii) with a film coating.
In yet another embodiment of the present invention is provided a method of using such compositions which comprises administering to a subject in need thereof an effective amount of the composition. The compositions comprising the antidiabetic agents are useful for the treatment of metabolic disorders, more especially diabetes and in particular type 2 diabetes mellitus (DM), or a disease or condition associated with diabetes. In a further embodiment, the composition of the present invention may be useful for the management such as prophylaxis, amelioration or treatment of disease(s)/disorder(s) more especially diabetes and in particular type 2 diabetes mellitus (DM), or a disease or condition associated with 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.
EXAMPLES
Example-l
A) Acarbose Tablet:
S.No. Ingredients Qty/ tab (mg)
1. Acarbose 50
2. Lactose 41.5
3. Polyvinyl pyrrolidone K-30 2.5
4. Magnesium stearate 1
5. Isopropyl alcohol q.s (lost in processing)
6. Purified water q.s (lost in processing)
Procedure:
i) All ingredients were weighed and passed through #40 except magnesium stearate.
ii) The sifted material of step (i) was mixed and then granulated with isopropyl alcohol
purified water mixture to obtain the granules, iii) The granules were dried.
iv) Magnesium stearate was added to the granules of step (iii) and mixed, v) The material of step (iv) was compressed into tablets.
B) Metformin hydrochloride
S.No. Ingredients Qty/ tab (mg)
1. Metformin hydrochloride 500
2. Microcrystalline cellulose (Avicel 102) 10
3. Lactose 265
4. Polyvinyl pyrrolidone K-90 40
5. Sodium carboxymethyl cellulose 80
6. Cetostearyl alcohol 10
7. Hydroxypropyl methylcellulose (HPMC K 100) 90
8. Magnesium stearate 5
9. Isopropyl alcohol q.s (lost in processing)
10. Purified water q.s (lost in processing)
Procedure:
i) Metformin hydrochloride, microcrystalline cellulose, lactose, polyvinyl pyrrolidone K-90, sodium carboxymethyl cellulose, cetostearyl alcohol and hydroxypropyl methylcellulose were passed through #40 and mixed well.
ii) The blend of step (i) was granulated with purified water and isopropyl alcohol to obtain the granules followed by drying of the granules.
iii) The dried granules were mixed with magnesium stearate.
iv) The material of step (iii) was compressed into tablet with the Acarbose tablets of A (v) within.
Dissolution profile of Metformin:
Time (hr) % average drug released
Parameters: USP Apparatus II, 50 rpm, DM water, 900 ml
2 52.8
4 75.2
6 84.7
8 92.1
10 96.7
Example-2
A) Acarbose Tablet:
S.No. Ingredients Qty/ tab (mg)
1. Acarbose 50
2. Lactose 40.5
3. Polyvinyl pyrrolidone K-30 2.5
4. Sodium starch glycolate 5
5. Zinc Stearate 1 Procedure:
i) All ingredients were weighed and passed through #40 except zinc stearate.
ii) The sifted material of step (i) was mixed.
iii) Zinc stearate (#60 pass) was added to the blend of step (ii) and mixed,
iv) The material of step (iii) was compressed into tablets.
B) Metformin hydrochloride
S.No. Ingredients Qty/ tab (mg)
1. Metformin hydrochloride 500
2. Dibasic calcium phosphate 10
3. Sodium carboxymethyl cellulose 80
4. Cetostearyl alcohol 10
5. Stearic acid 5
6. Hydroxypropyl methylcellulose 90 Procedure:
i) Metformin hydrochloride, dibasic calcium phosphate and sodium carboxymethyl cellulose
were weighed and passed through #60 and mixed well, ii) The blend of step (i) was granulated with water, iii) The wet granules were passed through #10 & dried.
iv) The semidried granules were passed through #16 followed by #24 & dried completely, v) The granules of step (iv) were mixed with #40 passed cetostearyl alcohol, stearic acid &
hydroxypropyl methylcellulose .
vi) The material of step (v) was compressed into tablet with the Acarbose tablets of A (iv) within.
C) Coating Composition
S.No. Ingredients Qty/ tab (mg)
1. Acarbose 50
2. Opadry yellow 19
3. Ethanol:Dichloromethane q.s. (lost in processing) Procedure:
i) Acarbose was dissolved in ethanol:dichloromethane followed by the addition of Opadry
yellow and continuous stirring to obtain a homogeneous dispersion, ii) The tablets of B(vi) were coated with the material of step (i) (Part C).
Example-3:
Part A: Metformin hydrochloride (Delayed release)
S. No. Ingredient Quantity (mg)
Core tablet composition
1. Metformin hydrochloride 500
2. Lactose 100
3. Crospovidone 17
4. Zinc stearate 2
5. Talc 1 Enteric coating composition
6. Methacrylic acid copolymer 10
7. Triethyl citrate 2
8. Talc 1
9. Isopropyl alcohol q.s. (lost in processing)
10. Dichloromethane q.s. (lost in processing) Procedure:
i) Metformin hydrochloride, a portion of zinc stearate and a portion of talc were mixed and the
mixture was compacted by means of roller compaction followed by breaking of the compacts.
ii) The material of step (i) was mixed with lactose and crospovidone and lubricated with remaining portions of zinc stearate and Talc.
iii) The material of step (ii) was compressed into tablets.
iv) A coating solution was prepared by dispersing Methacrylic acid copolymer, triethyl citrate
and talc in a mixture of isopropyl alcohol and dichloromethane. v) The tablets of step (iii) were coated with the material of step (iv) and dried.
Part B: Intermediate Polymeric Layer
S. No. Ingredients Quantity (mg)
1. Microcrystalline cellulose 10
2. Polyvinyl pyrrolidone K-90 40
3. Polyethylene oxide (PEO 303) 80
4. Cetostearyl alcohol 10
5. Magnesium stearate 5
6. Hydroxyethylcellulose 90 Procedure:
i) Microcrystalline cellulose and polyvinyl pyrrolidone K-90 were weighed and passed
through #60 and mixed well, ii) The blend of step (i) was granulated with water. iii) The wet granules were passed through #10 & dried.
iv) The semidried granules were passed through #16 followed by #24 & dried completely, v) The granules of step (iv) were mixed with #40 passed cetostearyl alcohol, magnesium
stearate, polyethylene oxide and hydroxyethylcellulose. vi) The material of step (v) was compressed on to the tablets of step (v) (Part A) with the
tablets of step (v) (Part A) within.
Part C: Acarbose (Immediate release)
S. No. Ingredient Quantity (mg)
1. Acarbose 50
2. Microcrystalline cellulose 100
3. Croscarmellose sodium 25
4. Stearic acid 5
5. Talc 5 Procedure:
i) Acarbose, microcrystalline cellulose, croscarmellose sodium, stearic acid and talc were
mixed together, ii) The material of step (i) (Part C) was compressed on to the tablets of step (vi) (Part B) to
obtain a trilayered tablet.
Part D: Film Coating Composition
S. No. Ingredients Quantity/ tablet (mg)
1. Opadry® white 2
2. Isopropyl alcohol q.s. (lost in processing)
3. Dichloromethane q.s. (lost in processing) Procedure:
i) Opadry® white was added into a mixture of isopropyl alcohol and dichloromethane with
continuous stirring, ii) The tablets of step (ii) (Part C) were coated with the material of step (i) (Part D).

We claim:
1. Multilayered antidiabetic pharmaceutical compositions comprising a combination of atleast two antidiabetic agents, or their pharmaceutically acceptable salts, esters, polymorphs, isomers, prodrugs, solvates, hydrates, or derivatives thereof, at least one release rate controlling polymer(s) or enteric polymer(s) that predominantly controls or delays the release of at least one antidiabetic active agent(s) and optionally one or more pharmaceutically acceptable excipient(s) wherein 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.
2. The compositions according to claim 1, wherein the composition comprises at least one release rate controlling polymer(s) that predominantly controls the release of at least one antidiabetic agent(s).
3. The compositions according to claim 1 or 2, wherein the composition comprises at least one enteric polymer(s) that predominantly delays the release of at least one antidiabetic agent(s).
4. The compositions according to claims 1 to 3, 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.
5. The compositions according to claim 1, wherein the compositions comprise atleast three layers wherein the first layer comprises one antidiabetic agent alongwith at least one release rate controlling polymer(s) or enteric polymer(s) optionally alongwith one or more pharmaceutically acceptable excipient(s) in the extended or sustained or prolonged or delayed release form; a second layer entirely covering the first layer comprising atleast one hydrophilic swellable polymer(s) and optionally one or more pharmaceutically acceptable excipient(s); and a third layer comprising at least one antidiabetic agent which is same or different from the first antidiabetic agent, 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.
6. The compositions according to claim 1, wherein the compositions comprise an antidiabetic agent which is an alpha glucosidase inhibitor 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 pharmaceutical ly acceptable excipient(s) in the sustained release form; and a third layer comprising an antidiabetic agent which is an alpha glucosidase inhibitor optionally alongwith one or more pharmaceutically acceptable excipient(s) in the immediate release form.
The compositions according to claim 1, wherein the compositions comprise three layers wherein the first layer comprises an antidiabetic agent which is an alpha glucosidase inhibitor 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 which is an alpha glucosidase inhibitor alongwith with a film former and optionally one or more pharmaceutically acceptable excipient(s) which provides an immediate release of the antidiabetic agent.
The compositions according to claim 7, wherein the compositions comprise three layers wherein the first layer comprises acarbose 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 acarbose 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.
The compositions according to any one of the preceding claims, which comprises acarbose in two distinct fractions, wherein the said dosage form provides an immediate release of first antidiabetic active agent acarbose 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 acarbose from the third layer.
10. The compositions according to any one of the preceding claims, which comprises antidiabetic agent in two distinct fractions, wherein the said dosage form provide extended or sustained or prolonged or delayed release of first fraction of antidiabetic agent from the first (innermost) layer; a second inert polymeric layer covering the first layer, and an immediate release of the antidiabetic agent from the third layer (outermost), such that the gap or lag or interval or delay or difference between the release of first and second pulse of the active agent from the first (innermost) and third (outermost) layer is atleast 3 hours after oral administration and wherein the said dosage form provides a sustained release of the first (innermost) layer for an extended period of time such as from 8-24 hours.
11. The compositions according to any one of the preceding claims wherein the said dosage form provide immediate release of first fraction of antidiabetic agent from the first (innermost) layer and sustained or prolonged or delayed release of second fraction of antidiabetic agent from the outermost layer.
12. The compositions according claim 11, wherein the said dosage form provide immediate release of first fraction of alpha glucosidase inhibitor from the first (innermost) layer and sustained or prolonged or delayed release of second fraction of biguanide from the outermost layer.
13. The compositions according to any one of the preceding claims, which may be prepared in the manner wherein the combination of an immediate release active agent with an extended/sustained/controlled release active agent can be formulated as an inlay tablet.
14. The compositions according to claim 13, wherein the 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.
15. The compositions according to any one of the preceding claims, wherein release rate controlling polymer(s) is selected from 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; non-ionic polymers; synthetic or natural polysaccharide, 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(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.
16. The compositions according to any one of the preceding claims, wherein the dosage form additionally 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.
17. The compositions according to claim 15, wherein the release rate controlling polymer(s) is 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 (PEO); starch; dextran; chitosan; or mixtures thereof.
18. The compositions according to claim 15, wherein 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.
19. The compositions according to any one of the preceding claims, wherein enteric polymer used to make the delayed release fraction comprising metformin is preferably a polyacrylate or a polymethacrylate or methacrylic acid copolymer or mixtures thereof.
20. The compositions according to any one of the preceding claims, which delivers acarbose 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, wherein the process comprise of the following steps:
i). A coating or a compressed layer of acarbose 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 acarbose) that provides a sustained release of metformin for an extended period of time, and
iii). An inner tablet of acarbose 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 any one of the preceding claims, wherein the dosage form
compositions are designed in the following manner:
i). A coating or a compressed layer of antidiabetic agent that is released almost
immediately (first pulse) after the oral dosage form is exposed to medium either in-
vivo or in vitro, ii). An intermediate inert polymeric layer comprising at least one hydrophilic swellable
polymer, and iii). An inner tablet of antidiabetic agent same or different from the first antidiabetic agent
that provides a delayed or sustained release of the active agent (second pulse).
The compositions according to claim 21, wherein the second (intermediate) inert or placebo layer comprises at least one hydrophilic swellable polymer(s) as the release rate controlling polymer.
The compositions according to any one of the preceding claims, wherein the compositions of the present invention comprises one or more pharmaceutically acceptable excipient(s) 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 such as glycerine, various grades of polyethylene oxides (PEO), 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.
The compositions according to any one of the preceding claims, wherein the compositions may additionally comprise a conventionally known antioxidant such as ascorbyl palmirate, butyl hydroxy anisole, butyl hydroxy toluene, propyl gallate, a-tocopherol; at least one
surfactant selected from a group comprising anionic surfactants, cationic surfactants, non-ionic surfactants, zwitterionic surfactants or mixtures thereof.
25. The compositions according to any one of the preceding claims, wherein the compositions are preferably formulated as a solid dosage form such as layered tablets or layered minitablets filled into capsules, compressed tablets, moulded tablets, mini-tablets, tablet in tablets, compacts, pellets, granules or the like.
26. A process for the preparation of multilayered antidiabetic pharmaceutical compositions according to claim 1, which comprises of the following steps:
i). treating the alpha glucosidase inhibitor 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 alpha glucosidase inhibitor 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).
27. A process for the preparation of multilayered antidiabetic pharmaceutical compositions
according to claim 1, which comprises of the following steps:
i). treating the alpha glucosidase inhibitor 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 alpha glucosidase inhibitor 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).
28. A process for the preparation of multilayered antidiabetic pharmaceutical compositions
according to claim 1, which comprises of the following steps:
i). treating the alpha glucosidase inhibitor 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 tablet in tablet.
iii). optionally coating the tablet in tablet of step (ii) with a film coating.
29. The pharmaceutical compositions and processes for the preparation of pharmaceutical compositions substantially as herein described and illustrated by the examples.