Pharmaceutical composition comprising pioglitazone and glimepiride for use in treatment of diabetes

Description

[0001] The present invention relates to a pharmaceutical composition comprising an insulin sensitivity enhancer in combination with one or more other antidiabetics differing from said enhancer in the mechanism of action.

[0002] Recent years, the pathology of diabetes has become more and more understood and, in parallel, drugs specific for the respective pathologic states have been developed. Accordingly a variety of drugs having new mechanisms of action have appeared one after another.

[0003] Insulin sensitivity enhancers are also known as insulin resistance deblockers because they have the action to normalize the impaired insulin receptor function, and are gathering much attention in these years.

[0004] Regarding such insulin sensitivity enhancers, a very useful compound such as pioglitazone has been developed [Fujita et al., Diabetes, 32, 804-810, 1983, JP-A S55(1980)-22636 (EP-A 8203), JP-A S61(1986)-267580 (EP-A 193256)]. Pioglitazone restores the impaired insulin receptor function to normalize the uneven distribution of glucose transporters in cells, the cardinal enzyme systems associated with glycometabolism, such as glucokinase, and enzyme systems associated with lipidmetabolism, such as lipoprotein lipase. As the results, insulin resistance are deblocked to improve glucose tolerance, and lower the plasma concentrations of neutral lipids and free fatty acids. Since these actions of pioglitazone are comparatively gradual and the risk of side effect in long-term administration is also low, this compound is useful for obese patients who are presumed to be highly insulin-resistant.

[0005] Also, insulin sensitivity enhancers such as CS-045, thazolidinedione derivatives and substituted thiazolidinedione derivatives are reported to be used in combination with.insulin [JP-A H4(1992)-66579, JP-A H4(1992)-69383, JP-A H5(1993)-202042]. Clinic all around vol. 43, 1994, pages 2615-2621, mentions the combination of sulfonylurea and an insulin resistance improving drug including pioglitazone, ciglitazone and CS-045. Whitcomb et al. "Thiazolidionedines", Expert Opin. Invest. Drugs, vol. 4, n° 12, 1995 pages 1299-1309 discloses a combination of troglitazone and glibenclamide. However, the pharmaceutical composition having a specific combination of the present invention is unknown.

[0006] Diabetes is a chronic disease with diverse pathologic manifestations and is accompanied by lipidmetabolism disorders and circulatory disorders as well as glycometabolism disorders. As the results, diabetes tends to progress entailing various complications in many cases. Therefore, it is necessary to select the drug of choice for the prevailing disease state in each individual case. However, this selection is often difficult in clinical settings because single use of each individual drug can not bring sufficient effects in some disease states and there are various problems such as side effect which is caused by an increased dose or a long-term administration.

[0007] In view of the above state of the art, the inventors of the present invention did much research to develop antidiabetics which would not virtually cause adverse reactions even on long-term administration and could be effective for a large cohort of the diabetic population. As a consequence, they discovered that the above object can be accomplished by using an insulin sensitivity enhancer, such as the drug described above, in combination with other antidiabetics differing from said enhancer in the mechanism of action, and accordingly have perfected the present invention.

[0008] The present invention, therefore, relates to:

[0009] Pharmaceutical composition which comprises an insulin sensitivity enhancer selected from pioglitazone or a pharmacologically acceptable salt thereof in combination with the insulin secretion enhancer glimepiride. Pharmaceutical composition as above defined, which is for prophylaxis or treatment of diabetes.

[0010] The term "insulin sensitivity enhancer" as used in this specification means any and all drug substances that restore the impaired insulin receptor function to deblock insulin resistance and consequently enhance insulin sensitivity.

[0011] The pharmacologically acceptable salt of the pioglitazone are exemplified by salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.

[0012] Preferable examples of salts with inorganic bases include salts with alkali metals such as sodium, potassium, etc., salts with alkaline earth metals such as calcium, magnesium, etc., and salts with aluminum, ammonium, etc.

[0013] Preferable examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N-dibenzylethylenediamine, etc.

[0014] Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.

[0015] Preferable examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

[0016] Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc., and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc.

[0017] The pharmacologically acceptable salt of the pioglitazone is preferably a salt with an inorganic acid, more preferably a salt with hydrochloric acid. Especially, pioglitazone is preferably used in the form of salt with hydrochloric acid.

[0018] Pioglitazone or a salt thereof can be produced in accordance with, for example, methods described in JPA S55(1980)-22636(EP-A 8203), JPA S61(1986)-267580(EP-A 193256), etc. or methods analogous thereto.

[0019] Insulin secretion enhancers are drugs having the property to promote secretion of insulin from pancreatic β cells. Examples of the insulin secretion enhancers include sulfonylureas (SU). The sulfonylureas (SU) are drugs which promote secretion of insulin from pancreatic β cells by transmitting signals of insulin secretion via SU receptors in the cell membranes.

[0020] The pharmaceutical composition comprising the pioglitazone or a pharmacologically acceptable salt thereof in combination with the insulin secretion enhancer glimepiride, both provided in accordance with the present invention, can be respectively put to use by mixing the respective active components either all together or independently with a physiologically acceptable carrier, excipient, binder, diluent, etc. and administering the mixture or mixtures either orally or non-orally as a pharmaceutical composition. When the active components are formulated independently, the respective formulations can be extemporaneously admixed using a diluent or the like and administered or can be administered independently of each other, either concurrently or at staggered times to the same subject.

[0021] The dosage form for said pharmaceutical composition includes such oral dosage forms as granules, powders, tablets, capsules, syrups, emulsions, suspensions, etc. and such non-oral dosage forms as injections (e.g. subcutaneous, intravenous, intramuscular and intraperitoneal injections), drip infusions, external application forms (e.g. nasal spray preparations, transdermal preparations, ointments, etc.), and suppositories (e.g. rectal and vaginal suppositories).

[0022] These dosage forms can be manufactured by the per se known technique conventionally used in pharmaceutical procedures. The specific manufacturing procedures are as follows.

[0023] To manufacture an oral dosage form, an excipient (e.g. lactose, sucrose, starch, mannitol, etc.), a disintegrator (e.g. calcium carbonate, carboxymethylcellulose calcium, etc.), a binder (e.g. α-starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.), and a lubricant (e.g. talc, magnesium stearate, polyethylene glycol 6000, etc.), for instance, are added to the active component or components and the resulting composition is compressed. Where necessary, the compressed product is coated, by the per se known technique, for masking the taste or for enteric dissolution or sustained release. The coating material that can be used includes, for instance, ethylcellulose, hydroxymethylcellulose, polyoxyethylene glycol, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, and Eudragit (Rohm & Haas, Germany, methacrylic-acrylic copolymer).

[0024] Injections can be manufactured typically by the following procedure. The active component or components are dissolved, suspended or emulsified in an aqueous vehicle (e.g. distilled water, physiological saline, Ringer's solution, etc.) or an oily vehicle (e.g. vegitable oil such as olive oil, sesame oil, cottonseed oil, corn oil, etc. or propylene glycol) together with a dispersant (e.g. Tween 80 (Atlas Powder, U.S.A.), HCO 60 (Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.), a preservative (e.g. methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzyl alcohol, chlorobutanol, phenol, etc.), an isotonizing agent (e.g. sodium chloride, glycerol, sorbitol, glucose, inverted sugar, etc.) and other additives. If desired, a solubilizer (e.g. sodium salicylate, sodium acetate, etc.), a stabilizer (e.g. human serum albumin), a soothing agent (e.g. benzalkonium chloride, procaine hydrochloride, etc.) and other additives can also be added.

[0025] A dosage form for external application can be manufactured by processing the active component or components into a solid, semi-solid or liquid composition. To manufacture a solid composition, for instance, the active component or components, either as they are or in admixture with an excipient (e.g. lactose, mannitol, starch, microcrystalline cellulose, sucrose, etc.), a thickener (e.g. natural gums, cellulose derivatives, acrylic polymers, etc.), etc., are processed into powders. The liquid composition can be manufactured in substantially the same manner as the injections mentioned above. The semi-solid composition is preferably provided in a hydrous or oily gel form or an ointment form. These compositions may optionally contain a pH control agent (e.g. carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), and a preservative (e.g. p-hydroxybenzoic acid esters, chlorobutanol, benzalkonium chloride, etc.), among other additives.

[0026] Suppositories can be manufactured by processing the active component or components into an oily or aqueous composition, whether solid, semi-solid or liquid. The oleaginous base that can be used includes, for instance, higher fatty acid glycerides [e.g. cacao butter, Witepsols (Dinamit-Nobel), etc.], medium-chain fatty acids [e.g. Migriols (Dinamit-Nobel), etc.], vegetable oils (e.g. sesame oil, soybean oil, cottonseed oil, etc.), etc. The water-soluble base includes, for instance, polyethylene glycols, propylene glycol, etc. The hydrophilic base includes, for instance, natural gums, cellulose derivatives, vinyl polymers, and acrylic polymers, etc.

[0027] The pharmaceutical composition of the present invention is low in toxicity and can be safely used in mammals (e.g. humans, mice, rats, rabbits, dogs, cats, bovines, horses, swines, monkeys).

[0028] The dosage of the pharmaceutical composition of the present invention may be appropriately determined with reference to the dosages recommended for the respective active components and can be selected appropriately according to the recipient, the recipient's age and body weight, current clinical status, administration time, dosage form, method of administration, and combination of the active components, among other factors. For example, the dosage of the insulin sensitivity enhancer for an adult can be selected from the clinical oral dose range of 0.01 to 10 mg/kg body weight (preferably 0.05 to 10 mg/kg body weight, more preferably 0.05 to 5 mg/kg body weight) or the clinical parenteral dose range of 0.005 to 10 mg/kg body weight (preferably 0.01 to 10 mg/kg body weight, more preferably 0.01 to 1 mg/kg body weight). The other active component or components having different modes of action for use in combination can also be used in dose ranges selected by referring to the respective recommended clinical dose ranges. The preferred frequency of administration is 1 to 3 times a day.

[0029] The proportions of the active components in the pharmaceutical composition of the present invention can be appropriately selected according to the recipient, the recipient's age and body weight, current clinical status, administration time, dosage form, method of administration, and combination of active components, among other factors.

[0030] The pharmaceutical composition of the present invention shows a marked synergistic effect compared with administration of either active component alone. For example, compared with cases in which each of these active components was administered to diabetic Wistar fatty rats with genetical obsesity, administration of these active components in combination resulted in marked improvements in both hyperglycemia and reduced glucose tolerance. Thus, the pharmaceutical composition of the present invention lowers blood glucose in diabetics more effectively than it is the case with administration of each component drug alone and, therefore, can be used advantageously for the prophylaxis and.treatment of diabetic complications.

[0031] Furthermore, since the pharmaceutical composition of the present invention develops sufficient efficacy with reduced doses as compared with the administration of any one of the active components alone, the side effects of the respective components (e.g. gastrointestinal disorders such as diarrhea, etc.) can be reduced.

[0032] The following working example is merely intended to illustrate as a reference the present invention in further detail but is not within the scope of the invention.

Working Example

[0033] 

Tablets

(1) Pioglitazone hydrochloride	10 mg
(2) Glibenclamide	1.25 mg
(3) Lactose	86.25 mg
(4) Corn starch	20 mg
(5) Polyethylene glycol	2.5 mg
(6) Hydroxypropylcellulose	4 mg
(7) Carmellose calcium	5.5 mg
(8) Magnesium stearate	0.5 mg
	130 mg (per tablet)

[0034] The whole amounts of (1), (2), (3), (4), and (5), 2/3 amounts of (6) and (7), and 1/2 amount of (8) are mixed well and granulated in the conventional manner. Then, the balances of (6), (7) and (8) are added to the granules, which is mixed well and the whole composition is compressed with a tablet machine. The adult dosage is 3 tablets/day, to be taken in 1 to 3 divided doses.

[0035] The pharmaceutical composition of the present invention shows a potent depressive effect on diabetic hyperglycemia and is useful for prophylaxis and treatment of diabetes. Moreover, this pharmaceutical composition is useful for prophylaxis and treatment of diabetic complications such as diabetic neuropathy, nephropathy, retinopathy, macroangiopathy, and osteopenia. In addition, by appropriately selecting the kinds of component drugs, administration route, dosage, etc. according to clinical status, stable hypoglycemic efficacy in long-term therapy can be expected with an extremely low risk of side effect.

Claims

1. Pharmaceutical composition which comprises an insulin sensitivity enhancer selected from pioglitazone or a pharmacologically acceptable salt thereof in combination with the insulin secretion enhancer glimepiride.

2. Pharmaceutical composition according to claim 1, wherein the insulin sensitivity enhancer and the insulin secretion enhancer are mixed all together.

3. Pharmaceutical composition according to claim 1, wherein the insulin sensitivity enhancer and the insulin secretion enhancer are formulated independently for administration independently of each other, either concurrently or at staggered times to the same subject.

4. Pharmaceutical composition according to anyone of claims 1 to 3, for the prophylaxis or treatment of diabetes.

5. Pharmaceutical composition according to anyone of claims 1 to 3, for the prophylaxis or treatment of diabetic complications.

6. Pharmaceutical composition according to anyone of claims 1 to 5 wherein the insulin sensitivity enhancer is the salt of pioglitazone with hydrochloric acid.

7. Use of an insulin sensitivity enhancer selected from pioglitazone or a pharmacologically acceptable salt thereof in combination with the insulin secretion enhancer glimepiride, for the manufacture of a pharmaceutical composition for the prophylaxis and treatment of diabetes.

8. Use of an insulin sensitivity enhancer selected from pioglitazone or a pharmacologically acceptable salt thereof in combination with the insulin secretion enhancer glimepiride, for the manufacture of a pharmaceutical composition for the prophylaxis and treatment of diabetic complications.

9. Use of an insulin sensitivity enhancer selected from pioglitazone or a pharmacologically acceptable salt thereof in combination with the insulin secretion enhancer glimepiride for the manufacture of formulations wherein the insulin sensitivity enhancer and the insulin secretion enhancer are formulated independently, to be administered independently, either concurrently or at staggered times to the same subject, for the prophylaxis and treatment of diabetes.

10. Use of an insulin sensitivity enhancer selected from pioglitazone or a pharmacologically acceptable salt thereof in combination with the insulin secretion enhancer glimepiride for the manufacture of formulations wherein the insulin sensitivity enhancer and the insulin secretion enhancer are formulated independently, to be administered independently, either concurrently or at staggered times to the same subject, for the prophylaxis and treatment of diabetic complications.

11. Use according to anyone of claims 7 to 10 wherein the insulin sensitivity enhancer is the salt of pioglitazone with hydrochloric acid.

Ansprüche

1. Pharmazeutische Zusammensetzung, die einen Insulinempfindlichkeitsverstärker, der aus Pioglitazon oder einem pharmazeutisch annehmbaren Salz davon ausgewählt ist, in Kombination mit dem Insulinsekretionsverstärker Glimepirid umfasst.

2. Pharmazeutische Zusammensetzung gemäß Anspruch 1, wobei der Insulinempfindlichkeitsverstärker und der Insulinsekretionsverstärker ganz miteinander vermischt sind.

3. Pharmazeutische Zusammensetzung gemäß Anspruch 1, wobei der Insulinempfindlichkeitsverstärker und der Insulinsekretionsverstärker für eine unabhängig voneinander erfolgende Verabreichung, die entweder gleichzeitig oder an versetzten Zeitpunkten an denselben Patienten erfolgt, unabhängig voneinander zubereitet sind.

4. Pharmazeutische Zusammensetzung gemäß einem der Ansprüche 1 bis 3 für die Prophylaxe oder Behandlung von Diabetes.

5. Pharmazeutische Zusammensetzung gemäß einem der Ansprüche 1 bis 3 für die Prophylaxe oder Behandlung von Diabetes-Komplikationen.

6. Pharmazeutische Zusammensetzung gemäß einem der Ansprüche 1 bis 5, wobei der Insulinempfindlichkeitsverstärker das Salz von Pioglitazon mit Chlorwasserstoffsäure ist.

7. Verwendung eines Insulinempfindlichkeitsverstärkers, der aus Pioglitazon oder einem pharmazeutisch annehmbaren Salz davon ausgewählt ist, in Kombination mit dem Insulinsekretionsverstärker Glimepirid zur Herstellung einer pharmazeutischen Zusammensetzung für die Prophylaxe und Behandlung von Diabetes.

8. Verwendung eines Insulinempfindlichkeitsverstärkers, der aus Pioglitazon oder einem pharmazeutisch annehmbaren Salz davon ausgewählt ist, in Kombination mit dem Insulinsekretionsverstärker Glimepirid zur Herstellung einer pharmazeutischen Zusammensetzung für die Prophylaxe und Behandlung von Diabetes-Komplikationen.

9. Verwendung eines Insulinempfindlichkeitsverstärkers, der aus Pioglitazon oder einem pharmazeutisch annehmbaren Salz davon ausgewählt ist, in Kombination mit dem Insulinsekretionsverstärker Glimepirid zur Herstellung von Zubereitungen, bei denen der Insulinempfindlichkeitsverstärker und der Insulinsekretionsverstärker für eine unabhängig voneinander erfolgende Verabreichung, die entweder gleichzeitig oder an versetzten Zeitpunkten an denselben Patienten erfolgt, für die Prophylaxe und Behandlung von Diabetes unabhängig voneinander zubereitet sind.

10. Verwendung eines Insulinempfindlichkeitsverstärkers, der aus Pioglitazon oder einem pharmazeutisch annehmbaren Salz davon ausgewählt ist, in Kombination mit dem Insulinsekretionsverstärker Glimepirid zur Herstellung von Zubereitungen, bei denen der Insulinempfindlichkeitsverstärker und der Insulinsekretionsverstärker für eine unabhängig voneinander erfolgende Verabreichung, die entweder gleichzeitig oder an versetzten Zeitpunkten an denselben Patienten erfolgt, für die Prophylaxe und Behandlung von Diabetes-Komplikationen unabhängig voneinander zubereitet sind.

11. Verwendung gemäß einem der Ansprüche 7 bis 10, wobei der Insulinempfindlichkeitsverstärker das Salz von Pioglitazon mit Chlorwasserstoffsäure ist.

Revendications

1. Composition pharmaceutique qui comprend un agent renforçant la sensibilité à l'insuline, choisi parmi la pioglitazone et ses sels pharmacologiquement admissibles, associé avec l'agent stimulant la sécrétion d'insuline qu'est le glimépiride.

2. Composition pharmaceutique conforme à la revendication 1, dans laquelle l'agent renforçant la sensibilité à l'insuline et l'agent stimulant la sécrétion d'insuline sont mélangés ensemble.

3. Composition pharmaceutique conforme à la revendication 1, dans laquelle l'agent renforçant la sensibilité à l'insuline et l'agent stimulant la sécrétion d'insuline sont formulés séparément de manière à être administrés indépendamment l'un de l'autre, en même temps ou avec un décalage dans le temps, à un même sujet.

4. Composition pharmaceutique conforme à l'une des revendications 1 à 3, conçue pour la prophylaxie ou le traitement d'un diabète.

5. Composition pharmaceutique conforme à l'une des revendications 1 à 3, conçue pour la prophylaxie ou le traitement de complications d'un diabète.

6. Composition pharmaceutique conforme à l'une des revendications 1 à 5, dans laquelle l'agent renforçant la sensibilité à l'insuline est du sel de pioglitazone et d'acide chlorhydrique.

7. Emploi d'un agent renforçant la sensibilité à l'insuline, choisi parmi la pioglitazone et ses sels pharmacologiquement admissibles, associé avec l'agent stimulant la sécrétion d'insuline qu'est le glimépiride, en vue de la fabrication d'une composition pharmaceutique conçue pour la prophylaxie ou le traitement d'un diabète.

8. Emploi d'un agent renforçant la sensibilité à l'insuline, choisi parmi la pioglitazone et ses sels pharmacologiquement admissibles, associé avec l'agent stimulant la sécrétion d'insuline qu'est le glimépiride, en vue de la fabrication d'une composition pharmaceutique conçue pour la prophylaxie ou le traitement de complications d'un diabète.

9. Emploi d'un agent renforçant la sensibilité à l'insuline, choisi parmi la pioglitazone et ses sels pharmacologiquement admissibles, associé avec l'agent stimulant la sécrétion d'insuline qu'est le glimépiride, en vue de la fabrication de formulations dans lesquelles l'agent renforçant la sensibilité à l'insuline et l'agent stimulant la sécrétion d'insuline sont formulés séparément de manière à être administrés indépendamment l'un de l'autre, en même temps ou avec un décalage dans le temps, à un même sujet, et qui sont conçues pour la prophylaxie ou le traitement d'un diabète.

10. Emploi d'un agent renforçant la sensibilité à l'insuline, choisi parmi la pioglitazone et ses sels pharmacologiquement admissibles, associé avec l'agent stimulant la sécrétion d'insuline qu'est le glimépiride, en vue de la fabrication de formulations dans lesquelles l'agent renforçant la sensibilité à l'insuline et l'agent stimulant la sécrétion d'insuline sont formulés séparément de manière à être administrés indépendamment l'un de l'autre, en même temps ou avec un décalage dans le temps, à un même sujet, et qui sont conçues pour la prophylaxie ou le traitement de complications d'un diabète.

11. Emploi conforme à l'une des revendications 7 à 10, pour lequel l'agent renforçant la sensibilité à l'insuline est du sel de pioglitazone et d'acide chlorhydrique.