WO1999018944A1 - Use of thiazolidinediones for the treatment of hyperglycaemia - Google Patents

Use of thiazolidinediones for the treatment of hyperglycaemia Download PDF

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Publication number
WO1999018944A1
WO1999018944A1 PCT/GB1998/003067 GB9803067W WO9918944A1 WO 1999018944 A1 WO1999018944 A1 WO 1999018944A1 GB 9803067 W GB9803067 W GB 9803067W WO 9918944 A1 WO9918944 A1 WO 9918944A1
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WO
WIPO (PCT)
Prior art keywords
hyperglycaemia
glucose levels
plasma glucose
insulin sensitiser
range
Prior art date
Application number
PCT/GB1998/003067
Other languages
French (fr)
Inventor
Robin Edwin Buckingham
Stephen Alistair Smith
Original Assignee
Smithkline Beecham Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to PL98339804A priority Critical patent/PL339804A1/en
Priority to OA1200000107A priority patent/OA11519A/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to EA200000418A priority patent/EA200000418A1/en
Priority to SK532-2000A priority patent/SK5322000A3/en
Priority to BR9815220-3A priority patent/BR9815220A/en
Priority to UA2000042049A priority patent/UA66809C2/en
Priority to CA002305289A priority patent/CA2305289A1/en
Priority to HU0003673A priority patent/HUP0003673A3/en
Priority to KR1020007003935A priority patent/KR20010024482A/en
Priority to AU95471/98A priority patent/AU9547198A/en
Priority to EP98949088A priority patent/EP1023057A1/en
Priority to IL13551598A priority patent/IL135515A0/en
Priority to APAP/P/2000/001788A priority patent/AP1223A/en
Priority to JP2000515579A priority patent/JP2001519383A/en
Publication of WO1999018944A1 publication Critical patent/WO1999018944A1/en
Priority to NO20001897A priority patent/NO20001897L/en
Priority to HR20000256A priority patent/HRP20000256A2/en
Priority to BG104405A priority patent/BG104405A/en

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Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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

Definitions

  • This invention relates to a method of treatment, in particular to a method for the treatment of a certain, specified hyperglycaemia.
  • European Patent Application, Publication Number 0,306,228 relates to certain thiazolidinedione derivatives disclosed as having hypoglycaemic and hypolipidaemic activity.
  • One particular thiazolidinedione disclosed in EP 0306228 is 5-[4-[2-(N-methyl- N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (hereinafter 'Compound (I)').
  • WO94/05659 discloses certain salts of Compound (I) including the maleate salt.
  • Compound (I) is an example of a class of anti-hyperglycaemic agents known as
  • Compound (I) is a thiazolidinedione insulin sensitiser.
  • Another series of compounds generally recognised as having insulin sensitiser activity are those typified by the compounds disclosed in International Patent Applications, Publication Numbers WO93/21166 and WO94/01420. These compounds are herein referred to as 'acyclic insulin sensitisers'. Other examples of acyclic insulin sensitisers are those disclosed in United States Patent Number 5232945 and International Patent Applications, Publication Numbers WO92/03425 and WO91/19702.
  • insulin sensitisers examples include those disclosed in European Patent Application, Publication Number 0533933, Japanese Patent Application Publication Number 05271204 and United States Patent Number 5264451.
  • Type 2 diabetes is characterised by fasting plasma glucose levels of > 126mg/dl (where fasting is defined as no calorific intake for at least 8 hours). It is also described therein how the development of diabetes commonly occurs over a period of several years characterised by a rise in fasting serum glycaemia levels from levels generally considered to be normal - plasma glucose levels of approximately 1 lOmg/dl - through to the stated hyperglycaemia characteristic of frank Type 2 diabetes. The Report also refers to metabolic stages intermediate between normal glucose homeostasis and diabetes, including impaired glucose tolerance and impaired fasting glucose.
  • EP0306228 It is known from EP0306228 that Compound I is useful in the prophylaxis of hyperglycaemia and hence for the treatment of impaired glucose tolerance.
  • International Patent Application, Publication number WO 95/07694 also discloses that thiazolidinediones can be used to treat impaired glucose tolerance to prevent or delay the onset of Type 2 diabetes mellitus.
  • EP0306228 and WO 95/07694 do not disclose the treatment of any particular range of glycaemias.
  • Compound (I) provides a particularly beneficial effect on glycaemic control in the range of hyperglycaemia from >126mg/dl to 140mg/dl, thereby delaying or preventing further elevation of the hypergylcaemia.
  • the invention provides a method for the treatment of hyperglycaemia, especially fasting hyperglycaemia, wherein plasma glucose levels are in the range of from >126mg/dl to 140mg/dl, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, to a mammal in need thereof.
  • the invention provides a method for improving glycaemic control in conditions characterised by hyperglycaemia, especially fasting hyperglycaemias, wherein the improvement is provided wherein plasma glucose levels are in the range of from >126mg/dl to 140mg/dl, thereby delaying or preventing further elevation of the hypergylcaemia, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, to a mammal in need thereof.
  • the invention provides a method for the prophylaxis of hyperglycaemia, especially fasting hyperglycaemia, wherein plasma glucose levels are >140mg/dl, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, to a mammal in need thereof.
  • One particular group of conditions defined herein, in addition to being characterised by hyperglycaemia wherein fasting plasma glucose levels are in the range of from >126mg/dl to 140mg/dl are further characterised by hyperglycaemia wherein plasma glucose levels following an oral glucose tolerance test are ⁇ 140mg/dl.
  • a further group of conditions defined herein are those wherein in addition to being characterised by hyperglycaemia wherein fasting plasma glucose levels are in the range of from >126mg/dl to 140mg/dl, are further characterised by hyperglycaemias wherein plasma glucose levels following an oral glucose tolerance test are in the range of from 140 to ⁇ 200 mg/dl.
  • the hyperglycaemia is that associated with the Type 2 diabetes mellitus syndrome.
  • a suitable insulin sensitiser is a thiazolidinedione insulin sensitiser.
  • a suitable thiazolidinedione insulin sensitiser is Compound (I).
  • thiazolidinedione insulin sensitisers include (+) -5-[[4-[(3,4- dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-l-benzopyran-2-yl)methoxy]phenyl]methyl]- 2,4-thiazolidinedione (or troglitazone), 5-[4-[(l-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)
  • the method comprises the administration of 2 to 12 mg of Compound (I), especially when administered per day.
  • the method comprises the administration of 2 to 4 , 4 to 8 or 8 to 12 mg of Compound (I) per day.
  • the method comprises the administration of 2 to 4mg of Compound (I), especially when administered per day.
  • the method comprises the administration of 4 to 8mg, such as greater than 4 for example 4.1, to 8 mg, of Compound (I), especially when administered per day.
  • the method comprises the administration of 8 to 12 mg of Compound (I), especially when administered per day.
  • the method comprises the administration of 2 mg of Compound (I), especially when administered per day.
  • the method comprises the administration of 4 mg of Compound (I), especially when administered per day.
  • the method comprises the administration of 8 mg of Compound (I), especially when administered per day.
  • the insulin sensitiser such as compound (I) is administered in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters and solvates thereof, as appropriate.
  • 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 WO94/05659 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 WO94/05659 for Compound (I), in particular hydrates.
  • the thiazolidinedione insulin sensitisers may exist in one of several tautomeric forms, all of which are encompassed herein either as individual tautomeric forms or as mixtures thereof.
  • Certain of the insulin sensitisers, such as Compound (I) contain one or more chiral carbon atom, and hence can exist in two or more stereoisomeric forms: All such forms are encompassed herein whether as individual isomers or as mixtures of isomers, including racemates.
  • the term 'pharmaceutically acceptable' embraces both human and veterinary use: for example the term 'pharmaceutically acceptable' embraces a veterinarily acceptable compound.
  • 'elevated normal' hyperglycaemia is to be taken as generally understood in the art, with reference for example to the Report of the Expert Committee of the Diagnosis and Classification of Diabetes Mellitus but is usually taken to mean glycaemias wherein plasma glucose levels are >1 lOmg/dl.
  • plasma glucose levels are fasting plasma glucose levels.
  • the active medicaments are preferably administered in pharmaceutical composition form.
  • such compositions can include both medicaments or one only of the medicaments.
  • compositions may be prepared by admixing an insulin sensitiser, such as Compound (I) and especially 2 to 12 mg thereof, and a pharmaceutically acceptable carrier therefor.
  • 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.
  • 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, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stearate
  • disintegrants for example star
  • 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 above mentioned patents and patent applications.
  • Suitable dosages, including unit dosages, of Compound (I) comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of Compound (I).
  • the medicaments may be administered from 1 to 6 times a day, but most preferably 1 or 2 times 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 coating.
  • 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 gel, 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 agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose,
  • fluid 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.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle.
  • 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 medicament 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.
  • 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.
  • the composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
  • compositions are prepared and formulated according to conventional methods, such as those disclosed in standard reference texts, for example the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.),
  • the invention also provides the use of an insulin sensitiser, such as Compound
  • the invention also provides the use of an insulin sensitiser, such as
  • the invention provides the use of an insulin sensitiser, such as Compound (I) and especially 2 to 12 mg thereof, for the manufacture of a medicament for the prophylaxis of hyperglycaemia, especially fasting hyperglycaemia, wherein plasma glucose levels are >140mg/dl.
  • an insulin sensitiser such as Compound (I) and especially 2 to 12 mg thereof, for the manufacture of a medicament for the prophylaxis of hyperglycaemia, especially fasting hyperglycaemia, wherein plasma glucose levels are >140mg/dl.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an insulin sensitiser, such as Compound (I) and especially 2 to 12 mg thereof, and a pharmaceutically acceptable carrier therefor, for use in the treatment of hyperglycaemia, especially fasting hyperglycaemia, wherein plasma glucose levels are in the range of from

Abstract

A method for the treatment of hyperglycaemia wherein plasma glucose levels in the range of from > 126 mg/dl to 140 mg/dl, which method comprises administering an effective nontoxic and pharmaceutically acceptable amount of an insulin sensitiser, to a mammal in need thereof.

Description

USE OF THIAZOLIDINEDIONES FOR THE TREATMENT OF HYPERGLYCAEMIA
This invention relates to a method of treatment, in particular to a method for the treatment of a certain, specified hyperglycaemia. European Patent Application, Publication Number 0,306,228 relates to certain thiazolidinedione derivatives disclosed as having hypoglycaemic and hypolipidaemic activity. One particular thiazolidinedione disclosed in EP 0306228 is 5-[4-[2-(N-methyl- N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (hereinafter 'Compound (I)'). WO94/05659 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, 0155845, 0257781, 0208420, 0177353, 0319189, 0332331, 0332332, 0528734, 0508740; International Patent Application, Publication Numbers 92/18501, 93/02079, 93/22445 and United States Patent Numbers 5104888 and 5478852, also disclose certain thiazolidinedione 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 WO93/21166 and WO94/01420. These compounds are herein referred to as 'acyclic insulin sensitisers'. Other examples of acyclic insulin sensitisers are those disclosed in United States Patent Number 5232945 and International Patent Applications, Publication Numbers WO92/03425 and WO91/19702.
Examples of other insulin sensitisers are those disclosed in European Patent Application, Publication Number 0533933, Japanese Patent Application Publication Number 05271204 and United States Patent Number 5264451.
The Report of the Expert Committee of the Diagnosis and Classification of Diabetes Mellitus (Diabetes Care, vol 20(7), 1997, 1183-1197) states that Type 2 diabetes is characterised by fasting plasma glucose levels of > 126mg/dl (where fasting is defined as no calorific intake for at least 8 hours). It is also described therein how the development of diabetes commonly occurs over a period of several years characterised by a rise in fasting serum glycaemia levels from levels generally considered to be normal - plasma glucose levels of approximately 1 lOmg/dl - through to the stated hyperglycaemia characteristic of frank Type 2 diabetes. The Report also refers to metabolic stages intermediate between normal glucose homeostasis and diabetes, including impaired glucose tolerance and impaired fasting glucose.
It is known from EP0306228 that Compound I is useful in the prophylaxis of hyperglycaemia and hence for the treatment of impaired glucose tolerance. International Patent Application, Publication number WO 95/07694 also discloses that thiazolidinediones can be used to treat impaired glucose tolerance to prevent or delay the onset of Type 2 diabetes mellitus. However, EP0306228 and WO 95/07694 do not disclose the treatment of any particular range of glycaemias.
It is now surprisingly indicated that Compound (I) provides a particularly beneficial effect on glycaemic control in the range of hyperglycaemia from >126mg/dl to 140mg/dl, thereby delaying or preventing further elevation of the hypergylcaemia.
Accordingly, the invention provides a method for the treatment of hyperglycaemia, especially fasting hyperglycaemia, wherein plasma glucose levels are in the range of from >126mg/dl to 140mg/dl, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, to a mammal in need thereof.
In a further aspect the invention provides a method for improving glycaemic control in conditions characterised by hyperglycaemia, especially fasting hyperglycaemias, wherein the improvement is provided wherein plasma glucose levels are in the range of from >126mg/dl to 140mg/dl, thereby delaying or preventing further elevation of the hypergylcaemia, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, to a mammal in need thereof.
In yet a further aspect, the invention provides a method for the prophylaxis of hyperglycaemia, especially fasting hyperglycaemia, wherein plasma glucose levels are >140mg/dl, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, to a mammal in need thereof.
One particular group of conditions defined herein, in addition to being characterised by hyperglycaemia wherein fasting plasma glucose levels are in the range of from >126mg/dl to 140mg/dl are further characterised by hyperglycaemia wherein plasma glucose levels following an oral glucose tolerance test are <140mg/dl.
A further group of conditions defined herein are those wherein in addition to being characterised by hyperglycaemia wherein fasting plasma glucose levels are in the range of from >126mg/dl to 140mg/dl, are further characterised by hyperglycaemias wherein plasma glucose levels following an oral glucose tolerance test are in the range of from 140 to <200 mg/dl.
Suitably the hyperglycaemia is that associated with the Type 2 diabetes mellitus syndrome.
A suitable insulin sensitiser is a thiazolidinedione insulin sensitiser. A suitable thiazolidinedione insulin sensitiser is Compound (I).
Other suitable thiazolidinedione insulin sensitisers include (+) -5-[[4-[(3,4- dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-l-benzopyran-2-yl)methoxy]phenyl]methyl]- 2,4-thiazolidinedione (or troglitazone), 5-[4-[(l-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)
In one 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 4mg of Compound (I), especially when administered per day. Particularly, the method comprises the administration of 4 to 8mg, such as greater than 4 for example 4.1, to 8 mg, 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) is administered in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters and solvates thereof, as appropriate. 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 WO94/05659 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 WO94/05659 for Compound (I), in particular hydrates.
The thiazolidinedione insulin sensitisers, such as Compound (I), may exist in one of several tautomeric forms, all of which are encompassed herein either as individual tautomeric forms or as mixtures thereof. Certain of the insulin sensitisers, such as Compound (I), contain one or more chiral carbon atom, and hence can exist in two or more stereoisomeric forms: All such forms are encompassed herein whether as individual isomers or as mixtures of isomers, including racemates. As used herein the term 'pharmaceutically acceptable' embraces both human and veterinary use: for example the term 'pharmaceutically acceptable' embraces a veterinarily acceptable compound.
As used herein the oral glucose tolerance test is that referenced in Diabetes Care 1997, vol 20(7), 1183-1197.
As used herein 'elevated normal' hyperglycaemia is to be taken as generally understood in the art, with reference for example to the Report of the Expert Committee of the Diagnosis and Classification of Diabetes Mellitus but is usually taken to mean glycaemias wherein plasma glucose levels are >1 lOmg/dl. Suitably, plasma glucose levels are fasting plasma glucose levels.
In the method of the invention, the active medicaments are preferably administered in pharmaceutical composition form. As indicated above, such compositions can include both medicaments or one only of the medicaments.
Such compositions may be prepared by admixing an insulin sensitiser, such as Compound (I) and especially 2 to 12 mg thereof, 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, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, 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 above mentioned patents and patent applications.
Suitable dosages, including unit dosages, of Compound (I) comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of Compound (I). In the treatment the medicaments may be administered from 1 to 6 times a day, but most preferably 1 or 2 times per day.
In the treatment involving compounds other than Compound (I), the required dosages and formulations are generally as described in the above mentioned patent publications which as stated above are incorporated by reference herein: An example includes the administration of 200-800mg of Troglitazone, for example 200, 300 or 400mg.
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 coating.
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 gel, 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 agents.
For parenteral administration, fluid 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 medicament 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. The composition may, if desired, be in the form of a pack accompanied by 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, Remington's Pharmaceutical Sciences (Mack Publishing Co.),
Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) and Harry's
Cosmeticology (Leonard Hill Books).
The invention also provides the use of an insulin sensitiser, such as Compound
(I) and especially 2 to 12 mg thereof, for the manufacture of a medicament for the treatment of hyperglycaemia, especially fasting hyperglycaemia, wherein plasma glucose levels are in the range of from >126mg/dl to 140mg/dl.
In addition, the invention also provides the use of an insulin sensitiser, such as
Compound (I) and especially 2 to 12 mg thereof, for the manufacture of a medicament for improving glycaemic control in conditions characterised by hyperglycaemia, especially fasting hyperglycaemia, the improvement being provided wherein plasma glucose levels are in the range of from >126mg/dl to 140mg/dl, thereby delaying or preventing further elevation of the hypergylcaemia.
In yet a further aspect, the invention provides the use of an insulin sensitiser, such as Compound (I) and especially 2 to 12 mg thereof, for the manufacture of a medicament for the prophylaxis of hyperglycaemia, especially fasting hyperglycaemia, wherein plasma glucose levels are >140mg/dl.
The present invention also provides a pharmaceutical composition comprising an insulin sensitiser, such as Compound (I) and especially 2 to 12 mg thereof, and a pharmaceutically acceptable carrier therefor, for use in the treatment of hyperglycaemia, especially fasting hyperglycaemia, wherein plasma glucose levels are in the range of from
>126mg/dl to 140mg/dl or for the improvement of glycaemic control in conditions characterised by fasting hyperglycaemia, the improvement being provided in the range of hyperglycaemia wherein plasma glucose levels are in the range of from >126mg/dl to
140mg/dl, thereby delaying or preventing further elevation of the hypergylcaemia or for the prophylaxis of hyperglycaemia, especially fasting hyperglycaemia, wherein plasma glucose levels are >140mg/dl.
No adverse toxicological effects are expected for the compositions or methods of the invention in the above mentioned dosage ranges.

Claims

Claims:
1. A method for the treatment of hyperglycaemia wherein plasma glucose levels are in the range of from >126mg/dl to 140mg/dl, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, to a mammal in need thereof.
2. A method according to claim 1, wherein the hyperglycaemia is fasting hyperglycaemia.
3. A method according to claim 2, wherein the hyperglycaemia is characterised by fasting plasma glucose levels in the range of from >126mg/dl to 140mg/dl and is further characterised by hyperglycaemia wherein plasma glucose levels following an oral glucose tolerance test are <140mg/dl.
4. A method according to claim 2, wherein the hyperglycaemia is characterised by fasting plasma glucose levels in the range of from >126mg/dl to 140mg/dl. and is further characterised by hyperglycaemias wherein plasma glucose levels following an oral glucose tolerance test are in the range of from 140 to <200 mg/dl.
5. A method according to any one of claims 1 to 4, wherein the insulin sensitiser is a thiazolidinedione insulin sensitiser.
6. A method according to any one of claims 1 to 5, wherein the insulin sensitiser is Compound (I).
7. A method according to claim 6, wherein 2 to 12 mg of Compound (I) is administered per day.
8. A method according to any one of claims 1 to 4, wherein the insulin sensitiser is selected from the list consisting of: (+) -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-[(l-methylcyclohexyl)methoxy]benzyl] thiazolidine-2,4-dione (or ciglitazone), 5-[4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl] thiazolidine-2,4-dione (or ρioglitazone) and 5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl)thiazolidine-2,4- dione (or englitazone); or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
9. A method according to any one of claims 1 to 8, wherein the insulin sensitiser is in the form of a compositions adapted for oral administration.
10. A method according to claim 9, wherein the composition is in unit dosage form.
11 The use of an insulin sensitiser for the manufacture of a medicament for the treatment of hyperglycaemia wherein plasma glucose levels are in the range of from >126mg/dl to 140mg/dl.
12. A pharmaceutical composition comprising an insulin sensitiser and a pharmaceutically acceptable carrier, for use in the treatment of hyperglycaemia wherein plasma glucose levels in the range of from >126mg/dl to 140mg/dl.
PCT/GB1998/003067 1997-10-13 1998-10-12 Use of thiazolidinediones for the treatment of hyperglycaemia WO1999018944A1 (en)

Priority Applications (17)

Application Number Priority Date Filing Date Title
APAP/P/2000/001788A AP1223A (en) 1997-10-13 1998-10-12 Use of thiazolidinediones for the treatment of hyperglycaemia.
HU0003673A HUP0003673A3 (en) 1997-10-13 1998-10-12 Use of thiazolidinediones for the treatment of hyperglycaemia
EA200000418A EA200000418A1 (en) 1997-10-13 1998-10-12 APPLICATION OF THIAZOLIDINDION FOR THE TREATMENT OF HYPERGLYCEMIA
SK532-2000A SK5322000A3 (en) 1997-10-13 1998-10-12 Use of thiazolidinediones for the treatment of hyperglycaemia
BR9815220-3A BR9815220A (en) 1997-10-13 1998-10-12 Use of thiazolidinediones for the treatment of hyperglycemia
UA2000042049A UA66809C2 (en) 1997-10-13 1998-10-12 Method for treatment of hyperglycaemia
CA002305289A CA2305289A1 (en) 1997-10-13 1998-10-12 Use of thiazolidinediones for the treatment of hyperglycaemia
PL98339804A PL339804A1 (en) 1997-10-13 1998-10-12 Application of thiazolydine diones in treating hyperglycaemia
KR1020007003935A KR20010024482A (en) 1997-10-13 1998-10-12 Use of Thiazolidinediones for the Treatment of Hyperglycaemia
EP98949088A EP1023057A1 (en) 1997-10-13 1998-10-12 Use of thiazolidinediones for the treatment of hyperglycaemia
AU95471/98A AU9547198A (en) 1997-10-13 1998-10-12 Use of thiazolidinediones for the treatment of hyperglycaemia
IL13551598A IL135515A0 (en) 1997-10-13 1998-10-12 Use of thiazolidinediones for the treatment of hyperglycaemia
OA1200000107A OA11519A (en) 1997-10-13 1998-10-12 Use of thiazolidinediones for the treatment of hyperglycaemia.
JP2000515579A JP2001519383A (en) 1997-10-13 1998-10-12 Use of thiazolidinedione for the treatment of hyperglycemia
NO20001897A NO20001897L (en) 1997-10-13 2000-04-12 Use of thiazolidinediones for the treatment of hyperglycaemia
HR20000256A HRP20000256A2 (en) 1997-10-13 2000-05-02 Use of thiazolidinediones for the treatment of hyperglycaemia
BG104405A BG104405A (en) 1997-10-13 2000-05-05 The application of thiazolidindions for the treatment of hyperglycaemia

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9721692.3 1997-10-13
GBGB9721692.3A GB9721692D0 (en) 1997-10-13 1997-10-13 Novel treatment

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US09/949,585 Continuation US20020006939A1 (en) 1997-10-13 2001-09-10 Use of thiazolidinediones for the treatment of hyperglycaemia

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AU (1) AU9547198A (en)
BG (1) BG104405A (en)
BR (1) BR9815220A (en)
CA (1) CA2305289A1 (en)
CZ (1) CZ20001298A3 (en)
EA (1) EA200000418A1 (en)
GB (1) GB9721692D0 (en)
HR (1) HRP20000256A2 (en)
HU (1) HUP0003673A3 (en)
ID (1) ID24439A (en)
IL (1) IL135515A0 (en)
NO (1) NO20001897L (en)
OA (1) OA11519A (en)
PL (1) PL339804A1 (en)
SK (1) SK5322000A3 (en)
TR (1) TR200000957T2 (en)
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NO20001897L (en) 2000-06-09
PL339804A1 (en) 2001-01-02
HRP20000256A2 (en) 2000-12-31
EA200000418A1 (en) 2000-10-30
EP1023057A1 (en) 2000-08-02
YU28700A (en) 2003-10-31
AP1223A (en) 2003-11-13
CA2305289A1 (en) 1999-04-22
UA66809C2 (en) 2004-06-15
JP2001519383A (en) 2001-10-23
GB9721692D0 (en) 1997-12-10
TR200000957T2 (en) 2000-08-21
KR20010024482A (en) 2001-03-26
IL135515A0 (en) 2001-05-20
CN1281358A (en) 2001-01-24
AU9547198A (en) 1999-05-03
HUP0003673A3 (en) 2001-12-28
AP2000001788A0 (en) 2000-06-30
CZ20001298A3 (en) 2001-08-15
ID24439A (en) 2000-07-20
BG104405A (en) 2000-12-29
SK5322000A3 (en) 2000-09-12
NO20001897D0 (en) 2000-04-12
HUP0003673A2 (en) 2001-10-28
BR9815220A (en) 2000-11-14

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