Note: Descriptions are shown in the official language in which they were submitted.
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USE OF THIAZOLID1HEDIONES FOR THE TREATMENT OF HYPFRGLYCAEMIA
This invention relates to a novel method of treatment, in particular to a
method
for treatment and/or prophylaxis 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]benzylJthiazolidine-2,4-dione (hereinafter 'Compound
(I)').
W094/05659 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' (or 'insulin action enhancers'). In particular Compound
{I) is a
thiazolidinedione insulin sensidser.
European Patent Applications, Publication Numbers: 0008203, 0139421,
0032128, 0428312, 0489663, 0155845, 0257781, 0208420, Oi77353, 0319189,
0332331,
0332332, 0528734, 0508740; International Patent Application, Publication
Numbers
92/18501, 93/02079, 93/22445 and United States Patent Numbers S 104888 and
X478852,
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 W093/21166 and W094/01420. 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 W092/03425 and W091/19702.
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 l Omg/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
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WO 99/18943 PCT/GB98/03064
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
mention the treatment of any specified range of glycaemias.
It is indicated that Compound (I) provides a particularly beneficial effect on
glycaemic control in the range of hyperglycaemias from elevated normal to
5126mg/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 elevated normal to 5126mg/dl, which method comprises
administering an
effective non-toxic and pharmaceutically acceptable amount of an insulin
sensitises, to a
mammal in need thereof.
Accordingly, the invention provides a method for improving glycaemic control
in conditions characterised by hyperglycaemia, especially fasting
hyperglycaemia,
wherein the improvement is provided in hyperglycaemias wherein plasma glucose
levels
are in the range of from elevated normal to <_126mg/dl, thereby delaying or
preventing
further elevation of the hypergylcaemia, which method comprises administering
an
effective non-toxic acrd pharmaceutically acceptable amount of an insulin
sensitises, 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 in
the range of > 126mg/dl, which method comprises administering an effective non-
toxic
and pharmaceutically acceptable amount of an insulin sensitises, to a mammal
in need
thereof.
One particular group of the conditions defined herein, in addition to being
characterised by fasting hyperglycaemia wherein plasma glucose levels are in
the range of
from elevated normal to 5126mg/dl are further characterised by hyperglycaemias
wherein
plasma glucose levels following an oral glucose tolerance test are in the
range of
< 140mg/dl.
A further group of the conditions defined herein, in addition to being
characterised by fasting hyperglycaemia in the range of from elevated normal
to
<_126mg/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.
A suitable insulin sensitises is a thiazolidinedione insulin sensitises.
A suitable thiazolidinedione insulin sensitises is Compound (I), or a
tautomeric
form thereof, or a pharmaceutically acceptable salt thereof, or a
pharmaceutically
acceptable solvate thereof.
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Other suitable thiazolidinedione insulin sensitisers include (+) -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), S-[4-[2-(5-ethylpyridin-2-
yl)ethoxy]benzylJ
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 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 W094/05659 for Compound (I), in
particular
3 5 hydrates.
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
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WO 99/189$3 PCT/GB98/03064
applications, such as EP 0306228 and W094/05659 for Compound (i). The
disclosures
of the above mentioned patents and patent applications, such as EP 0306228 and
W094/05659, are incorporated herein by reference.
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), contains one or more chirai 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
vol 20{7), 1997, 1183-1197.
As used herein 'elevated normal' hyperglycaemia is to be taken as generally
understood is 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 > 110mg/dl.
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,
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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 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.
In the treatment 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, carboxymethyicellulose, 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
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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 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).
Accordingly, 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 treatment of hyperglycaemia, especially fasting hyperglycaemia,
wherein plasma
glucose levels are in the range of from elevated normal to S126mg/dl.
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 elevated normal to 5126mg/dl, thereby delaying or preventing
fiuther
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 >126mg/dl.
In particular, the present invention provides a pharmaceutical composition
comprising an insulin sensitiser, such as Compound (I) and especially 2 to 12
mg thereof,
and a pharmaceutically acceptable Garner therefor, for use in the treatment of
hyperglycaemia, especially fasting hyperglycaemia, wherein plasma glucose
levels are in
the range of from elevated normal to s126mg/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 elevated normal to <_126mg/dl, thereby delaying or preventing further
elevation
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of the hypergylcaemia or for the prophylaxis of hyperglycaemia, especially
fasting
hyperglycaemia, wherein plasma glucose levels are >126mg/dl.
No adverse toxicological effects are expected for the compositions or methods
of the
invention in the above mentioned dosage ranges.
