AP1214A

AP1214A - Composition comprising 5-[4-[2-(n-methyl-n-2-pyridyl)amino) ethoxy} benzyl} thiazolidine-2, 4-dione.

Info

Publication number: AP1214A
Application number: APAP/P/1999/001696A
Authority: AP
Inventors: Jai Patel; Hamish Ross; Jeffrey Roger Granett; Robin Price; Paul Nigel Wray
Original assignee: Smithkline Beecham Plc; Smithkline Beecham Corp
Priority date: 1997-06-05
Filing date: 1998-06-02
Publication date: 2003-10-08
Also published as: JP2001521553A; NO995938D0; EA199901116A1; PL337201A1; AR015120A1; BR9810405A; WO1998055122A1; CN1430959A; CA2292629A1; AU8215098A; IL133074A0; ID24264A; PE78899A1; CA2292629C; KR20010013410A; BG104048A; NZ513922A; ZA984826B; NZ523725A; CO4940400A1

Abstract

A pharmaceutical composition 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, the use of such a composition in medicine, processes for the preparation of such a composition and intermediate composition useful in such a process.

Description

This invention relates to 3 composition, in p”rticular to ~ •'hormr’ceutir 4 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 thiazolidinedion: derivatives disclosed as having hypoglycaemic and hypolipidaemic activity. One particular thiazolidinedione disclosed in EP 0306228 is 5-[4-[2-(N-i.iethyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine2,4-dione (hereinafter 'Compound (I)'). International Patent Application, publication number WC 94/05659 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 iseful 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 composi ions, especially unit dosage compositions, containing Compound (I). The nev. 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 pre taration of tablets of Compound (I).

Accordingly, in ι first aspect the present invention provides a pharmaceutical composi·. on, suitably in unit dosage form, comprising Compound (I), characterised in that: ie composition comprises 2 to 12 mg of Compound (I) in a pharmaceutically ac< ‘ptable form and optionally a pharmaceutically acceptable carrier therefc .

Suitable pharma eutically acceptable forms of Compound (I) include pharmaceutically acceptable salted forms and pharmaceutically acceptable solvated forms, including pharmaceutically acceptable solvated forms of pharmaceutically accept le salts.

Suitable compos ions comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of Compound (I) in a pharrr .ceutically acceptable form.

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Particular compositions comprise 2 to 4mg of Compound (I) in .·; 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 WO94/05659. A preferred pharmaceutically acceptable salt is a maleate.

Suitable pharmaceutically acceptable solvated forms of Compound (1) include those described in EP 0306228 and WO94/05639, in particular hydrates.

Compound (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, may be prepared using know, methods, for example those disclosed in EP 0306228 and WO94/05659. The disclosures of EP 0306228 and WO94/05659 are incorporated herein by tefcrence.

Compound (I) may exist in one of several tautomeric forms, all of which are encompassed by the term ‘Compound (I)’ as indiv^; dual tautomeric forms or as mixtures thereof.

Compound (I) contains a chiral carbon atom, 8 td 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 nvxtures 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 mellinis.

When used herein the term 'conditions associated with the pre-diabetic state' includes conditions such as insulin resistance, including hereditary insulin resistance, impaired ;.iucosc tolerance and hyperinsulinaemia.

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ο '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 disea.se, 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 mads 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 sc: For example 2 mg of Compound (I) in the form of the ;;, a:eat; salt is that amount cf 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 preoaring 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 (Γ; in a pharmaceutically acceptable form and the pharmaceutically acceptable carrier and optionally thereafter formulating the composition produced into an administerable form.

As indicated above the invention also provides a further process lor preparing a pharmaceutical composition comprising Compound (I) in a , ·οΐίθ8ΐίν accep-ab’e 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 tbe 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.

Λ 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 os 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 (Γ> 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 tbe composition is a pharmaceutically acceptable, pre-administration composition.

A suitable pharmaceutically acceptable, pre-administration composition is a concentrate, preferably a granular concentrate, of Compound (1) 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 (1) in a pharmaceutically acceptable form and a pharmaceutically acceptable carrier, characterised in ihat the composition is a concentrate of Compound (ij in a pharmaceutically acceptable form, adapted to be diluted sc as io 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 oralf or parenterally adminsterable forms. They are particularly well adapted for preparing orally administrable forms, especially tablet forms of Compound (I) in a pharmaceutically acceptable form.

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. How'ever, 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 fi ~Z ;o, ’pmf.ou co/./,,//.· m Co../,· /..· ,2; % c phannaceutically acceptable form, a disintegrant, a binder and a diluent.

A suitable ifisjntegrant is sodium starch glycoilate.

Λ suitable bidder is a metuyl cellulose binder, such as hydroxynropyl methylcellulose 2910.

Suitable diluents include cellulose, for example a microcrystaliine 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 glycoilate, hydroxypropyi methylcellulose 2910, microcrystalline cellulose and lactose o

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©i id» monohydrate, especially when in a granular form. This granular form has been found io be particularly stable.

When dte first composition contains about 10% by weight of Compound (it in a pharmaceutically acceptable form, it is readily dilutable to give unis aose compositions comprising in the range of between 2 to 12 mg , especially 1 ίο 8 mg, 2 to 4mg, 4 to 8 mg and 8 to 12 mg of Compound (Ij in a phannaceutically acceptable form.

The preparation of the first composition is suitably carried using any conventional method appropriate le the nature of die said first composition, tor example wet granulation methods provide the first composition in granular form.

Methods for formulating the compositions of the invention into admini storable 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 transriermal administration.

The administerable compositions may be in the fonn of tablets, capsuies, 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, sucar, maize-starch, calcium phosphate, sorbitol o'glycine; tabletting lubricants, for example magnesium stearate: disintegrauts, Ik examp-e starch, polyvinylpyrrolidone, sodium starch glycollate or nucrocrystallms cellulose; or pharmaceutically acceptable wetting agent;; .such as sodium lauryl sulphate.

Unless otliervvi.se prescribed, compositions of the invention a:c preferably in unit dosage form in. an amount appropriate for the rclevan·. . dosage, suitable unit dosages comprise 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or ’ : m. of Compound (1) in a pharmaceutically acceptable form.

The solid compositions for example the oral compositions ma v 1 >·' prepared by conventional methods of blending, filling or table; ting , ,i _vrepeated blending operations may be used to distribute the acti e eem h · ' those compositions employing large quantities of fillers. Such op_v* Tira e course conventional in the art. The tablets may be coated accor ho ’ * > ,i €£>

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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 lOrm ·. . emulsion?, syrups, cr wixu's, ortney may ,?e in a Ay rmduct 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 almcnd oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hvdroxybenzoate 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 ayeef on u?d four sunnzsd before tilling into a suitable vhn -.:: 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 lo ethylene oxide before suroendfoy fo ihe sicrhe vehicle. Advantage.'⁵ ciy, a surfactant or wetting agent L suets ,wv in ibs OeHb'efoion W foUlfo'*; Wfo^;w' % W ~fowfo’'. of the tce'.pw rfo.

Unless otherwise specified the compositions of the invention mav contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of tbe act:,: material, depending upon tne method of administration.

The composition Iffoesurd, he in the form of a pack accomwehed 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 Cosmeticcmtiv (Leonard Hill Books).

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The present invention also provides a pharmaceutical composition comprising 2 to 12 mg of Compound (!) 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 12 mg of Compound (I) in a pharmaceutically acceptable form, for use in the treatment of diabetes mellitus, especially h yps II diabetes, and conditions associated with diabetes melhtus..

The composition of the invention may be administered from 1 ίο ό 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 melhtus, 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 12 mg of Compound ti) in a pharmaceutically acceptable form.

Particular dosages are 2mg/day, 4mg/day, including 2mg twice per day, and 8 mg/day, including 4rng 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 8rng of Compound (I) in a pharmaceutically acceptable fei.

Particularly, the method comprises the administration of 8 to 12 mg of Compound (I) in a pharmaceutically acceptable form.

Preferably, the method comprises the administration of 2 mg of Compound (1) in a pharmaceutically acceptable form.

Preferably, the method comprises the administration of 4 mg of Compound (I) in a pharmaceutical Iv acceptable form.

Preferably, the method comprises the administration of 8 mg oi' Compound (i) in a pharmaceutically acceptable fonn.

A range of 2 to 4mg includes a range of 2.1 to 4, 2.2 to 4, 2.3 io 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.

Λ range of 4 to 8rng includes a range of 4.1 to 8, 4.2 to 8, 4.3 to S, 4.4 to 8, 4.5 to 8, 4.6 to 8, 4.7 to 8, 4.8 to 8, 4.9 to 8, 5 to 8, 6 to 8 or 7 to 8mg.

Λ 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 i 2mg.

No adverse toxicological effects have been established for the compositions or methods of the invention in the above mentioned 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 (1).

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.

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Ingredient	Quantity (%)
Milled Compound (I) as maleate salt	13.25 (pure maleate salt)
Sodium Starch Glycollate	5.00
Hydoxypropyl Methylcellulose 2910	5.00
Microcrystalline Cellulose	20.0
Lactose Monohydrate, regular grade	to 100
Purified water	*

* Removed during processing.

Example 2: Formulation of Είο concentrate into tablets.

The granules from Example 1 are placed into a tumble blender. Approximately t wo 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 4rng tablets and to a target weight of 300mg for the 8mg tablets.

The tablet cores are then transferred to a tablet coating machine, pre-wanned with warm air (approximately 65°C) and film coated until the tablet v,'eight has increased by 2.0% to 3.5%.

Quantity (mg per Tablet)
Tablet Strcisgth	1.3 mg	«.Omg 4.'Lay	S.Ontg
Active Ingredient:
Compound (I) maleate Concentrate granules	10.00	20.00	40.00	80.00
Other Ingredients:
Sodium Starch Glycollate	6.96	6.46	5.46	10.92
M icrocryst a 11 ine Cellu lose	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	> .50
Total Weight of Tablet Core	150.0	1 50.0	150,0	300.0
Aqueous film coating material	4.5	4.5	4.5	9.0
Total Weight of Film Coated Tablet	154.5	154.5	154.5	2 09.0

Claims

Claims:

1. A pharmaceutical composition comprising 5-[4-[2-(N-methyl-N-(2pyridy!)aminc4ethoxy]benzyl]thiazolidine· 2,4-dione (hereinafter ‘Compound (I)'), characterised in that the composition comprises 2 to 12 mg of Compound (1) in a pharmaceutically acceptable form and optionally a pharmaceutically acceptable carrier therefor.
2. A composition according to claim 1. which comprises 2 to 4mg of Compound (I) in a pharmaceutically acceptable form.
3. Λ composition according to claim 1, which comprises 4 to 8mg of Compound (I) in a pharmaceutically acceptable form.
4. A composition according to claim 1, which comprises 8 to 12 ing of Compound (I) in a pharmaceutically acceptable form.
5. A composition according to claim 1, which comprises 2 mg of Compound (I) in a phermaceufen'iy acceptable form.
6. A composition according to claim 1, which comprises 4 mg of Compound (I) in a pharmaceutically acceptable form.
7. A composition according to Haim 1, which comprises 8 mg of Compound (I) in a pharmaceutic::!:y aecemat’s form.

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8. A composition according to any one of claims 1 to 7, which comprises the maleate s-rit of Compound (· )
9. A process for preparing a pharmaceutical composition comprising 2 to 12 mg of Compound (I) in a phar raceutically acceptable form, and a pharmaceutically acceptable carrier therefor, which process comprises admixing 2 tc 12 mg of Compound (ί) in a pharmaceutically acceptable form and the pharmaceutically acceptable carrier.

Η) 1 I Ή i 0. A process for preparing a pharmaceutical composition of Compound (I) in a pharmaceutically acceptable foun and a pharmaceutically acceptable earner, 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 .
11. A process according to claim 9 or claim 10, wherein the composition prepared is in unit dosage fonn.
12. A process according to claim 9 or claim 10, wherein the composition prepared is a tablet.
13. A composition for use as a first composition in a process according to claim 10, for preparing a unit dose of Compound (I) in a pharmaceutically acceptable form.
14. \ - ··-, 'Arion 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.
15. A pre-administration composition according to claim 13, which is a concentrate of Compound (I) in a pharmaceutically acceptable form.

’ ti. A composition comprising Compound (1) 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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17. A composition according to any one of claims 13 to 16, which contains up to 50% by weight of Compound (I) in a pharmaceutically acceptable form.
18. A composition according to any one of claims 13 to 17, which contains an amount of Compound (I) in a pharmaceutically acceptable form in the range of from 5 to 20% by weight.
19. A composition according to any one of claims 13 to 18, which contains

5%, 10% or 15% by weight of Compound (I) in a pharmaceutically acceptable form.
20. A composition according to any one of claims 13 to 19, which contains

Compound (I) in a pharmaceutically acceptable form, sodium starch glycollate, hydroxypropyl methylcellulose 2910, microcrystaliine cellulose and lactose monohydrate.
21. A composition according to any one of claims 13 to 20, in granular form