Note: Descriptions are shown in the official language in which they were submitted.
CA 02297133 2000-O1-18
WO 99/03478 PCT/GB98/02112
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
6232946
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.
CA 02297133 2000-O1-18
WO 99/03478 PCT/GB98/02112
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
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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.
-3-
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WO 99/03478 PCT/GB98/02112
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.
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- '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_
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WO 99/03478 PCT/GB98/02112
- 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,
-6-
T _...._.._~ _ _... ...._..____._M_~.._.T....
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WO 99/03478 PCT/GB98/02112
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
CA 02297133 2000-O1-18
WO 99/03478 PCT/GB98/02112
- 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_
____.
CA 02297133 2000-O1-18
WO 99/03478 PCT/GB98/02112
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.
-9-
CA 02297133 2000-O1-18
WO 99/03478 PCT/GB98/02112
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