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Title:  Composition and method for maintaining blood glucose level

United States Patent:  6,703,045

Issued:  March 9, 2004

Inventors:  Dhawan; Sanju (Chandigarh, IN); Singla; Anil Kumar (Chandigarh, IN)

Assignee:  Council of Scientific & Industrial Research (New Delhi, IN)

Appl. No.:  935057

Filed:  August 21, 2001

Abstract

A composition useful for reducing serum glucose levels by an oral controlled release system and a method for treating diabetes in a human being by controlling the blood glucose level (BGL) and reducing the complications associated with diabetic hyperglycemia and also the long term management of Non-Insulin Dependent Diabetes Mellitus (NIDDM) by avoiding the problems associated with the tight control of BGL, i.e., hypoglycemia tolerance and seizures. The composition is directed to a solid, hydrophilic matrix controlled release oral dosage form where the dosage form contains a therapeutically effective amount of antidiabetic drug in the matrix ensuring complete bioavailability of the drug from the matrix of the tablet. The formulation undergoes substantially or approaches zero order release of active drug and the concentration of the excepients and the water swellable polymers is chosen in such a way that the erosion or dissolution rate of the polymer is equal to the swelling rate of the polymer to get a constant release. Also, the concentration is chosen in such a way that the tablet will be fully dissolved at the same time the last of the drug is released and in addition a bioadhesive polymer may also be added to increase the residence time of the dosage form in the g.i.t. and at high concentration of the polymer, beta cyclodextrin may also be added to improve the release kinetics.

BRIEF SUMMARY OF THE INVENTION

The present invention provides a composition useful for reducing serum glucose levels by an oral controlled release system

The present invention is directed to an improved and more economical method for the stable and convenient treatment of diabetes of the type II that is responsive to control by a sulfonylurea antidiabetic agent. Also the present invention is directed to a method for preparing a bioavailable controlled release 24 hour formulation for antidiabetic drugs such as sulfonylurea, glipizide drugs.

Accordingly, the present invention relates to a composition useful for reducing serum glucose levels by an oral controlled release system and a method for treating diabetes in a human being by controlling the blood glucose level (BGL) and reducing the complications associated with diabetic hyperglycemia and also the long term management of Non-Insulin Dependent Diabetes Mellitus (NIDDM) by avoiding the problems associated with the tight control of BGL, i.e., hypoglycemia tolerance and seizures. The invention is directed to a novel, solid, hydrophilic matrix controlled release oral dosage form where the dosage form contains a therapeutically effective amount of antidiabetic drug in the matrix ensuring complete bioavailability of the drug from the matrix of the tablet and the formulation undergoes substantially or approaches zero order release of active drug and the concentration of the excepients and the water swellable polymers is chosen in such a way that the erosion or dissolution rate of the polymer is equal to the swelling rate of the polymer to get a constant release. Also, the concentration is chosen in such a way that the tablet will be fully dissolved at the same time the last of the drug is released and in addition a bioadhesive polymer may also be added to increase the residence time of the dosage form in the g.i.t. and at high concentration of the polymer, beta cyclodextrin may also be added to improve the release kinetics.

An object of this invention is to provide a dosage form for delivering glipizide in a rate controlled amount, and which dosage form substantially overcomes the hypoglycemia associated with the tight control of blood glucose levels.

One of the main objects of the invention is to provide a composition for reducing glucose serum levels by oral controlled release system.

Another object of the invention is to provide a regimen to achieve near normal blood glucose levels in the patient, with a low incidence of undesirable side effects for the therapy.

Still another object of the present invention is to reduce the risk of long term damage to organs and tissues resulting from sustained hyperglycemia.

Still another object of the present invention is to enable the patient to maintain as near normal a lifestyle as possible while ensuring adequate control of his or her diabetes.

Yet another object of the present invention is to provide a dosage form for orally administering glipizide in a rate-controlled dose for blood-glucose lowering therapy.

Yet another object of the invention is to provide a method for treating hyperglycemia by orally administering glipizide in a rate-controlled dose per unit time to a human being in need of hyperglycemia therapy.

One more objects of the invention is to provide a pharmaceutical dosage form that makes available controlled and sustained glipizide therapeutic activity to a patient in need of glipizide therapy.

Another object of the invention is to provide a novel dosage form manufactured as hydrophilic, swellable and erodible device that can administer glipizide to a biological receptor site to produce the desired glipizide pharmacological effects.

Another object of the present invention is to provide a dosage form that can deliver the substantially aqueous insoluble drug glipizide at a controlled and beneficial known rate over time.

Another object of the present invention is to provide a complete pharmaceutical glipizide regimen comprising a composition comprising glipizide that can be dispensed from a drug delivery dosage form, the use of which requires intervention only for initiation and possibly for termination of the regimen.

It is also an object of the invention to provide oral anti-diabetic glipizide pharmaceutical compositions.

It is a further object of the invention to provide a process for preparing said glipizide compositions.

Another object of the invention is to provide a dosage form comprising the drug N-[2-[4-[[[(cyclohexylamino)carbonyl]-amino]sulfonyl]phenyl]ethyl]-5-methy l pyrazinecarboxamide and a pharmaceutically acceptable carrier that forms and provides a dispensable composition when the dosage form is delivering the drug to the patient.

It is also an object of the invention to provide a novel and economical controlled release dosage formulation of glipizide.

Further objects and advantages of the invention will be brought out in the following portions of the specification, wherein the detailed description is for the purpose of fully disclosing preferred embodiments of the invention without placing limitations thereon.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly the present invention provides a composition for reducing serum glucose levels having an oral controlled release system, said composition comprising:

i. a medicament;

ii. one or more water soluble, high viscosity, bioadhesieve polymer for slow release of medicament; and

iii. optionally pharmaceutically acceptable additive.

In an embodimant of the present invention, the said polymer used in the composition is an hydrophilic and water swellable polymer and also having bioadhesieve properties.

In another embodiment of the invention relates to the medicament which, is an antidiabetic selected from group consisting essentially of sulphonylurea and glipizide.

In still another embodiment of the invention, wherein the polymer is selected from the group consisting of poly(ethylene oxide), hydroxypropylmethylcellulose, carboxypolymethylene (carbopol) and mixtures thereof.

In yet another embodiment of the invention, the polyethylene oxide is selected from the group comprising polyethylene oxides having molecular weight ranging from 4,000,000 to 8,000,000.

In yet another embodiment of the invention, the hydroxypropylmethylcellulose is selected from group comprising hydroxypropylmethylcellulose having a viscosity ranging rom 4,000 to 21,000 cps.

In yet another embodiment of the invention, the pharmaceutically acceptable additives consisting of one or more lubricants and diluents selected from the group comprising magnesium stearate, stearic acid, talc, dicalcium phosphate, lactose and microcrystalline cellulose.

Yet another embodiment of the present invention the lubricant is selelcted from the group comprising magnesium stearate, stearic acid and talc.

Yet another embodiment of the present invention the diluent is selelcted from the group comprising dicalcium phosphate, lactose and microcrystalline cellulose

In yet another embodiment of the invention, the medicament and optionally pharmaceutically acceptable additives are in the form of a core which is encapsulated with the water soluble, high viscosity, bioadhesieve polymer.

In yet another embodimen of the invention, the composition is in the form of tablet or capsule.

One more embodiment of the invention relates to a composition for reducing serum glucose levels by an oral controlled release system, said composition comprising polythene oxide 10-40% by weight, drug 5-10%, an pharmaceutically acceptable additive 0 to 5% and dicalcium Phosphate q.s.

In another embodiment of the invention relates to once a day controlled release tablet for reducing serum glucose level and for treating hyperglycemia, said tablet comprising:

i. a medicament;

ii. one or more water soluble, high viscosity, bioadhesieve polymers for slow release of medicaments; and

iii. optionally pharmaceutically acceptable additive.

In another embodiment of the invetion wherein, the pharmaceutically acceptable additive comprising a lubricant and a diluent, the medicament is an antidiabetic drug selected from sulphonylurea, glipizide and, the polymer is hydrophilic and water swellable.

Yet another embodiment of the invention, the polymer used in the once a day controlled release tablet for reducing the serum glucose level and treating the mammals, is selected from the group consisting of poly(ethylene oxide), hydroxypropylmethylcellulose, carboxypolymethylene (carbopol) and mixtures thereof.

Yet another embodiment of the invention relates to the lubricant which is selected from magnesium stearate,stearic acid and talc and the diluent selected from dicalcium phosphate, lactose and microcrystalline cellulose.

One more embodiment of the invention relates to a method of reducing a patient's serum glucose level, said method comprising administering to the patient orally a therapeutically effective amount of controlled release medicament encapsulated with water soluble, high viscosity, bioadhesieve polymer, and the said medicament is delivered to the patient's circulatory system at a continual rate over a period of several hours.

Another embodiment of the present invention relates to a method for treating hyperglycemia in a patient, wherein the method comprises administering to the patient a dosage form comprising 2 mg to 50 mg glipizide , which is administered at a therapeutical dose effective over 24 hours from the dosage form comprising one or more hydrogel selected from the group consisting of poly(ethylene oxide) having a 4,000,000 to 8,000,000 molecular weight and a hydroxy propylmethylcellulose (viscosity 4000 to 21000 cps ) and carboxypolymethylene (carbopol 934P) to the patient to produce the intended effect.

In another embodiment of the present invention relates to a process for producing a pharmaceutical composition used for treating mammals, said process comprising a core made of medicament and optionally one or more pharmaceutically acceptable additive, encapsulated with water soluble, high viscosity, bioadhesieve polymer.

In accordance to the present invention provides a controlled release tablet including a pharmaceutical agent glipizide and an excipient. The excipient includes at least about 5-80% of a mixture of water swellable polymers and a lubricant. The water swellable polymer is chosen such that the swelling rate of the polymer is equal to the dissolution rate of the swollen polymer. The lubricant is generally present in an amount of up to 3% of the excipient as a whole. The excipient may also include such other ingredients as diluents, fillers, binders and other pharmacologically inactive compounds. Further, the polymer and pharmaceutical agent are complementary. In selecting a water swellable polymer, the polymer should be chosen with the pharmaceutical agent in mind such that the tablet will be fully dissolved at the same time that the last of the pharmaceutical agent is released so that the whole of the drug may be made bioavailable.

The second necessary characteristic of the formulation is that it does not release all of the active ingredient at one time but rather releases the active ingredient gradually over time. This is particularly important because

(1) glipizide has a relatively short half life and

(2) a desired level of glipizide in blood serum must be maintained over a long period to obtain the desired effect.

If all of the glipizide is released at once it will all enter the circulatory system at once and be metabolized in the liver thereby causing the drug serum level to drop below the desired level. When this occurs the effect on reducing glucose levels is suboptimal.

In summary, it will be appreciated that the present invention contributes to the art an unexpected and unforseen dosage form that possesses the practical utility for administering aqueous insoluble glipizide from hydrphilic matrix dosage form. While the invention has been described and pointed out in detail with reference to operative embodiments thereof it will be understood that those skilled in the art that various changes, modifications, substitutions and omissions can be made without departing from the spirit of the invention.

Formulation in General

Monolithic systems, composed of hydrophobic polymers and other excipients, are commonly used for extended release dosage forms because they are not costly or difficult to produce. However, such systems often provide a square-root-of-time kinetics (i.e. the amount of pharmaceutical agent released is proportional to the square root of the time since the drug was ingested). There are several ways to improve the release kinetics of extended release dosage forms. Incorporation of hydrophilic polymers into monolithic matrices modifies square root kinetics due to the swelling of the polymer. In particular, monolithic matrix systems controlled by the swelling/erosion processes of hydrophilic polymers can improve the pharmaceutical agent release kinetics. However, even in these systems, the release rate of the pharmaceutical agent generally varies significantly with time.

Hydrophilic polymers alone have also been investigated for controlled drug release. The hydrophilic polymers such as hydroxypropylmethyl cellulose (HPMC) and polyvinylalcohol (PVA), which form gels upon contact with water and erode slowly, have been utilized for oral drug delivery systems.

The excipients of the present invention have been formulated to allow controlled release of glipizide. The excipients of the present invention generally comprise a hydrophilic polymer and a lubricant. Other pharmacologically inactive materials also can be added. Polyethylene glycol and cyclodextrins are generally used to increase the solubility of relatively insoluble drugs to encourage absorption by the body. Other solubilizers may also be used. The polymers set forth herein may be compressed into tablets directly. Optionally, binders, fillers, or other typical compounding agents may be added to adjust the properties of the final tablets. Particularly, but without limitation, the following compounds may be included: lactose, dextrose, sucrose, and calcium phosphate. Specifically, the polymeric materials useful in the present invention will depend to a certain extent on the amount of glipizide chosen to be administered. Polymers of choice include uncrosslinked polyethylene oxide (PEO) and hydroxypropylmethylcellulose (HPMC) both of varying molecular weight and viscosity, respectively. HPMC is available on the basis of viscosity measured in a 2% solution in water. PEO is available on the basis of molecular weight. Both PEO and HPMC are useful alone. Alternatively, mixtures of the two materials, or mixtures of various viscosities or molecular weights of either compound may be used in the present invention. Carbopol 934P (carboxypolymethylene) may also be added.

It was found that it is the concentration of polymer (hydrophilic moiety) and dicalcium phosphate (hydrophobic ingredient) which is responsible for the desired release of the drug from the tablet. At high DCP concentration (above 90%), hydrophobicity of DCP played a major role in initial slowing of the release and the release essentially followed due to erosion. While at low DCP concentration or high polymer concentration polymer swelling played a major role in the release. Hence it is the concentration of polymer and other excepients which affects the release of the drug from the dosage forms.

Claim 1 of 11 Claims

What is claimed is:

1. A composition with an oral controlled release system useful for reducing serum glucose levels, said composition comprising:

sulphonylurea at a concentration ranging from 5 to 20% by weight,

polyethylene oxide polymer having a molecular weight of from 4 million to 8 million at a concentration ranging from 5 to 18% by weight,

lubricant at a concentration ranging from 1 to 3% by weight, and

dicalcium phosphate at a concentration of more than 50% by weight.




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