HK1083452B - Pharmaceutical compositions - Google Patents

Description

Pharmaceutical composition

The present invention relates to solid oral dosage forms comprising valsartan.

It is known that the angiotensin II receptor antagonist valsartan is effective in the treatment of congestive heart failure and in lowering blood pressure irrespective of age, sex or race and is well tolerated. It is also known to treat hypertension in combination with HCTZ.

Compressed solid oral dosage forms obtained by compressing valsartan, optionally in salt form, for example with or without Hydrochlorothiazide (HCTZ), the content of which, in particular but not exclusively, the claimed subject matter, is disclosed in WO 97/49394, the content of which is incorporated herein by reference.

It has now surprisingly been found that it is possible to prepare solid formulations (hereinafter "compositions of the invention") of valsartan or a pharmaceutically acceptable salt thereof or a hydrate thereof (hereinafter "active agent") having improved bioavailability characteristics when compared to known valsartan formulations.

In a first aspect the present invention relates to an oral solid pharmaceutical composition, e.g. in the form of a tablet, comprising a pharmacologically effective amount ofValsartan, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and at least one pharmaceutically acceptable excipient, and is encapsulated with valsartan, for example as a capsuleCommercially available capsules, e.g. containing 20, 40, 80 or 160mg of valsartan, or any corresponding capsule containing a unit dose of 1 to 500mg of valsartan, have on average at least a 1.2-fold, e.g. 1.2 to 3-fold, e.g. 1.3 to 2-fold, e.g. 1.7-fold higher bioavailability.

The present invention relates in one embodiment to an oral solid pharmaceutical composition, e.g. in the form of a tablet, comprising a pharmacologically effective amount of valsartan or a pharmaceutically acceptable salt thereof or hydrate thereof and at least one pharmaceutically acceptable excipient and which, when administered at a dose of 40mg in a single dose human bioavailability study, has an average bioavailability that is at least higher than that of a valsartan capsule (e.g. as a tabletCommercially available capsules containing e.g. 20, 40, 80 or 160mg of valsartan or any corresponding capsules containing a unit dose of 1 to 500mg of valsartan) are 1.5 times, e.g. up to 3 times, e.g. 2.5 times more bioavailable.

The invention particularly relates to an oral solid pharmaceutical composition, e.g. in the form of a tablet, comprising a pharmacologically effective amount of valsartan or a pharmaceutically acceptable salt thereof or hydrate thereof and at least one pharmaceutically acceptable excipient and which, when administered in a single dose human bioavailability study at a dose of 320mg, has an average bioavailability at least higher than that of a valsartan capsule (e.g. as a valsartan capsule)Commercially available capsules containing e.g. 20, 40, 80 or 160mg of valsartan or any corresponding capsules containing a unit dose of 1 to 500mg of valsartan) are 1.2 times, e.g. up to 2 times, e.g. 1.5 times more bioavailable.

In another aspect the present invention relates to an oral solid pharmaceutical composition, e.g. in the form of a tablet, comprising a pharmacologically effective amount of valsartan or a pharmaceutically acceptable salt thereof or hydrate thereof and at least one pharmaceutically acceptable excipient and which has an AUC higher than 4.5h.mg/l, e.g. up to 8h.mg/l, e.g. 6h.mg/l under the same conditions as a 40mg capsule has an AUC of 3.9 h.mg/l. The AUC values described in this application are least squares means, if not otherwise stated.

In another aspect the present invention relates to an oral solid pharmaceutical composition, e.g. in the form of a tablet, comprising a pharmacologically effective amount of valsartan or a pharmaceutically acceptable salt thereof or hydrate thereof and at least one pharmaceutically acceptable excipient and which has an AUC higher than 30h.mg/l, e.g. up to 40h.mg/l, e.g. 35h.mg/l under the same conditions as 320mg capsules have an AUC of 29.4 h.mg/l.

In another aspect the present invention relates to an oral solid pharmaceutical composition, e.g. in the form of a tablet, comprising a pharmacologically effective amount of valsartan or a pharmaceutically acceptable salt thereof or hydrate thereof and at least one pharmaceutically acceptable excipient and having a Cmax of at least about 0.77mg/l, e.g. up to 3.5mg/l, e.g. 1.3mg/l, when administered at a dose of 40mg in a single dose human bioavailability study.

In another aspect the present invention relates to an oral solid pharmaceutical composition, e.g. in the form of a tablet, comprising a pharmacologically effective amount of valsartan or a pharmaceutically acceptable salt thereof or hydrate thereof and at least one pharmaceutically acceptable excipient and having a Cmax of at least about 4.75mg/l, e.g. up to 15mg/l, e.g. 6mg/l, when administered at a dose of 320mg in a single dose human bioavailability study.

The compositions of the invention may comprise from 1 to 500mg, such as from 2 to 400mg, such as from 5 to 300mg, such as from 10 to 200mg, such as from 20 to 200mg, such as from 30 to 100mg of active agent in a unit dose. Examples of dosages are 10, 20, 40, 80, 160 or 320 mg.

In addition to the above advantages, the improved bioavailability also allows the preparation of low dose solid oral dosage forms of the active agent that are better tolerated by patients. The invention thus relates in another aspect to an oral solid pharmaceutical composition of valsartan or a pharmaceutically acceptable salt thereof or hydrate thereof, e.g. in the form of a tablet, comprising less than 20mg, e.g. 1 to 15mg, e.g. 1, 5 or 10mg or any other intermediate dose of the active agent. The solid oral dosage form (e.g., tablet) may be smaller than any known formulation of such an active agent for a given amount of active agent.

In the first set of compositions, example 2 was not included. In the second group of compositions, example 3 was not included.

In another aspect the present invention relates to an oral solid pharmaceutical, e.g. in the form of a tablet, of valsartan or a pharmaceutically acceptable salt thereof or hydrate thereof comprising 10 to 80%, e.g. 20 to 80%, e.g. 25 to 75%, e.g. 30 to 70%, e.g. 35 to 65%, e.g. 40 to 60%, e.g. 50% of disintegrant based on the total weight of the composition.

In another aspect the invention relates to an oral solid medicament, e.g. in the form of a tablet, in which the weight ratio of valsartan or a pharmaceutically acceptable salt thereof or hydrate thereof to disintegrant is e.g. 10: 1 to 0.5: 1, e.g. 9.5: 1, e.g. 8: 1, e.g. 5: 1 to 0.5: 1, e.g. 5: 1 to 1: 1, e.g. 2.9: 1 to 1: 1, e.g. 2.5 to 1: 1, e.g. 2 to 1: 1, e.g. 1.5: 1.

In a preferred embodiment, the composition of the invention comprises more than 30% by weight of filler, such as microcrystalline cellulose, based on the total weight of the core ingredients of the solid oral dosage form, e.g. 31 to 65%, such as 40 to 60%, such as 50%.

Preferably in the compositions of the present invention, the active agent and the filler are present in a weight ratio of from 4: 1 to 0.3: 1, such as from 3: 1 to 0.3: 1, such as from 2.5: 1 to 0.5: 1, such as from 2: 1 to 1: 1, such as 1.4: 1.

The composition of the invention may be in the form of a tablet, for example a compressed tablet, which may be obtained by the preparation process disclosed below.

The compositions of the present invention include additives typically found in such dosage forms. Tableting aids commonly used for the preparation of tablets may be used and reference is made to a number of documents for this subject matter, see in particular "Lexikon der Hilffsstoffe" by Fiedler, 4 th edition, ECV Aulendorf, 1996, the contents of which are incorporated herein by reference. These include, but are not limited to, disintegrants, binders, lubricants, glidants, stabilizers, fillers or diluents, surfactants, and the like.

As disintegrants suitable for the compositions of the invention, mention may in particular be made of:

-calcium carboxymethylcellulose (CMC-Ca);

sodium carboxymethylcellulose (CMC-Na, croscarmellose sodium), e.g. sodium carboxymethylcelluloseXL、AndZSX, for example those having a molecular weight of 90000-;

crospovidone (PVP), e.g. crospovidone, e.g.XL andCL, in particular those having a molecular weight of more than 1000000, more in particular having a particle size distribution of less than 400 microns or less than 74 microns;

alginic acid, sodium alginate and guar gum.

Preferably, the disintegrant may be crosslinked PVP, crospovidone, crosslinked CMC andthe most preferred disintegrant is crospovidone.

As binders suitable for the composition of the invention, mention may be made in particular of:

starches, such as potato starch, wheat starch, corn starch;

cellulose, such as microcrystalline cellulose, for example under the registered trade markOrHydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropylmethyl cellulose, for example hydroxypropyl cellulose having a hydroxypropyl content of from 5 to 16% by weight and a molecular weight of from 80000 to 1150000, in particular from 140000 to 850000.

As glidants suitable for the composition of the invention, mention may be made in particular of:

colloidal silica, e.g.

-magnesium trisilicate;

-powdered cellulose;

-a starch;

-talc; and

-calcium orthophosphate.

As fillers or diluents suitable for the composition of the invention, mention may be made of:

-refined granulated sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, sorbitol, sucrose;

microcrystalline cellulose, in particular having a density of about 0.45g/cm³Dense microcrystalline cellulose, e.g.Or powdered cellulose; and

-talc.

Preferred fillers may be

As lubricants suitable for the composition of the invention, mention may be made in particular of:

-magnesium, aluminium or calcium stearate;

-polyethylene glycol (PEG) having a molecular weight of 4000 to 8000; and

-talc.

One skilled in the art can select and use one or more of these additives based on the specific desired characteristics of the solid oral dosage form by routine experimentation and without undue effort.

The amount of each type of additive used (e.g., glidant, binder, disintegrant, filler or diluent, and lubricant) may vary within ranges commonly used in the art. Thus, for example, the amount of glidant may vary from 0.1 to 10% by weight, in particular from 0.1 to 5% by weight, for example from 0.1 to 0.5% by weight; the amount of binder may vary from about 10 to 65.3% by weight, such as 10 to 45%, such as 20 to 30% by weight; the amount of disintegrant may vary from 5 to 60% by weight, such as 13 to 50%, such as 15 to 40%, such as 20 to 30%, such as 25%; the amount of filler or diluent may vary from 15 to 65% by weight, such as 20 to 50%, such as 25 to 40%, such as 30%; while the amount of lubricant may vary from 0.1 to 5.0% by weight.

Solid oral dosage forms of the invention, e.g. tablets, are characterized in that they may contain only relatively small amounts of additives at high levels of active agent. This enables the production of physically small unit dosage forms. The total amount of additives in a given unit dose may be about 65% or less than 65%, especially about 50% or less than 50% of the total weight of the solid oral dosage form. Preferably, the additive is present in an amount in the range of from about 35 to 55% by weight, especially 45 to 55% by weight, for example 38 to 43% by weight.

Similarly, the absolute amounts of each additive and the relative amounts with other additives depend on the desired properties of the solid oral dosage form and can also be selected by the skilled person by routine experimentation without undue effort. For example, the solid oral dosage form may be selected to exhibit accelerated and/or delayed release of the active agent with or without quantitative control of the release of the active agent.

Thus, if an accelerated release is desired, for example a release of about 90% within 10 minutes, more particularly a release of about 90% within a period of 5 minutes, a disintegrant, such as crosslinked polyvinylpyrrolidone, for example of the registered trade markXL orThose products of CL, in particular those having a molecular weight of more than 1000000, more in particular those having a particle size distribution of less than 400 microns or less than 74 microns; or reactive additives (effervescent mixtures) which bring about rapid disintegration of the tablets in the presence of water, e.g. so-called effervescent tablets containing the acid in solid formTypically citric acid, which reacts in water with a base containing chemically bound carbon dioxide, such as sodium bicarbonate or sodium carbonate, and releases the carbon dioxide.

The pharmaceutical compositions of the invention may be used for known indications of this particular active agent contained therein, including lowering blood pressure, i.e. systolic or diastolic blood pressure or both. Diseases to which the present invention is applicable include, but are not limited to, hypertension (whether malignant, essential, renovascular, diabetic, isolated systolic, or other secondary), congestive heart failure, angina (whether stable or unstable), myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction (such as alzheimer's disease), and stroke.

The exact amount of active agent and the particular formulation to be administered depends on a number of factors, such as the condition to be treated, the desired duration of treatment, and the release rate of the active agent. The amount of active agent required and its release rate can be determined, for example, based on in vitro or in vivo techniques to determine how long the plasma concentration of a particular active agent remains at an acceptable level for therapeutic effect.

For example, the compositions of the present invention are more commercially available in clinical trialsHas higher bioavailability.

Preferably, the drug release rate of the composition of the invention is 70% or more within 10 minutes, 80% or more within 30 minutes, such as 90% or more, and 95% or more within 45 minutes, for example at pH 4 to 7.2, for example at pH 4.5 to 7, for example at pH 6.8.

For example, for a 75 kg mammal, such as a human, and in standard animal models, a dose ranging from 1mg to 400mg of valsartan per day may be used. The excellent tolerance to valsartan provided by the compositions of the present invention can be observed in standard animal tests and clinical trials.

In another aspect, the present invention relates to a method of administering valsartan to a patient in need of valsartan treatment comprising administering to said patient a composition of the present invention.

In another aspect, the present invention relates to the use of valsartan as an active agent in the preparation of any of the compositions as described above.

In another of its aspects, the present invention provides a process for the preparation of a solid oral dosage form, e.g. a tablet, as described above. Such solid oral dosage forms may be produced by formulating appropriate amounts of the ingredients, as described in WO 97/49394 (incorporated herein by reference), for example the ingredients as described above, into unit dosage forms.

For example, the present invention provides a process for the preparation of a composition of the invention as described above, comprising the steps of:

i) comminuting the active agent and pharmaceutically acceptable additives;

ii) compressing the mixture of comminuted active agent and additive into a compacted mass (coprimate);

iii) converting said compressed mass into granules; and

iv) compressing said granules into said solid oral dosage form.

The process is carried out in the absence of water, i.e. it is a dry tabletting process. The process may be carried out under ambient temperature and humidity conditions; it is not necessary to ensure that the process is carried out in a dry environment.

The initial comminution step i) can be carried out according to conventional grinding methods or micronization methods.

The active agent and additive, alone or in combination, can be milled to a particle size of about 0.1 microns (μ) to about 1500 μ, e.g., 1.0 μ to 900 μ, e.g., 60 μ to 600 μ. At least 90% of the crystals of active agent and additive should be within these ranges. Particles of this size can be obtained by conventional methods, for example grinding in air jet mills, hammer and screen mills, ultrafine impact mills, ball mills or vibration mills.

The micronization is preferably carried out by stirring the suspension by a known method using an ultrasonic pulverizer such as a BRANSON Sonifier type or using a high-speed stirrer such as a HOMOREX type stirrer.

The comminuted granules may optionally be sieved and mixed at this stage according to known methods.

Pressing into a compacted mass requires compacting the dried comminuted ingredients. The extrusion can be carried out using a heavy pressing technique or preferably a roller pressing method. Rolling devices are common and essentially use two rollers that roll against each other. The hydraulic press forces the two rollers toward each other to exert a compressive force on the comminuted particles loaded into the roller press by the screw conveyor system.

A compressive force of 25 to 65kN, for example 25 to 45kN, may be used. Within this range of compaction forces it has surprisingly been found that for each particular formulation a minimum compaction force should be used in order to obtain a solid oral dosage form in which the particles will disintegrate into discrete primary particles at the desired rate, for example disintegration occurs at a rate of about 6 times faster for a solid oral dosage form compressed above the minimum compaction force. This rapid disintegration rate is rare for tablets and is similar to the disintegration rate of capsule formulations. The specific minimum compaction force depends on the active agent content in any given formulation and thus also on the amount and nature of the additives present.

With this information, it will be apparent to those skilled in the art that the minimum compaction force for other formulations can be determined using routine experimentation without undue effort.

The drum speed may be set between 1 and 20rpm and preferably between 9 and 15 rpm. After passing through the rollers, the compression blocks resemble lengths of thin ribbon.

The compacted mass may be sieved and/or milled to produce granules. The simplest way of sieving involves passing the compacted cake pressed out by the drum through a sieve under mechanical pressure. More preferably, the compressed mass is sieved using an oscillating or rotary mill such as MGI 624Frewitt (Key International Inc.).

The granules can be compressed into tablet cores, for example, with a compression force of more than 2kN in a conventional tablet press, for example, an EK-0Korsch eccentric tablet press or a rotary tablet press. The tablet cores may be of different shapes and may be, for example, circular, oval, rectangular, cylindrical or any other suitable shape, and may also vary in size depending on the concentration of the therapeutic agent. One of the characteristics of the tablets of the invention is their small size with respect to the amount of active agent contained therein.

In a preferred embodiment of the invention, the tablets obtained by the above-described tabletting method are slightly oval in transverse and/or longitudinal section. The edges of the tablet may be bevelled or rounded.

In a particularly preferred embodiment of the invention, a solid oral dosage form is compressed in the form of a tablet having a rectangular shape, wherein the ratio of the dimensions length: width: thickness is, for example, 2.5-5.0: 0.9-2.0: 1.0, for example 2.86-3.16: 1.1-1.3: 1.0, for example 14.0-14.2 mm: 5.5-5.7 mm: 4.5-4.9mm, and preferably the lower and upper surfaces of the tablet are, independently of one another, planar or convexly curved around the longitudinal axis; the sides are planar, the end faces can be of any shape and the edges can optionally be beveled or rounded.

In a particularly preferred embodiment of the invention, the granules are compressed into a solid oral dosage form in the form of a tablet, for example a tablet containing 40mg or 80mg of valsartan, which is essentially disc-shaped with slightly convex upper and lower surfaces. Preferably the tablet has a diameter of about 6 to 6.5mm and a thickness of about 2.5 to 3.5mm, or a diameter of about 8 to 8.5mm and a thickness of about 3 to 4 mm.

In another particularly preferred embodiment of the invention, the granules are compressed into a solid oral dosage form in the form of a rectangular tablet, for example a tablet containing 160mg of valsartan, wherein the length is about 10.0 to 15.0mm, the width is about 5.0 to 6.0mm and the thickness is about 3 to 6mm, for example 3.0 to 4.0 mm.

In another particularly preferred embodiment of the invention, the granules are compressed into a solid oral dosage form in the form of an almond-shaped tablet, for example a tablet containing 80, 160 or 320mg of valsartan, wherein the length is about 9 to 11mm, the width is about 5 to 6.5mm at its widest point and the thickness is about 3 to 4mm, or wherein the length is about 12 to 14mm, the width is about 7 to 8mm at its widest point and the thickness is about 4 to 5mm, or wherein the length is about 15 to 17mm, the width is about 9 to 10mm at its widest point and the thickness is about 5 to 6.5 mm.

In another particularly preferred embodiment of the invention, the granules are compressed into a solid oral dosage form in the form of an almond-shaped tablet, for example a tablet containing 320mg of valsartan wherein the length is about 15 to 17mm, the width is about 9 to 10mm at its widest point and the thickness is about 5 to 7 mm.

Yet another preferred embodiment of the present invention provides a tablet which is slightly convex on the upper and lower surfaces and is substantially disc-shaped. Preferably the tablet has a diameter of about 8 to 8.5mm and a thickness of about 3 to 3.5mm, or a diameter of about 16mm and a thickness of about 6 mm. The tablet may occupy a volume of about 0.1cm³To about 1cm³E.g. 0.1cm³To about 0.45cm³E.g. 0.2 to 0.3cm³E.g. about 0.125cm³Or 0.25cm³。

They may also be transparent, colourless or coloured and they may also be marked in order to give the product a unique appearance and make it instantly recognizable. The use of dyes can enhance the appearance and identify the composition. Dyes suitable for pharmaceutical use typically include carotenoids, iron oxides or chlorophyll.

Drawings

FIG. 1 is a graph of the mean concentration time for 40mg tablets and 40mg capsules.

FIG. 2 is a graph of mean concentration time for 320mg tablets and 2X 160mg capsules.

The compositions of the present invention are described below by way of example only.

Examples 1 to 4:

	1	2	3	4
					composition (I)	composition/Unit (mg)	composition/Unit (mg)	composition/Unit (mg)	composition/Unit (mg)
Granulating
					Diovan medicinal material	20.0	40.0	80.0	320.0
Hydrochlorothiazide medicinal material		---		---
					Microcrystalline cellulose (NF, Ph. Eur.)/Avicel PH 102	62.0	124.0	54.0	216.0
Crospovidone (NF, Ph. Eur.)	10.0	20.0	20.0	80.0
					Colloidal anhydrous silica (Ph. Eur.)/colloidal silica (NF)/Aerosil 200	0.5	1.0	0.75	3.0
Magnesium stearate (NF, Ph. Eur.)	1.0	2.0	2.5	10.0
					Mixing
Colloidal anhydrous silica (Ph. Eur.)/colloidal silica (NF)/Aerosil 200	0.5	1.0	0.75	3.0
					Magnesium stearate, NF, ph.	1.0	2.0	2.0	8.0
Medicine core/batch weight	95.0/47.5kg	190.0/47.5kg	160.0/48.0kg	640.0/73.5kg

Example 5:

table 1 (see figure 1) summary analysis of least squares means of valsartan pharmacokinetic parameters (all subjects completed with evaluable parameters for both treatments)

N represents the number of observations including repeat dosing.

^aThe least squares means are represented as raw (anti-log) values.

^bThe ratio of the original means is estimated by the inverse logarithm of the log difference of the least squares means.

^cThe confidence interval for the tablet to capsule ratio on the original order of magnitude was obtained by calculating the inverse logarithm of the confidence limit for the log difference of the least squares means of the two treatments.

Commercial 40mg DiovanAnd (3) capsule preparation:

internal phase: 40.0mg of valsartan; microcrystalline cellulose/Avicel PH 102: 12.55 mg; polyvinylpyrrolidone K30: 6.25 mg; sodium lauryl sulfate: 0.3 mg;

external phase: cross-linked povidone: 6.5 mg; magnesium stearate: 0.65mg

Total weight: 66.25 mg; capsule size: no. 3

Example 6:

table 2 (see figure 2) summary analysis of least squares means of valsartan pharmacokinetic parameters (all subjects completed with evaluable parameters for both treatments)

N represents the number of observations including repeat dosing.

^aThe least squares means are represented as raw (anti-log) values.

^bThe ratio of the original means is estimated by the inverse logarithm of the log difference of the least squares means.

^cThe confidence interval for the tablet to capsule ratio on the original order of magnitude was obtained by calculating the inverse logarithm of the confidence limit for the log difference of the least squares means of the two treatments.

Commercial 160mg DiovanAnd (3) capsule preparation:

internal phase: valsartan 160.0 mg; microcrystalline cellulose/Avicel PH 102: 50.2 mg; polyvinylpyrrolidone K30: 125.0 mg; sodium lauryl sulfate: 1.2 mg;

external phase: cross-linked povidone: 26.0 mg; magnesium stearate: 2.6mg

Total weight: 265.0 mg; capsule size: number 1

Example 7:

TABLE-pharmacokinetic parameters of the 40mg tablet and 40mg capsule formulations (commercially available)

Example 8:

TABLE 4320 mg tablet and 2X 160mg Capsule formulations (commercially available) pharmacokinetic parameters are summarized

Claims (20)

1. An oral solid pharmaceutical composition comprising valsartan or a pharmaceutically acceptable salt thereof or a hydrate thereof, crospovidone as a disintegrant and a filler, wherein the weight ratio of valsartan or a pharmaceutically acceptable salt thereof or a hydrate thereof to crospovidone is from 2.9: 1 to 1: 1 and the weight ratio of valsartan to filler in the composition is from 1.4: 1 to 0.3: 1.

2. A composition according to claim 1, wherein the weight ratio of valsartan to filler is 1.4: 1.

3. The composition of claim 1, wherein the composition comprises greater than 30% by weight of the filler, based on the total weight of the core ingredients of the composition.

4. The composition of claim 3, wherein the composition comprises from 31 wt% to 65 wt% of the filler, based on the total weight of the core ingredients of the composition.

5. The composition of claim 1, wherein the composition comprises from 40 wt% to 60 wt% of the filler, based on the total weight of the core ingredients of the composition.

6. The composition of claim 1 wherein the filler is microcrystalline cellulose.

7. The composition of claim 1, additionally comprising an adjuvant selected from the group consisting of binders, glidants, and lubricants.

8. The composition of claim 7, wherein the binder is present in an amount of 10 wt% to 65.3 wt%, the glidant is present in an amount of 0.1 wt% to 10 wt%, and the lubricant is present in an amount of 0.1 wt% to 5.0 wt%.

9. The composition of any one of claims 1 to 8, which is in the form of a tablet.

10. The composition of claim 9, wherein the tablet is almond-shaped, wherein the length is 9 to 11mm, the width is 5m to 6.5mm at its widest point and the thickness is 3 to 4mm, or wherein the length is 12 to 14mm, the width is 7m to 8mm at its widest point and the thickness is 4 to 5mm, or wherein the length is 15 to 17mm, the width is 9m to 10mm at its widest point and the thickness is 5 to 6.5 mm.

11. A composition according to claim 9, wherein the active ingredient is a pharmaceutically acceptable salt of valsartan or a hydrate thereof.

12. The composition of claim 9, wherein its bioavailability is on average at least 1.2 times higher compared to valsartan capsules.

13. The composition of claim 9 which, when administered at a dose of 40mg in a single dose human bioavailability study, has an average bioavailability that is at least 1.5 times higher compared to valsartan capsules.

14. The composition of claim 9 which, when administered at a dose of 320mg in a single dose human bioavailability study, has an average bioavailability that is at least 1.2 times higher compared to valsartan capsules.

15. The composition of claim 9 which has an AUC higher than 4.5h.mg/l under the same conditions as a 40mg capsule has an AUC of 3.9 h.mg/l.

16. The composition of claim 9 which has an AUC higher than 30h.mg/l under the same conditions as a 320mg capsule has an AUC of 29.4 h.mg/l.

17. The composition of claim 9 having a Cmax of at least 0.77mg/l when administered at a 40mg dose in a single dose human bioavailability study.

18. The composition of claim 9 having a Cmax of at least 4.75mg/l when administered as a 320mg dose in a single dose human bioavailability study.

19. Use of a composition according to claim 9 in the manufacture of a medicament for the treatment of: malignant hypertension, essential hypertension, renovascular hypertension, diabetic hypertension, isolated systolic hypertension and other forms of hypertension secondary to hypertension; congestive heart failure; stable or unstable angina; myocardial infarction; atherosclerosis; diabetic nephropathy; diabetic cardiomyopathy; renal insufficiency; peripheral vascular disease; left ventricular hypertrophy; cognitive dysfunction and stroke.

20. The use according to claim 19, wherein the cognitive dysfunction is alzheimer's disease.