CA2297133A1 - Treatment of diabetes with thiazolidinedione, insulin secretagogue and alpha glucocidase inhibitor - Google Patents
Treatment of diabetes with thiazolidinedione, insulin secretagogue and alpha glucocidase inhibitor Download PDFInfo
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- CA2297133A1 CA2297133A1 CA002297133A CA2297133A CA2297133A1 CA 2297133 A1 CA2297133 A1 CA 2297133A1 CA 002297133 A CA002297133 A CA 002297133A CA 2297133 A CA2297133 A CA 2297133A CA 2297133 A1 CA2297133 A1 CA 2297133A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
A method for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in a mammal, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemic agent, to amammal in need thereof; and composition for use in such method.
Description
TREATMENT OF DIABETES WTI'~1 THIAZOLIDINEDIONE, INSULIN SECRETAGOGUE AND ALPHA
GLUCOCIDASE
INHIBITOR
This invention relates to a method of treatment, in particular to a method for the treatment of diabetes mellitus, especially non-insulin dependent diabetes (NIDDM) or Type 2 diabetes and conditions associated with diabetes mellitus.
Insulin secretagogues are compounds which promote increased secretion of insulin by the pancreatic beta cells.
The sulphonvlureas are well known examples of insulin secretagogues. The sulphonylureas act as antihyperglycaemic agents and are used in the treatment of Type 2 diabetes. Examples of sulphonylureas include ~iibenclamide, glipizide, gliclazide, glimepiride, tolazamide and tolbutamide.
Alpha glucosidase inhibitor antihyperglycaemic agents, such as acarbose, emiglitate and miglitol, are commonly used in the treatment of Type 2 diabetes.
European Patent Application. Publication Number 0.306.228 relates to certain 1 ~ thiazolidinedione derivatives disclosed as having antihyperglycaemic and antihyperlipidaemic activity. One particular thiazolidinedione disclosed in EP
0306228 is ~-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy)benzyl]thiazolidine-2,4-dione (hereinafter 'Compound (I)'). W094/06669 discloses certain salts of Compound (I) including the maleate salt.
Compound (I) is an example of a class of anti-hyperglycaemic agents known as 'insulin sensitisers'. In particular Compound (I) is a thiazolidinedione insulin sensitiser.
European Patent Applications, Publication Numbers: 0008203, 0139421, 0032128, 0428312, 0489663, 0166846, 0267781, 0208420. 0177363, 0319189, 26 0332331, 0332332, 0628734, 0608740: International Patent Application, Publication Numbers 92/18501, 93/02079, 93122446 and United States Patent Numbers 6104888 and 5478852, also disclose certain thiazoiidinedione insulin sensitisers.
Another series of compounds generally recognised as having insulin sensitiser activity are those typified by the compounds disclosed in International Patent Applications, Publication Numbers W093/21166 and W094/01420. These compounds are herein referred to as 'acvclic insulin sensitisers'. Other examples of acyclic insulin sensitisers are those disclosed in United States Patent Number and International Patent Applications, Publication Numbers W092/03426 and W091 / 19702.
36 Examples of other insulin sensitisers are those disclosed in European Patent Application. Publication Number 063393.1, Japanese Patent Application Publication Number 06271204 and United States Patent Number 6264461.
The above mentioned publications are incorporated herein by reference.
provides a particularly beneficial effect on glycaemic control, such combination is _ therefore particularly useful for the treatment of diabetes mellitus.
especially Type 2 diabetes, and conditions associated with diabetes mellitus. The treatment is also indicated to proceed with minimum side effects.
Accordingly, the invention provides a method for the treatment of diabetes mellitus, especially Type 2 diabetes. and conditions associated with diabetes mellitus, in a mammal such as a human, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemic agent, to a mammal in need thereof.
The method comprises either co-administration of the insulin sensitiser, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglvcaemic agent or 1 ~ sequential administration thereof.
Co-administration includes administration of a formulation which includes an insulin sensitiser, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemic agent or the essentially simultaneous administration of separate formulations of each agent.
In another aspect the invention provides the use of an insulin sensitiser, such as Compound (I), an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemic agent, in the manufacture of a composition for the treatment of diabetes mellitus, especially Type ? diabetes and conditions associated with diabetes mellitus.
2~ A suitable insulin sensitiser is a thiazolidinedione insulin sensitiser.
A suitable thiazolidinedione insulin sensitiser is Compound (I).
Other suitable thiazolidinedione insulin sensitisers include (+) -~-[[4-[(3,4-dihydro-6-hydroxy-2, 5, 7, 8-tetramethyl-2H-1-benzopyran-2-yl)methoxv]phenyl]methyl]-2,4-thiazolidinedione (or troglitazone), ~-[4-[(1-methylcyclohexyl)methoxy]benzyl] thiazolidine-2,4-dione (or ciglitazone), 5-[4-[2-(~-ethylpyridin-2-vl)ethoxy]benzyl] thiazolidine-2,4-dione (or pioglitazone) or ~-[(2-benzyl-2,3-dihvdrobenzopyran)-5-ylmethyl)thiazolidine-2,4-dione (or englitazone) Suitable insulin secretagogues include sulphonylureas.
Suitable sulphonylureas include glibenclamide, glipizide, gliclazide, 3~ glimepiride. tolazamide and tolbutamide.
Further sulphonylureas include acetohexamide, carbutamide, chlorpropamide, giibomuride, gliquidone, giisentide, glisolamide, glisoxepide.
glyclopyamide and glycylamide.
~.__~_..__._ __ _ ..__. _. _.._..._~..__. ... . _.. __ ._ .__._. __ .
T
Further suitable insulin secretagogues include repaglinide.
A suitable alpha glucosidase inhibitor antihyperglycaemic agent is acarbose.
Other suitable alpha glucosidase inhibitor antihyperglycaemic agents are emiglitate and miglitol.
In ane particular aspect, the method comprises the administration of 2 to 12 mg of Compound (I), especially when administered per day.
Particularly, the method comprises the administration of 2 to 4. 4 to 8 or 8 to 12 mg of Compound (I) per day.
Particularly, the method comprises the administration of 2 to 4mQ of Compound (I), especially when administered per day.
Particularly, the method comprises the administration of 4 to 8mg of Compound (I), especially when administered per day.
Particularly, the method comprises the administration of 8 to 12 mg of Compound (I), especially when administered per day.
Preferably, the method comprises the administration of 2 mg of Compound (I), especially when administered per day.
Preferably, the method comprises the administration of 4 mg of Compound (I), especially when administered per day.
Preferably, the method comprises the administration of 8 mg of Compound (I), especially when administered per day.
It will be understood that the insulin sensitiser, such as compound (I), the insulin secretagogue and the alpha glucosidase inhibitor antihyperglycaemic agent are each administered in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters and sol~,rates 2~ thereof, as appropriate. In certain instances herein the names used for the relevant insulin secretagogues and the alpha glucosidase inhibitor antihyperglycaemic agents may relate to a particular pharmaceutical form of the relevant active agent:
It will be understood that all pharmaceutically acceptable forms of the active agents per se are encompassed by this invention.
Suitable pharmaceutically acceptable salted forms of the insulin sensitisers, such as Compound (I), include those described in the above mentioned patents and patent applications such as in EP 0306228 and W094/05659 for Compound (I). A
preferred pharmaceutically acceptable salt for Compound (I) is a maleate.
Suitable pharmaceutically acceptable solvated forms of the insulin sensitisers. such as Compound (I), include those described in the above mentioned patents and patent applications, such as in EP 0306228 and W094/056~9 for Compound (I), in particular hydrates.
Suitable pharmaceutically acceptable forms of the insulin secretagogue and the alpha glucosidase inhibitor antihyperglycaemic agent depend upon the particular compound used but include known pharmaceutically acceptable forms of the particular compound chosen. Such derivatives are found or are referred to in standard reference texts such as the British and US Pharmacopoeias. Remington's Pharmaceutical Sciences (Llack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31 st Edition page 341 and pages cited therein).
The insulin sensitisers, such as Compound (I) or. a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, may be prepared using known methods. for example those disclosed in the above mentioned patents and patent applications, such as EP 0306228 and W094/0~6~9 for Compound (I). The disclosures of the above mentioned patents and patent applications.
such as EP 0306228 and W094/0~6~9, are incorporated herein by reference.
1 ~ Compound {I) may exist in one of several tautomeric forms, all of which are encompassed by the term Compound (I) as individual tautomeric forms or as mixtures thereof. Compound (I) contains a chirai carbon atom, and hence can exist in up to two stereoisomeric forms, the term Compound (I) encompasses all of these isomeric forms whether as individual isomers or as mixtures of isomers, including racemates.
The insulin secretagogue and alpha glucosidase inhibitor antihyperglycaemic agent of choice is prepared according to known methods, such methods are found or are referred to in standard reference felts, such as the British and US
Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein).
When used herein the term 'conditions associated with diabetes' includes conditions associated with diabetes mellitus itself and complications associated with diabetes mellitus. Also included in 'conditions associated with diabetes' are those conditions associated with the pre-diabetic state.
When used herein the term 'conditions associated with the pre-diabetic state' includes conditions such as insulin resistance, includine hereditary insulin resistance, impaired glucose tolerance and hyperinsulinaemia.
'Conditions associated with diabetes mellitus itself include hyperglycaemia, insulin resistance, including acquired insulin resistance. Further conditions associated 3~ with diabetes mellitus itself include hypertension and cardiovascular disease.
especially atherosclerosis and conditions associated with insulin resistance.
Conditions associated with insulin resistance include polycystic ovarian syndrome and steroid induced insulin resistance and Qestational diabetes.
GLUCOCIDASE
INHIBITOR
This invention relates to a method of treatment, in particular to a method for the treatment of diabetes mellitus, especially non-insulin dependent diabetes (NIDDM) or Type 2 diabetes and conditions associated with diabetes mellitus.
Insulin secretagogues are compounds which promote increased secretion of insulin by the pancreatic beta cells.
The sulphonvlureas are well known examples of insulin secretagogues. The sulphonylureas act as antihyperglycaemic agents and are used in the treatment of Type 2 diabetes. Examples of sulphonylureas include ~iibenclamide, glipizide, gliclazide, glimepiride, tolazamide and tolbutamide.
Alpha glucosidase inhibitor antihyperglycaemic agents, such as acarbose, emiglitate and miglitol, are commonly used in the treatment of Type 2 diabetes.
European Patent Application. Publication Number 0.306.228 relates to certain 1 ~ thiazolidinedione derivatives disclosed as having antihyperglycaemic and antihyperlipidaemic activity. One particular thiazolidinedione disclosed in EP
0306228 is ~-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy)benzyl]thiazolidine-2,4-dione (hereinafter 'Compound (I)'). W094/06669 discloses certain salts of Compound (I) including the maleate salt.
Compound (I) is an example of a class of anti-hyperglycaemic agents known as 'insulin sensitisers'. In particular Compound (I) is a thiazolidinedione insulin sensitiser.
European Patent Applications, Publication Numbers: 0008203, 0139421, 0032128, 0428312, 0489663, 0166846, 0267781, 0208420. 0177363, 0319189, 26 0332331, 0332332, 0628734, 0608740: International Patent Application, Publication Numbers 92/18501, 93/02079, 93122446 and United States Patent Numbers 6104888 and 5478852, also disclose certain thiazoiidinedione insulin sensitisers.
Another series of compounds generally recognised as having insulin sensitiser activity are those typified by the compounds disclosed in International Patent Applications, Publication Numbers W093/21166 and W094/01420. These compounds are herein referred to as 'acvclic insulin sensitisers'. Other examples of acyclic insulin sensitisers are those disclosed in United States Patent Number and International Patent Applications, Publication Numbers W092/03426 and W091 / 19702.
36 Examples of other insulin sensitisers are those disclosed in European Patent Application. Publication Number 063393.1, Japanese Patent Application Publication Number 06271204 and United States Patent Number 6264461.
The above mentioned publications are incorporated herein by reference.
provides a particularly beneficial effect on glycaemic control, such combination is _ therefore particularly useful for the treatment of diabetes mellitus.
especially Type 2 diabetes, and conditions associated with diabetes mellitus. The treatment is also indicated to proceed with minimum side effects.
Accordingly, the invention provides a method for the treatment of diabetes mellitus, especially Type 2 diabetes. and conditions associated with diabetes mellitus, in a mammal such as a human, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemic agent, to a mammal in need thereof.
The method comprises either co-administration of the insulin sensitiser, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglvcaemic agent or 1 ~ sequential administration thereof.
Co-administration includes administration of a formulation which includes an insulin sensitiser, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemic agent or the essentially simultaneous administration of separate formulations of each agent.
In another aspect the invention provides the use of an insulin sensitiser, such as Compound (I), an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemic agent, in the manufacture of a composition for the treatment of diabetes mellitus, especially Type ? diabetes and conditions associated with diabetes mellitus.
2~ A suitable insulin sensitiser is a thiazolidinedione insulin sensitiser.
A suitable thiazolidinedione insulin sensitiser is Compound (I).
Other suitable thiazolidinedione insulin sensitisers include (+) -~-[[4-[(3,4-dihydro-6-hydroxy-2, 5, 7, 8-tetramethyl-2H-1-benzopyran-2-yl)methoxv]phenyl]methyl]-2,4-thiazolidinedione (or troglitazone), ~-[4-[(1-methylcyclohexyl)methoxy]benzyl] thiazolidine-2,4-dione (or ciglitazone), 5-[4-[2-(~-ethylpyridin-2-vl)ethoxy]benzyl] thiazolidine-2,4-dione (or pioglitazone) or ~-[(2-benzyl-2,3-dihvdrobenzopyran)-5-ylmethyl)thiazolidine-2,4-dione (or englitazone) Suitable insulin secretagogues include sulphonylureas.
Suitable sulphonylureas include glibenclamide, glipizide, gliclazide, 3~ glimepiride. tolazamide and tolbutamide.
Further sulphonylureas include acetohexamide, carbutamide, chlorpropamide, giibomuride, gliquidone, giisentide, glisolamide, glisoxepide.
glyclopyamide and glycylamide.
~.__~_..__._ __ _ ..__. _. _.._..._~..__. ... . _.. __ ._ .__._. __ .
T
Further suitable insulin secretagogues include repaglinide.
A suitable alpha glucosidase inhibitor antihyperglycaemic agent is acarbose.
Other suitable alpha glucosidase inhibitor antihyperglycaemic agents are emiglitate and miglitol.
In ane particular aspect, the method comprises the administration of 2 to 12 mg of Compound (I), especially when administered per day.
Particularly, the method comprises the administration of 2 to 4. 4 to 8 or 8 to 12 mg of Compound (I) per day.
Particularly, the method comprises the administration of 2 to 4mQ of Compound (I), especially when administered per day.
Particularly, the method comprises the administration of 4 to 8mg of Compound (I), especially when administered per day.
Particularly, the method comprises the administration of 8 to 12 mg of Compound (I), especially when administered per day.
Preferably, the method comprises the administration of 2 mg of Compound (I), especially when administered per day.
Preferably, the method comprises the administration of 4 mg of Compound (I), especially when administered per day.
Preferably, the method comprises the administration of 8 mg of Compound (I), especially when administered per day.
It will be understood that the insulin sensitiser, such as compound (I), the insulin secretagogue and the alpha glucosidase inhibitor antihyperglycaemic agent are each administered in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters and sol~,rates 2~ thereof, as appropriate. In certain instances herein the names used for the relevant insulin secretagogues and the alpha glucosidase inhibitor antihyperglycaemic agents may relate to a particular pharmaceutical form of the relevant active agent:
It will be understood that all pharmaceutically acceptable forms of the active agents per se are encompassed by this invention.
Suitable pharmaceutically acceptable salted forms of the insulin sensitisers, such as Compound (I), include those described in the above mentioned patents and patent applications such as in EP 0306228 and W094/05659 for Compound (I). A
preferred pharmaceutically acceptable salt for Compound (I) is a maleate.
Suitable pharmaceutically acceptable solvated forms of the insulin sensitisers. such as Compound (I), include those described in the above mentioned patents and patent applications, such as in EP 0306228 and W094/056~9 for Compound (I), in particular hydrates.
Suitable pharmaceutically acceptable forms of the insulin secretagogue and the alpha glucosidase inhibitor antihyperglycaemic agent depend upon the particular compound used but include known pharmaceutically acceptable forms of the particular compound chosen. Such derivatives are found or are referred to in standard reference texts such as the British and US Pharmacopoeias. Remington's Pharmaceutical Sciences (Llack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31 st Edition page 341 and pages cited therein).
The insulin sensitisers, such as Compound (I) or. a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, may be prepared using known methods. for example those disclosed in the above mentioned patents and patent applications, such as EP 0306228 and W094/0~6~9 for Compound (I). The disclosures of the above mentioned patents and patent applications.
such as EP 0306228 and W094/0~6~9, are incorporated herein by reference.
1 ~ Compound {I) may exist in one of several tautomeric forms, all of which are encompassed by the term Compound (I) as individual tautomeric forms or as mixtures thereof. Compound (I) contains a chirai carbon atom, and hence can exist in up to two stereoisomeric forms, the term Compound (I) encompasses all of these isomeric forms whether as individual isomers or as mixtures of isomers, including racemates.
The insulin secretagogue and alpha glucosidase inhibitor antihyperglycaemic agent of choice is prepared according to known methods, such methods are found or are referred to in standard reference felts, such as the British and US
Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein).
When used herein the term 'conditions associated with diabetes' includes conditions associated with diabetes mellitus itself and complications associated with diabetes mellitus. Also included in 'conditions associated with diabetes' are those conditions associated with the pre-diabetic state.
When used herein the term 'conditions associated with the pre-diabetic state' includes conditions such as insulin resistance, includine hereditary insulin resistance, impaired glucose tolerance and hyperinsulinaemia.
'Conditions associated with diabetes mellitus itself include hyperglycaemia, insulin resistance, including acquired insulin resistance. Further conditions associated 3~ with diabetes mellitus itself include hypertension and cardiovascular disease.
especially atherosclerosis and conditions associated with insulin resistance.
Conditions associated with insulin resistance include polycystic ovarian syndrome and steroid induced insulin resistance and Qestational diabetes.
- 'Complications associated with diabetes mellitus' includes renal disease, especially renal disease associated with Type 2 diabetes, neuropathy and retinopathy.
Renal diseases associated with Type 2 diabetes include nephropathy, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis and end stage renal disease. Additional renal diseases associated with Type 2 diabetes include nephrotic syndrome.
For the avoidance of doubt, when reference is made herein to scalar amounts, including mg amounts, of Compound (I) in a pharmaceutically acceptable form, the scalar amount referred to is made in respect of Compound (I) per se: For example 2 mg of Compound (I) in the form of the maleate salt is that amount of maleate salt which contains 2 mg of Compound (I).
Diabetes mellitus is preferably Type 2 diabetes.
The particularly beneficial effect on glycaemic control provided by the treatment of the invention is indicated to be a synergistic effect relative to the control 1 ~ expected for the sum of the effects of the individual active agents.
Glycaemic control may be characterised using conventional methods, for example by measurement of a typically used index of glycaemic control such as fasting plasma glucose or glycosylated haemoglobin (HbAlc). Such indices are determined using standard methodology, for example those described in:
Tuescher A, Richterich, P., Schweiz. med. Wschr. 101 (1971), 345 and 390 and Frank P., 'Monitoring the Diabetic Patent with Glycosolated Hemoglobin Measurements', Clinical Products 1988 In a preferred aspect, the dosage level of each of the active agents when used in accordance with the treatment of the invention will be less than would have been 2~ required from a purely additive effect upon glycaemic control.
Suitably, the insulin sensitiser is the agent of first administration.
Suitably the insulin secretagogue is the agent of second administration.
Suitably the alpha glucosidase inhibitor is the agent of third administration.
There is also an indication that the treatment of the invention will effect an improvement, relative to the individual agents, in the levels of advanced glycosylation end products (AGES), leptin and serum lipids including total cholesterol, HDL-cholesterol, LDL-cholesterol including improvements in the ratios thereof, in particular an improvement in serum lipids including total cholesterol, HDL-cholesterol, LDL-cholesterol including improvements in the ratios thereof.
3~ As used herein the term 'pharmaceutically acceptable' embraces both human and veterinary use: for example the term 'pharmaceutically acceptable' embraces a veterinarily acceptable compound.
_j_ - In the method of the invention. the active medicaments are preferably administered in pharmaceutical composition form. As indicated above, such compositions can include all medicaments or one only of the medicaments.
Accordingly, in one aspect the present invention also provides a pharmaceutical composition comprising an insulin sensitises, such as Compound (I) and especially 2 to 12 mg thereof, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemic agent and a pharmaceutically acceptable carrier therefor.
Such compositions may be prepared by admixing an insulin sensitises, such as Compound (I) and especially 2 to 1? mg thereof, an insulin secretagogue and an alpha glucosidase inhibitor antihvperglvcaemic agent and a pharmaceutically acceptable carrier therefor.
Usually the compositions are adapted for oral administration. However, they may be adapted for other modes of administration, for example parenteral administration. sublingual or transdermal administration.
The compositions may be in the form of tablets. capsules, powders, granules.
lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
In order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose.
Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents. for example syrup, acacia, gelatin, sorbitol, tra~acanth, or polvvinylpyrrotidone:
fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine;
tabletting lubricants, for example magnesium stearate; disintegrants, for example 2~ starch. poivvinyipyrrolidone. sodium starch glycollate or microcrystalline cellulose;
or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
The compositions are preferably in a unit dosage form in an amount appropriate for the relevant daily dosage.
Suitable dosages for the insulin sensitisers include those disclosed in the abovementioned patents and patent applications.
Suitable dosages, including unit dosages, of Compound (I) comprise 1, 2, 3, 4, 5, 6, 7. 8. 9, I0, 11 or 12 mg of Compound (I).
In the treatment the medicaments may be administered from 1 to 6 times a dav, but most preferably 1 or 2 times per day.
>j Particular dosages of Compound (I) are ?mg/dav, ~mg/day, including 2mg twice per dav, and 8 mg/dav, includine 4mg twice per dav.
Suitable dosages including unit dosages of the insulin secretagogue, such as the sulphonylurea_ or the alpha glucosidase inhibitor antihyperglycaemic agent, T _...._.._~ _ _... ...._..____._M_~.._.T....
include the known dosages including unit doses for these compounds as described or referred to in reference text such as the British and US Pharmacopoeias.
Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31 st Edition page 341 and pages cited therein).
Thus for the sulphonvlureas, a typical daily dosage of glibenclamide is in the range of from 2.5 to 20 mg, for example lOmg twice per day or 20mg once per day; a typical daily dosage of glipizide is in the range of from 2.5 to 40 mg; a typical daily dosage of gliclazide is in the range of from 40 to 320 mg; a typical daily dosage of tolazamide is in the range of from 100 to 1000 mg; a typical daily dosage of tolbutamide is in the range of from 1000 to 3000 mg; a typical daily dosage of chlorpropamide is in the range of from 100 to 500 mg; and a typical daily dosage of gliquidone is in the range of from 1 ~ to 180 mg.
Repaglinide may be taken in amounts, usually in the range of from O.~mg to 1 ~ 4mg and usually with meals, up to a typical maximum daily dosage of 16mg per day.
With regard to the alpha glucosidase inhibitor antihyperglycaemic agents, a typical daily dosage of acarbose is in the range of from ~0 to 600 mg, an example 100mg or 200mg per day.
The solid oral compositions may be prepared by conventional methods of blending. filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coatins.
2~ Oral liquid preparations may be in the form of. for example. emulsions, syrups, or elixirs. or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate .el, hydrogenated edible fats; emulsifying agents, for example lecithin.
sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring 3 ~ agents.
For parenteral administration, f3uid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and. depending on the concentration used.
can be either suspended or dissolved in the vehicle. In preparing solutions the compound can - be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the Compound (I) is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
Compositions may contain from 0.1 % to 99% by weight, preferably from 10-60% by weight, of the active material, depending upon the method of administration.
Composition may, if desired, be in the form of a pack accompanied by 1 ~ written or printed instructions for use.
The compositions are prepared and formulated according to conventional methods. such as those disclosed in standard reference texts, for example the British and US Pharmacopoeias, 's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) and Harry's Cosmeticology (Leonard Hill Books) (for example see the 31st Edition page 341 and pages cited therein).
The present invention also provides a pharmaceutical composition comprising an insulin sensitiser, such as Compound (I) and especially 2 to 12 mg thereof, an insulin secretagogue and an alpha glucosidase inhibitor 2~ antihyperglycaemic agent and a pharmaceutically acceptable carrier therefor. for use as an active therapeutic substance.
The invention also provides the use of an insulin sensitiser, such as Compound (I) and especially 2 to 12 mg thereof, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemic agent for the manufacture of a medicament for the treatment of diabetes mellitus and conditions associated with diabetes mellitus.
In particular, the present invention provides a pharmaceutical composition comprising an insulin sensitiser, such as Compound (I) and especially 2 to 12 mg thereof, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemic agent and a pharmaceutically acceptable carrier therefor, for use in the treatment of diabetes mellitus and conditions associated with diabetes mellitus.
A range of 2 to 4mg includes a range of 2.1 to 4, 2.2 to 4, 2.3 to 4. 2.4 to 4, 2.~to4,2.6to4,2.7to4,2.8to=1,2.9to4or3to4mQ.
A range of =1 to 8mg includes a range of 4.1 to 8. 4.2 to 8, 4.3 to 8, 4.4 to 8, 4.~to8,4.6to8,4.7to8,4.8to8.4.9to8,5to8,6to8or7to8mg.
_g_ ____.
A range of 8 to 12 mg incl-udes a range of 8. I to 12, 8.2 to 12, 8.3 to 12, 8.4 to 12, 8.5 to 12, 8.6 to I2, 8.7 to 12, 8.8 to 12, 8.9 to 12, 9 to 12. 10 to 12 or 1 I to l2mg.
No adverse toxicological effects are expected for the compositions or methods of the invention in the abovementioned dosage ranges.
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Renal diseases associated with Type 2 diabetes include nephropathy, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis and end stage renal disease. Additional renal diseases associated with Type 2 diabetes include nephrotic syndrome.
For the avoidance of doubt, when reference is made herein to scalar amounts, including mg amounts, of Compound (I) in a pharmaceutically acceptable form, the scalar amount referred to is made in respect of Compound (I) per se: For example 2 mg of Compound (I) in the form of the maleate salt is that amount of maleate salt which contains 2 mg of Compound (I).
Diabetes mellitus is preferably Type 2 diabetes.
The particularly beneficial effect on glycaemic control provided by the treatment of the invention is indicated to be a synergistic effect relative to the control 1 ~ expected for the sum of the effects of the individual active agents.
Glycaemic control may be characterised using conventional methods, for example by measurement of a typically used index of glycaemic control such as fasting plasma glucose or glycosylated haemoglobin (HbAlc). Such indices are determined using standard methodology, for example those described in:
Tuescher A, Richterich, P., Schweiz. med. Wschr. 101 (1971), 345 and 390 and Frank P., 'Monitoring the Diabetic Patent with Glycosolated Hemoglobin Measurements', Clinical Products 1988 In a preferred aspect, the dosage level of each of the active agents when used in accordance with the treatment of the invention will be less than would have been 2~ required from a purely additive effect upon glycaemic control.
Suitably, the insulin sensitiser is the agent of first administration.
Suitably the insulin secretagogue is the agent of second administration.
Suitably the alpha glucosidase inhibitor is the agent of third administration.
There is also an indication that the treatment of the invention will effect an improvement, relative to the individual agents, in the levels of advanced glycosylation end products (AGES), leptin and serum lipids including total cholesterol, HDL-cholesterol, LDL-cholesterol including improvements in the ratios thereof, in particular an improvement in serum lipids including total cholesterol, HDL-cholesterol, LDL-cholesterol including improvements in the ratios thereof.
3~ As used herein the term 'pharmaceutically acceptable' embraces both human and veterinary use: for example the term 'pharmaceutically acceptable' embraces a veterinarily acceptable compound.
_j_ - In the method of the invention. the active medicaments are preferably administered in pharmaceutical composition form. As indicated above, such compositions can include all medicaments or one only of the medicaments.
Accordingly, in one aspect the present invention also provides a pharmaceutical composition comprising an insulin sensitises, such as Compound (I) and especially 2 to 12 mg thereof, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemic agent and a pharmaceutically acceptable carrier therefor.
Such compositions may be prepared by admixing an insulin sensitises, such as Compound (I) and especially 2 to 1? mg thereof, an insulin secretagogue and an alpha glucosidase inhibitor antihvperglvcaemic agent and a pharmaceutically acceptable carrier therefor.
Usually the compositions are adapted for oral administration. However, they may be adapted for other modes of administration, for example parenteral administration. sublingual or transdermal administration.
The compositions may be in the form of tablets. capsules, powders, granules.
lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
In order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose.
Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents. for example syrup, acacia, gelatin, sorbitol, tra~acanth, or polvvinylpyrrotidone:
fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine;
tabletting lubricants, for example magnesium stearate; disintegrants, for example 2~ starch. poivvinyipyrrolidone. sodium starch glycollate or microcrystalline cellulose;
or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
The compositions are preferably in a unit dosage form in an amount appropriate for the relevant daily dosage.
Suitable dosages for the insulin sensitisers include those disclosed in the abovementioned patents and patent applications.
Suitable dosages, including unit dosages, of Compound (I) comprise 1, 2, 3, 4, 5, 6, 7. 8. 9, I0, 11 or 12 mg of Compound (I).
In the treatment the medicaments may be administered from 1 to 6 times a dav, but most preferably 1 or 2 times per day.
>j Particular dosages of Compound (I) are ?mg/dav, ~mg/day, including 2mg twice per dav, and 8 mg/dav, includine 4mg twice per dav.
Suitable dosages including unit dosages of the insulin secretagogue, such as the sulphonylurea_ or the alpha glucosidase inhibitor antihyperglycaemic agent, T _...._.._~ _ _... ...._..____._M_~.._.T....
include the known dosages including unit doses for these compounds as described or referred to in reference text such as the British and US Pharmacopoeias.
Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31 st Edition page 341 and pages cited therein).
Thus for the sulphonvlureas, a typical daily dosage of glibenclamide is in the range of from 2.5 to 20 mg, for example lOmg twice per day or 20mg once per day; a typical daily dosage of glipizide is in the range of from 2.5 to 40 mg; a typical daily dosage of gliclazide is in the range of from 40 to 320 mg; a typical daily dosage of tolazamide is in the range of from 100 to 1000 mg; a typical daily dosage of tolbutamide is in the range of from 1000 to 3000 mg; a typical daily dosage of chlorpropamide is in the range of from 100 to 500 mg; and a typical daily dosage of gliquidone is in the range of from 1 ~ to 180 mg.
Repaglinide may be taken in amounts, usually in the range of from O.~mg to 1 ~ 4mg and usually with meals, up to a typical maximum daily dosage of 16mg per day.
With regard to the alpha glucosidase inhibitor antihyperglycaemic agents, a typical daily dosage of acarbose is in the range of from ~0 to 600 mg, an example 100mg or 200mg per day.
The solid oral compositions may be prepared by conventional methods of blending. filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coatins.
2~ Oral liquid preparations may be in the form of. for example. emulsions, syrups, or elixirs. or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate .el, hydrogenated edible fats; emulsifying agents, for example lecithin.
sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring 3 ~ agents.
For parenteral administration, f3uid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and. depending on the concentration used.
can be either suspended or dissolved in the vehicle. In preparing solutions the compound can - be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the Compound (I) is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
Compositions may contain from 0.1 % to 99% by weight, preferably from 10-60% by weight, of the active material, depending upon the method of administration.
Composition may, if desired, be in the form of a pack accompanied by 1 ~ written or printed instructions for use.
The compositions are prepared and formulated according to conventional methods. such as those disclosed in standard reference texts, for example the British and US Pharmacopoeias, 's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) and Harry's Cosmeticology (Leonard Hill Books) (for example see the 31st Edition page 341 and pages cited therein).
The present invention also provides a pharmaceutical composition comprising an insulin sensitiser, such as Compound (I) and especially 2 to 12 mg thereof, an insulin secretagogue and an alpha glucosidase inhibitor 2~ antihyperglycaemic agent and a pharmaceutically acceptable carrier therefor. for use as an active therapeutic substance.
The invention also provides the use of an insulin sensitiser, such as Compound (I) and especially 2 to 12 mg thereof, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemic agent for the manufacture of a medicament for the treatment of diabetes mellitus and conditions associated with diabetes mellitus.
In particular, the present invention provides a pharmaceutical composition comprising an insulin sensitiser, such as Compound (I) and especially 2 to 12 mg thereof, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemic agent and a pharmaceutically acceptable carrier therefor, for use in the treatment of diabetes mellitus and conditions associated with diabetes mellitus.
A range of 2 to 4mg includes a range of 2.1 to 4, 2.2 to 4, 2.3 to 4. 2.4 to 4, 2.~to4,2.6to4,2.7to4,2.8to=1,2.9to4or3to4mQ.
A range of =1 to 8mg includes a range of 4.1 to 8. 4.2 to 8, 4.3 to 8, 4.4 to 8, 4.~to8,4.6to8,4.7to8,4.8to8.4.9to8,5to8,6to8or7to8mg.
_g_ ____.
A range of 8 to 12 mg incl-udes a range of 8. I to 12, 8.2 to 12, 8.3 to 12, 8.4 to 12, 8.5 to 12, 8.6 to I2, 8.7 to 12, 8.8 to 12, 8.9 to 12, 9 to 12. 10 to 12 or 1 I to l2mg.
No adverse toxicological effects are expected for the compositions or methods of the invention in the abovementioned dosage ranges.
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Claims (22)
1. A method for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in a mammal, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemic agent, to a mammal in need thereof.
2. A method according to claim 1, wherein the insulin secretagogue is glibenclamide, glipizide, gliclazide, glimepiride, tolazamide, tolbutamide, acetohexamide, carbutamide, chlorprogamide, glibornuride, gliquidone, glisentide, glisolamide, glisoxepide, glyclopyamide, glycylamide or repaglinide.
3. A method according to claim 1, wherein the alpha glucosidase inhibitor antihyperglycaemic agent is acarbose, emiglitate and miglitol.
4. A method according to any one of claims 1 to 3, wherein the insulin sensitiser is 5-(4-[2-(N-methyl-N-(2-pyridyl)amino)thoxy)benzyl]thiazotidine-2,4-dione (Compound I).
5. A method according to any one of claims 1 to 4, which comprises the administration of 2 to 12 mg of Compound (I).
6. A method according to any one of claims 1 to 5, which comprises the administration of 2 to 4, 4 to 8 or 8 to 12 mg of Compound (I).
7. A method according to any one of claims 1 to 6, which comprises the administration of 2 to 4mg of Compound (I).
8. A method according to any one of claims 1 to 6, which comprises the method the administration of 4 to 8mg of Compound (I).
9. A method according to any one of claims 1 to 6, which comprises the administration of 8 to 12 mg of Compound (I).
10. A method according to any one of claims 1 to 6, which comprises the administration of 2 mg of Compound (I).
11. A method according to any one of claims 1 to 6, which comprises the administration of 4 mg of Compound (I).
12. A method according to any one of claims 1 to 6, which comprises the administration of 8 mg of Compound (I).
13. A method according to claim 1, wherein the insulin sensitiser is (+) -5-[[4-[(3,4-dihydro-6-hydroxy-2, 5, 7, 8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione (or troglitazone), 5-[4-[(1-methylcyclohexyl)methoxy]benzyl] thiazolidine-2,4-dione (or ciglitazone), 5-[4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl] thiazolidine-2,4-dione (or pioglitazone) or 5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl)thiazolidine-2,4-dione (or englitazone); or a pharmaceutically acceptable form thereof.
14. A pharmaceutical composition comprising an insulin sensitiser, an insulin secretagogue, an alpha glucosidase inhibitor antihyperglycaemic agent and a pharmaceutically acceptable carrier therefor.
15. A composition according to claim 14, wherein the insulin secretagogue is a sulphonylurea.
16. A composition according to claim 14 or claim 15, wherein the insulin secretagogue is glibenclamide, glipizide, gliclazide, glimepiride, tolazamide or tolbutamide, acetohexamide, carbutamide, chlorpropamide, glibomuride, gliquidone, glisentide, glisolamide, glisoxepide, glyclopyamide, glycylamide or repaglinide.
17. A composition according to claim 1, wherein the alpha glucosidase inhibitor antihyperglycaemic agent is acarbose, emiglitate and miglitol.
18. A composition according to any one of claims 14 to 17, wherein the insulin sensitiser is Compound (I)
19. A composition according to any one of claims 14 to 17, which comprises 2 to 12 mg of Compound (I).
20. A pharmaceutical composition comprising an insulin sensitiser an insulin secretagogue and a pharmaceutically acceptable carrier therefor, for use as an active therapeutic substance.
21. A pharmaceutical composition comprising an insulin sensitiser, an insulin secretagogue, an alpha glucosidase inhibitor antihyperglycaemic agent and a pharmaceutically acceptable carrier therefor, for use in the treatment of diabetes mellitus and conditions associated with diabetes mellitus.
22. A composition according to any one of claims 14, 20 or 21, wherein the insulin sensitiser is (+)-5-[[4-[(3,4-dihydro-6-hydroxy-2, 5, 7, 8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione (or troglitazone), 5-[4-[(1-methylcyclohexyl)methoxy]benzyl] thiazolidine-2,4-dione (or ciglitazone), 5-[4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl] thiazolidine-2,4-dione (or pioglitazone) or 5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl)thiazolidine-2,4-dione (or englitazone); or a pharmaceutically acceptable form thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9715298A GB9715298D0 (en) | 1997-07-18 | 1997-07-18 | Novel method of treatment |
| GB9715298.7 | 1997-07-18 | ||
| PCT/GB1998/002112 WO1999003478A1 (en) | 1997-07-18 | 1998-07-16 | Treatment of diabetes with thiazolidinedione, insulin secretagogue and alpha glucocidase inhibitor |
Publications (1)
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|---|---|
| CA2297133A1 true CA2297133A1 (en) | 1999-01-28 |
Family
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Family Applications (1)
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|---|---|---|---|
| CA002297133A Abandoned CA2297133A1 (en) | 1997-07-18 | 1998-07-16 | Treatment of diabetes with thiazolidinedione, insulin secretagogue and alpha glucocidase inhibitor |
Country Status (27)
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| EP (1) | EP1001784A1 (en) |
| JP (1) | JP2001510160A (en) |
| KR (1) | KR20010021952A (en) |
| CN (1) | CN1263467A (en) |
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| AU (1) | AU8449098A (en) |
| BG (1) | BG104062A (en) |
| BR (1) | BR9810292A (en) |
| CA (1) | CA2297133A1 (en) |
| CO (1) | CO4940489A1 (en) |
| DZ (1) | DZ2563A1 (en) |
| EA (1) | EA200000140A1 (en) |
| GB (1) | GB9715298D0 (en) |
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| ID (1) | ID23804A (en) |
| IL (1) | IL133907A0 (en) |
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| PL (1) | PL338140A1 (en) |
| SK (1) | SK612000A3 (en) |
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| TW438587B (en) * | 1995-06-20 | 2001-06-07 | Takeda Chemical Industries Ltd | A pharmaceutical composition for prophylaxis and treatment of diabetes |
| WO2000078333A2 (en) | 1999-06-21 | 2000-12-28 | Eli Lilly And Company | Synergetic use of thiazolidinediones with glucagon-like peptide-1 and agonists thereof to treat non-insulin dependant diabetes |
| BRPI0107715B8 (en) * | 2000-01-21 | 2021-05-25 | Novartis Ag | pharmaceutical product comprising an inhibitor of dipeptidyl peptidase-iv and metformin, as well as uses of said pharmaceutical product and inhibitor of dipeptidyl peptidase-iv |
| WO2001062295A1 (en) * | 2000-02-24 | 2001-08-30 | Takeda Chemical Industries, Ltd. | Drugs containing combined active ingredients |
| JP4917712B2 (en) * | 2000-02-24 | 2012-04-18 | 武田薬品工業株式会社 | Concomitant medication |
| WO2002055009A1 (en) | 2001-01-12 | 2002-07-18 | Sun Pharmaceutical Industries Limited | Spaced drug delivery system |
| FR2832930A1 (en) * | 2001-12-03 | 2003-06-06 | Lipha | PHARMACEUTICAL COMPOSITION COMPRISING AN ALPHA-GLUCOSIDASE INHIBITOR AND A THIAZOLIDINEDIONE DERIVATIVE AND USE THEREOF FOR THE PREPARATION OF MEDICINES FOR TREATING DIABETES |
| NZ546337A (en) | 2003-10-31 | 2009-03-31 | Takeda Pharmaceutical | Solid preparation comprising an insulin sensitizer such as pioglitazone hydrochloride, an insulin secretagogue such as glimepiride and a polyoxyethylene sorbitan fatty acid ester such as Polysorbate 80 |
| CN101103993B (en) * | 2006-07-14 | 2011-03-30 | 北京华安佛医药研究中心有限公司 | Hypoglycemic medicine composition |
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|---|---|---|---|---|
| US5900435A (en) * | 1991-08-26 | 1999-05-04 | Pharmacia & Upjohn Company | Composition, food product and uses of 3-guanidinopropionic acid |
| US5917052A (en) * | 1994-09-28 | 1999-06-29 | Shaman Pharmaceuticals, Inc. | Hypoglycemic agent from cryptolepis |
| TW438587B (en) * | 1995-06-20 | 2001-06-07 | Takeda Chemical Industries Ltd | A pharmaceutical composition for prophylaxis and treatment of diabetes |
-
1997
- 1997-07-18 GB GB9715298A patent/GB9715298D0/en active Pending
-
1998
- 1998-07-15 DZ DZ980173A patent/DZ2563A1/en active
- 1998-07-16 SK SK61-2000A patent/SK612000A3/en unknown
- 1998-07-16 CN CN98807147A patent/CN1263467A/en active Pending
- 1998-07-16 AR ARP980103482A patent/AR016350A1/en unknown
- 1998-07-16 IL IL13390798A patent/IL133907A0/en unknown
- 1998-07-16 KR KR1020007000517A patent/KR20010021952A/en not_active Application Discontinuation
- 1998-07-16 PL PL98338140A patent/PL338140A1/en unknown
- 1998-07-16 ID IDW20000077A patent/ID23804A/en unknown
- 1998-07-16 PE PE1998000630A patent/PE99499A1/en not_active Application Discontinuation
- 1998-07-16 CA CA002297133A patent/CA2297133A1/en not_active Abandoned
- 1998-07-16 HU HU0003626A patent/HUP0003626A3/en unknown
- 1998-07-16 EA EA200000140A patent/EA200000140A1/en unknown
- 1998-07-16 EP EP98935129A patent/EP1001784A1/en not_active Withdrawn
- 1998-07-16 BR BR9810292-3A patent/BR9810292A/en not_active IP Right Cessation
- 1998-07-16 MA MA25172A patent/MA24608A1/en unknown
- 1998-07-16 WO PCT/GB1998/002112 patent/WO1999003478A1/en not_active Application Discontinuation
- 1998-07-16 TR TR2000/00133T patent/TR200000133T2/en unknown
- 1998-07-16 AU AU84490/98A patent/AU8449098A/en not_active Abandoned
- 1998-07-16 JP JP2000502777A patent/JP2001510160A/en active Pending
- 1998-07-17 UY UY25101A patent/UY25101A1/en not_active Application Discontinuation
- 1998-07-17 CO CO98040749A patent/CO4940489A1/en unknown
- 1998-07-17 ZA ZA9806364A patent/ZA986364B/en unknown
-
1999
- 1999-06-28 AR ARP990103110A patent/AR019724A2/en unknown
-
2000
- 2000-01-06 BG BG104062A patent/BG104062A/en unknown
- 2000-01-14 AP APAP/P/2000/001735A patent/AP2000001735A0/en unknown
- 2000-01-17 NO NO20000230A patent/NO20000230D0/en not_active Application Discontinuation
- 2000-01-18 OA OA1200000013A patent/OA11312A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PE99499A1 (en) | 1999-12-18 |
| MA24608A1 (en) | 1999-04-01 |
| AU8449098A (en) | 1999-02-10 |
| JP2001510160A (en) | 2001-07-31 |
| UY25101A1 (en) | 2000-12-29 |
| BG104062A (en) | 2000-11-30 |
| ZA986364B (en) | 2000-01-17 |
| WO1999003478A1 (en) | 1999-01-28 |
| DZ2563A1 (en) | 2003-02-15 |
| EA200000140A1 (en) | 2000-06-26 |
| AR019724A2 (en) | 2002-03-13 |
| ID23804A (en) | 2000-05-11 |
| OA11312A (en) | 2003-10-24 |
| PL338140A1 (en) | 2000-09-25 |
| NO20000230L (en) | 2000-01-17 |
| AR016350A1 (en) | 2001-07-04 |
| CN1263467A (en) | 2000-08-16 |
| HUP0003626A3 (en) | 2001-12-28 |
| BR9810292A (en) | 2000-09-19 |
| KR20010021952A (en) | 2001-03-15 |
| NO20000230D0 (en) | 2000-01-17 |
| SK612000A3 (en) | 2000-07-11 |
| IL133907A0 (en) | 2001-04-30 |
| GB9715298D0 (en) | 1997-09-24 |
| EP1001784A1 (en) | 2000-05-24 |
| TR200000133T2 (en) | 2000-09-21 |
| HUP0003626A2 (en) | 2001-05-28 |
| AP2000001735A0 (en) | 2000-01-16 |
| CO4940489A1 (en) | 2000-07-24 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |