Note: Descriptions are shown in the official language in which they were submitted.
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TREATMENT OF DIABETES WITH THIAZOLIDINEDIONE AND ALPHA-GLUCOSIDASE 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
S Type II diabetes and conditions associated with diabetes mellitus.
Alpha glucosidase inhibitor antihyperglycaemic agents, such as Acarbose,
Emiglitate and Miglitol, are commonly used in the treatment of NIDDM (or Type
II
diabetes).
European Patent Application, Publication Number 0,306,228 relates to certain
thiazolidinedione derivatives disclosed as having antihyperglycaemic and
hypolipidaemic activity. One particular thiazolidinedione disclosed in EP
0306228 is
5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxyJbenzyl]thiazolidine-2,4-dione
(hereinafter 'Compound (I)'). W094/05659 discloses certain salts of Compound
(I)
including the maleate salt at example 1 thereof.
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, OI55845, 0257781, 0208420, 0177353, 0319189,
0332331, 0332332, 0528734, 0508740; International Patent Application,
Publication
Numbers 92/18501, 93/02079, 93/22445 and United StateslPatent 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 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 contents of the above mentioned publications are incorporated herein by
reference.
It is now surprisingly indicated that Compound (I) in combination with an
alpha glucosidase inhibitor antihyperglycaemic agent provides a particularly
beneficial effect on glycaemic control, with minimal adverse side effects,
such
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combination is therefore particularly useful for the treatment of diabetes
mellitus,
especially Type II diabetes and conditions associated with diabetes mellitus.
Accordingly, the invention provides a method for the treatment of diabetes
mellitus, especially Type II 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,
such as
Compound (I), and an alpha glucosidase inhibitor antihyperglycaemic agent, to
a
mammal in need thereof.
In another aspect the invention provides an insulin sensitiser, such as
Compound (I), together with an alpha glucosidase inhibitor antihyperglycaemic
agent
for use in a method for the treatment of diabetes mellitus, especially Type II
diabetes
and conditions associated with diabetes mellitus.
The method comprises either co-administration of an insulin sensitiser, such
as Compound (I), and an alpha glucosidase inhibitor antihyperglycaemic agent
or the
sequential administration thereof.
Co-administration includes administration of a formulation which
includes both an insulin sensitiser, such as Compound (I), and a biguanide
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), and an alpha glucosidase inhibitor antihyperglycaemic agent
for use
in the manufacture of a composition for the treatment of diabetes mellitus,
especially
Type II diabetes and conditions associated with diabetes mellitus.
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-1-benzopyran-2-
yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione (or troglitazone), S-[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)
A suitable alpha glucosidase inhibitor antihyperglycaemic agent is acarbose.
Other suitable alpha glucosidase inhibitor antihyperglycaemic agents are
Emiglitate and Miglitol.
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 An insulin sensitiser, such as Compound (I), per day.
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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 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) 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 solvates thereof, as
appropriate
of the relevant pharmaceutically active agent. In certain instances herein the
names
used for the relevant alpha glucosidase inhibitor 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 forms of insulin sensitisers include
those described in the above mentioned publications.
Suitable pharmaceutically acceptable salted forms of Compound (I) include
those described in EP 0306228 and W094/05659. A preferred pharmaceutically
acceptable salt is a maleate.
Suitable pharmaceutically acceptable solvated forms of Compound (I)
include those described in EP 0306228 and W094/05659, in particular hydrates.
Suitable pharmaceutically acceptable forms of the alpha glucosidase inhibitor
antihyperglycaemic agent depend upon the particular agent used but includes
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 (Mack Publishing
Co.) and Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press)
(for example see the 31 st Edition page 341 and pages cited therein).
The insulin sensitisers may be prepared using known methods, for example
those disclosed in the above mentioned publications which are incorporated
herein by
reference. '
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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 EP 0306228 and W094/05659. The disclosures of
EP
0306228 and W094/05659 are incorporated herein by reference.
S 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 chiral 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 alpha glucosidase inhibitor antihyperglycaemic agent of choice is
prepared according to known methods, such methods are found or are referred to
in
standard reference texts, such as the British and US Pharmacopoeias,
Remington's
Pharmaceutical Sciences (Mack Publishing Co.) and Martindale The Extra
Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31 st
Edition
page 341 and pages cited therein).
When used herein the term 'conditions associated with diabetes' includes those
conditions associated with the pre-diabetic state, conditions associated with
diabetes
mellitus itself and complications associated with diabetes mellitus.
When used herein the term 'conditions associated with the pre-diabetic state'
includes conditions such as insulin resistance, including hereditary insulin
resistance,
impaired glucose tolerance, obesity and hyperinsulinaemia.
'Conditions associated with diabetes mellitus itself include hyperglycaemia,
insulin resistance, including acquired insulin resistance and obesity. Further
conditions associated 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 gestational
diabetes.
'Complications associated with diabetes mellitus' includes renal disease,
especially renal disease associated with Type II diabetes, neuropathy and
retinopathy.
Renal diseases associated with Type II diabetes include nephropathy,
glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive
nephrosclerosis and end stage renal disease.
As used herein the term 'pharmaceutically acceptable' embraces both human
and veterinary use: for example the term 'pharmaceutically acceptable'
embraces a
veterinarily acceptable compound.
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
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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 II 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
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 (Hb Alc). 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
required from a purely additive effect upon glycaemic control.
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.
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.
Accordingly, in one aspect of the invention provides a pharmaceutical
composition comprising an insulin sensitisers, such as Compound (I) especially
2 to
12 mg thereof, an alpha glucosidase inhibitor antihyperglycaemic agent and a
pharmaceutically acceptable carrier therefor.
Such compositions may be prepared by admixing an insulin sensitisers, such
as Compound (I) especially 2 to 12 mg thereof, the alpha glucosidase inhibitor
antihyperglycaemic 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.
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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 including unit dosages of the Compound of formula (I)
comprise l, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of Compound (I).
In the treatments the medicaments may be administered from 1 to 6 times a
day, but most preferably 1 or 2 times per day.
Particular dosages of Compound (I) are 2mg/day, 4mg/day, including 2mg
twice per day, and 8 mg/day, including 4mg twice per day.
Suitable dosages including unit dosages of the insulin sensitisers and the
alpha glucosidase inhibitor antihyperglycaemic agent, include the known
dosages and
unit doses for these compounds as described or referred to in reference texts
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) or
the
above mentioned publications.
Thus, a typical daily dosage of acarbose is in the range of from 50 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 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
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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 Compound (I)s 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
I O-60% by weight, of the active material, depending upon the method of
administration.
Compositions may, if desired, be in the form of a pack accompanied by
written or printed instructions for use.
The compositions are 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.) and
Martindale The Extra Pharmacopoeia (London The Pharmaceutical Press) (for
example see the 31 st Edition page 341 and pages cited therein) and Harry's
Cosmeticology (Leonard Hill Books).
In a further aspect, the present invention also provides a pharmaceutical
composition comprising Compound (I), especially 2 to 12 mg thereof, an alpha
glucosidase inhibitor antihyperglycaemic agent and a pharmaceutically
acceptable
carrier therefor, for use as an active therapeutic substance.
In particular, the present invention provides a pharmaceutical composition
comprising Compound (I), especially 2 to 12 mg thereof, an alpha glucosidase
inhibitor antihyperglycaemic agent and a pharmaceutically acceptable carrier
therefor,
for use in the treatment of diabetes mellitus, especially Type II diabetes and
conditions associated with diabetes mellitus. '
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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.Sto4,2.6to4,2.7to4,2.8to4,2.9to4or3to4mg.
A range of 4 to 8mg includes a range of 4.1 to 8, 4.2 to 8, 4.3 to 8, 4.4 to
8,
4.Sto8,4.6to8,4.7to8,4.8to8,4.9to8,5to8,6to8or7to8mg.
A range of 8 to 12 mg includes a range of 8.1 to 12, 8.2 to 12, 8.3 to 12, 8.4
to 12, 8.5 to 12, 8.6 to 12, 8.7 to 12, 8.8 to 12, 8.9 to 12, 9 to 12, 10 to
12 or 11 to
l2mg.
No adverse toxicological effects have been established for the compositions or
methods of the invention in the abovementioned dosage ranges.
The following example illustrates the invention but does not limit it in any
way.
Example
This study investigated whether administration of acarbose (A) alters the PK
of co-
administered Compound (I). Sixteen healthy volunteers (24-59 yo) received a
single oral dose
1 S of Compound (I) (8 mg) on Day 1, followed by 7 days of repeat dosing with
A (100 mg tid
with meals). On Day 8, a single oral dose of Compound (I) was coadministered
with the
morning dose of A. PK profiles following Compound (I) dosing on Days 1 and 8
were
compared. Coadministration of Compound (I) and A was well tolerated. PK data
and point
estimates [95% confidence intervals] for Compound (I) +A: Compound (I) alone
were
analyzed.
Parameter [units] Compound (I) Compound (I) + A
Alone
AUC (0-ink [ng.h/mL] 2793 (581) 2502 (755)
Cmax [ng/mL] 428 (86) 451 (141)
Tmax* [hours] 1.48 (0.97-5.95) 1.24 (0.95-3.98)
T1/2 [hours] 4.93 (0.78) 3.79 (0.78)
Data presented as median (range)
Compound (I) absorption (Cmax and Tmax) was unaffected by coadministration
with A but
exposure to Compound (I) (AUC [0-infj) decreased by an average of 12% (PE 0.88
[0.79,
0.98]) during Compound (I) +A coadministration and was accompanied by an
approximate 1
hour reduction in Tl/2. Thus, acarbose appears to slightly increase Compound
(I) clearance,
although the changes are small and are not likely to be clinically relevant.
In conclusion,
Compound (I) may be coadministered with acarbose without adversely affecting
Compound
(I) pharmacokinetics and/or its potential clinical benefit.
_g_
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COMPOUND (I) COMPOSITIONS
A Concentrate Preparation
Approximately two thirds of the lactose monohydrate is passed through a
suitable
screen and blended with the milled maleate salt of Compound (I).
Sodium starch glycollate, hydoxypropyl methylcellulose, microcrystalline
cellulose and the remaining lactose are passed through a suitable screen and
added
to the mixture. Blending is then continued. The resulting mixture is then wet
granulated with purified water. The wet granules are then screened, dried on a
fluid bed drier and the dried granules are passed through a further screen and
finally homogenised.
COMPOSITION OF GRANULAR CONCENTRATE
Ingredient Quantity (%)
Milled Compound (I) as maleate 13.25 (pure
salt maieate salt)
Sodium Starch Glycollate 5.00
Hydoxypropyl Methylcellulose 5.00
2910
Microcrystalline Cellulose 20.0
Lactose Monohydrate, regular to 100
grade
Purified water
* Removed during processing.
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B Formulation of the concentrate into tablets.
The granules from above are placed into a tumble blender. Approximately two
thirds of the lactose is screened and added to the blender. The
microcrystalline
cellulose, sodium starch glycollate, magnesium stearate and remaining lactose
are
screened and added to the blender and the mixture blended together. The
resulting mix is then compressed on a rotary tablet press to a target weight
of
150mg for the 1, 2 and 4mg tablets and to a target weight of 300mg for the 8mg
tablets.
The tablet cores are then transferred to a tablet coating machine,
pre-warmed with warm air (approximately 65°C) and film coated until the
tablet
weight has increased by 2.0% to 3.5%.
Quantity (mg per Tablet)
Tablet Strength LOmg 2.Omg 4.Omg 8.Omg
Active Ingredient:
Compound (I) maleate Concentrate10.00 20.0040.00 80.00
granules
Other Ingredients:
Sodium Starch Glycollate 6.96 6.46 5.46 10.92
Microcrystalline Cellulose 27.85 25.8521.85 43.70
Lactose monohydrate 104.44 96.9481.94 163.88
Magnesium Stearate 0.75 0.75 0.75 1.50
Total Weight of Tablet Core 150.0 150.0150.0 300.0
Aqueous film coating material 4.5 4.5 4.5 9.0
Total Weight of Film Coated 154.5 154.5154.5 309.0
Tablet
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