Note: Descriptions are shown in the official language in which they were submitted.
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COI~OSIT10N COMPRISING 5-(4-(2-(N-METHYL-N-2-
PYRIDYL)AIvtINO)ETHOXY]BENZYL)THIAZOLIDINE-2.4-
DIONE
This invention relates to a composition, in particular to a pharmaceutical
composition, and to the use of such a composition in medicine, to processes
for
the preparation of such a composition and to a composition useful in such a
process.
European Patent Application, Publication Number 0,306,228 relates to
certain thiazolidinedione derivatives disclosed as having hypoglycaemic and
hypolipidaemic activity. One particular thiazolidined.ione disclosed in EP
0306228 is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-
2,4-dione (hereinafter 'Compound (I)'). International Patent Application,
publication number W094/05659 discloses certain salts of Compound (I),
including the maleate salt at Example 1 thereof.
It is now surprisingly indicated that a discrete and particular daily dosage
of Compound (I) provides an especially beneficial effect on glycaemic control
and
is therefore particularly useful for treatment of diabetes mellitus,
especially Type
II diabetes and conditions associated with diabetes mellitus.
We have also discovered a new and advantageous method for preparing
pharmaceutical compositions, especially unit dosage compositions, containing
Compound (I). The new method involves the preparation of a pre-administration
concentrate. of Compound (I) which thereafter is formulated into the required
unit
dose in an efficient and economical manner. The new process is particularly
advantageous for the preparation of tablets of Compound (I).
Accordingly, in a first aspect the present invention provides a
pharmaceutical composition, suitably in unit dosage form, comprising Compound
(I), characterised in that the composition comprises 2 to 12 mg of Compound
(I)
in a pharmaceutically acceptable form and optionally a pharmaceutically
acceptable carrier therefor.
Suitable pharmaceutically acceptable forms of Compound (I) include
pharmaceutically acceptable salted forms and pharmaceutically acceptable
solvated forms, including pharmaceutically acceptable solvated forms of
pharmaceutically acceptable salts.
Suitable compositions comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of
Compound (I) in a pharmaceutically acceptable form.
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Particular compositions comprise 2 to 4mg of Compound (I) in a
pharmaceutically acceptable form.
Particular compositions comprise 4 to 8mg of Compound (I) in a
pharmaceutically acceptable form.
Particular compositions comprise 8 to 12 mg of Compound (I) in a
pharmaceutically acceptable form.
One composition comprises 2 mg of Compound (I) in a pharmaceutically
acceptable form.
Preferred compositions comprise 4 mg of Compound (I) in a
pharmaceutically acceptable form.
Preferred compositions comprise 8 mg of Compound (I) in a
pharmaceutically acceptable form.
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.
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.
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.
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 and hyperinsulinaemia.
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'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, cardiovascular disease, especially atherosclerosis, certain
eating
disorders, in particular those requiring the regulation of appetite and food
intake,
such as disorders associated with under-eating, for example anorexia nervosa
and
disorders associated with over-eating, for example obesity and anorexia
bulimia.
Additional conditions associated with diabetes mellitus itself 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, including diabetic
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.
As used herein the term concentrate with respect to Compound (I) in a
pharmaceutically acceptable form means a proportionate amount of Compound (I)
in a pharmaceutically acceptable form greater than that present in an
administerable composition.
For the avoidance of doubt, when reference is made herein to scalar
amounts, including mg amounts and % weight 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 II diabetes.
In a further aspect, the invention provides a process for preparing a
pharmaceutical composition comprising 2 to 12 mg of Compound.(I) in a
pharmaceutically acceptable form, and a pharmaceutically acceptable carrier
therefor, which process comprises admixing 2 to 12 mg of Compound (I) in a
pharmaceutically acceptable form and the pharmaceutically acceptable carrier
and
optionally thereafter formulating the composition produced into an
administerable
form.
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As indicated above the invention also provides a further process for
preparing a pharmaceutical composition comprising Compound (I) in a
pharmaceutically acceptable form which is particularly suitable for preparing
a
range of unit dosage forms of Compound (I). Accordingly, the invention further
provides a process for preparing a pharmaceutical composition of Compound (I)
in a pharmaceutically acceptable form and a pharmaceutically acceptable
carrier,
which process comprises:
(i) preparing a first composition comprising Compound (I) in a
pharmaceutically
acceptable form and a first pharmaceutically acceptable carrier;
(ii) admixing the first composition with a second pharmaceutically acceptable
carrier to provide the required composition of Compound (I) and optionally
thereafter formulating the composition produced into an administerable form.
A preferred administerable form of the pharmaceutical composition of
Compound (I) is a unit dose composition.
Unless otherwise specified, suitable unit doses comprise up to 12 mg, such
as 1 to 12 mg, of Compound (I) in a pharmaceutically acceptable form.
Other unit doses include those mentioned herein.
A key component of the last above mentioned process is the first
composition. Accordingly, the present invention also provides a composition
for
use as a first composition in a process for preparing a unit dose of Compound
(I)
in a pharmaceutically acceptable form.
The invention also provides a composition comprising Compound (I) in a
pharmaceutically acceptable form and optionally a pharmaceutically acceptable
carrier, characterised in that the composition is a pharmaceutically
acceptable,
pre-administration composition.
A suitable pharmaceutically acceptable, pre-administration composition is
a concentrate, preferably a granular concentrate, of Compound (I) in a
pharmaceutically acceptable form. The granular concentrate is particularly
well
adapted to be diluted to provide a composition for administration, preferably
a
tablet.
In a further aspect the invention provides a composition comprising
Compound (I) in a pharmaceutically acceptable form and a pharmaceutically
acceptable carrier, characterised in that the composition is a concentrate of
Compound (I) in a pharmaceutically acceptable form, adapted to be diluted so
as '
to provide a composition for administration.
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Suitably, the first composition, pre-administration composition
or dilutable composition (hereinafter referred to for convenience as 'the
first
composition') contains up to 50% by weight, for example an amount in the range
of from 2 to 50% by weight, of Compound (I) in a pharmaceutically acceptable
form.
Favourably, the first composition contains an amount of Compound (I) in
a pharmaceutically acceptable form in the range of from 5 to 20% by weight, in
particular 5%, 10% or 15% by weight, for example 10% by weight.
The processes of the invention can provide pharmaceutical compositions
of Compound (I) in any conventionally administerable form, including orally or
parenterally adminsterable forms. iThe~ are~articularly well adapted for
preparing orally administrable forms, especially tablet forms of Compound (I)
in a
pharmaceutically acceptable forrrl,.
The first pharmaceutically acceptable carrier can comprise any
conventional pharmaceutically acceptable carrier comprising conventional
pharmaceutically acceptable excipients, including those disclosed in the
reference
texts mentioned below. However, as it is not essential that the first
pharmaceutically acceptable carrier is in an administerable form, then it need
not
contain excipients solely associated with administration. For example the
first
pharmaceutically acceptable carrier need not contain a lubricant.
The second pharmaceutically acceptable carrier includes any conventional
pharmaceutically acceptable carrier comprising any conventional
pharmaceutically acceptable excipient, including disintegrants, diluents and
lubricants, including those disclosed in the reference texts mentioned below.
One particular first composition comprises Compound (I) in a
pharmaceutically acceptable form, a disintegrant, a binder and a diluent.
A suitable disintegrant is sodium starch glycollate.
A suitable binder is a methyl cellulose binder, such as hydroxypropyl
methylceIlulose 2910.
Suitable diluents include cellulose, for example a microcrystalline
cellulose, and lactose monohydrate.
A suitable lubricant is magnesium stearate.
We have found that a particularly advantageous first composition contains
Compound (I) in a pharmaceutically acceptable form, sodium starch glycollate,
hydroxypropyl methylcellulose 2910, microcrystalline cellulose and lactose
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monohydrate, especially when in a granular form. This granular form has been
found to be particularly stable.
When the first composition contains about 10% by weight of Compound
(I) in a pharmaceutically acceptable form, it is readily dilutable to give
unit dose
compositions comprising in the range of between 2 to 12 mg , especially 2 to 8
mg, 2 to 4mg, 4 to 8 mg and 8 to I2 mg of Compound (I) in a pharmaceutically
acceptable form.
The preparation of the first composition is suitably carried using any
conventional method appropriate to the nature of the said first composition,
for
example wet granulation methods provide the first composition in granular
form.
Methods for formulating the compositions of the invention into
administerable forms include conventional formulation methods as disclosed in
the reference texts cited herein, including tabletting methods.
The administerable compositions of the invention are preferably adapted
for oral administration. However, they may also be adapted for other modes of
administration, for example parenteral administration, sublingual or
transdermal
administration.
The administerable 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.
Unless otherwise prescribed, compositions of the invention are
preferably in unit dosage form in an amount appropriate for the relevant daily
dosage, suitable unit dosages comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12
mg of
Compound (I) in a pharmaceutically acceptable form.
The solid compositions for example the oral compositions may be
prepared by conventional methods of blending, filling or tabletting. As
required
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
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well known in normal pharmaceutical practice, in particular with an aqueous
film
coating.
Liquid compositions, for example oral liquid compositions, may be in
the form of emulsions, syrups, or elixirs, or they may be in a dry product
form to
be reconstituted 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.
Parenteral compositions, including parenteral administration
compositions for example unit dosage compositions, comprise the active
compound and a sterile vehicle, and, depending upon the concentration used,
can
be either suspended or dissolved in the vehicle. In preparing solutions for
parenteral administration the composition of the invention may 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 active compound 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.
Unless otherwise specified the compositions of the invention may contain
from 0. I % to 99% by weight, preferably from I 0-60% 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 of the invention may be 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).
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The present invention also provides a pharmaceutical composition
comprising 2 to 12 mg of Compound (I) and a pharmaceutically acceptable
carrier
therefor, for use as an active therapeutic substance.
In particular, the present invention provides a pharmaceutical
composition comprising 2 to I2 mg of Compound (I) in a pharmaceutically
acceptable form, for use in the treatment of diabetes mellitus, especially
Type II
diabetes, and conditions associated with diabetes mellitus..
The composition of the invention may be administered from 1 to 6 times
a day, but most preferably 1 or 2 times per day.
Accordingly, in a further aspect the invention provides a method for
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 per day 2 to 12 mg of Compound (I) in a
pharmaceutically acceptable form, to a mammal in need thereof.
Particularly, the method comprises the administration of 2 to 4 , 4 to 8 or
8 to 1,2 mg of Compound (I) in a pharmaceutically acceptable form.
Particular dosages are 2mg/day, 4mg/day, including 2mg twice per day,
and 8 mg/day, including 4mg twice per day.
Particularly, the method comprises the administration of 2 to 4mg of
Compound (I) in a pharmaceutically acceptable form.
Particularly, the method comprises the administration of 4 to 8mg of
Compound (I) in a pharmaceutically acceptable form.
Particularly, the method comprises the administration of 8 to I2 mg of
Compound (I) in a pharmaceutically acceptable form.
Preferably, the method comprises the administration of 2 mg of
Compound (I) in a pharmaceutically acceptable form.
Preferably, the method comprises the administration of 4 mg of
Compound (I) in a pharmaceutically acceptable form.
Preferably, the method comprises the administration of 8 mg of
Compound (I) in a pharmaceutically acceptable form.
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, 2.5 to 4, 2.6 to 4, 2.7 to 4, 2.8 to 4, 2.9 to 4 or 3 to 4mg.
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 I2, 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. t
No adverse toxicological effects have been established for the
compositions or methods of the invention in the abovementioned dosage ranges.
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The following examples illustrate the invention but do not limit it in any
way.
Example 1: 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 mixtuz~e 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 maleate 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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Example 2: Formulation of the concentrate into tablets.
The granules from Example 1 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 l.Omg 2.Omg 4.Omg 8.Omg
Active Ingredient:
Compound (I) maleate Concentrate10.00 20.00 40.00 80.00
granules
Other Ingredients:
Sodium Starch Glycollate 6.96 6.46 5.46 10.92
Microcrystalline Cellulose 27.85 25.85 21.85 43.70
Lactose monohydrate 104.44 96.94 81.94 163.88
Magnesium Stearate 0.75 0.75 0.75 1.50
Total Weight of Tablet Core 150.0 I50.0 150.0 300.0
Aqueous film coating material 4.5 4.5 4.5 9.0
Total Weight of Film Coated 154.5 154.5 154.5 309.0
Tablet
