AU2003255176B2 - Use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors for the manufacture of a medicament for the treatment of diabetic neuropathy - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANTS: AstraZeneca AB AND The University Court of the University of Aberdeen ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.

INVENTION TITLE: "Use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors for the manufacture of a medicament for the treatment of diabetic neuropathy" The following statement is a full description of this invention, including the best method of performing. it known-to us: Q:\OPER\MAL\DIVISIONAL\12359940 288.DOC 16/10/03 -1- USE OF 3-HYDROXY-3-METHYLGLUTARYL COENZYME A REDUCTASE INHIBITORS FOR THE MANUFACTURE OF A MEDICAMENT FOR THE TREATMENT OF DIABETIC NEUROPATHY This is a divisional of Australian patent application No. 763970 (23047/00), the entire contents of which are incorporated herein by reference.

The present invention relates to a new use of a statin drug in the improvement of diabetic neuropathy, specifically in improving nerve conduction velocity and nerve blood flow in patients suffering diabetes, in particular to pharmaceutical combinations of the statin drug and other agents known to improve diabetic neuropathy such as an aldose reductase inhibitor (ARI), an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II (AII) antagonist which combinations are useful in the prevention and treatment of the complications of diabetes.

3-Hydroxy-3-methylglutaryl Coenzyme A (HMG Co A) reductase inhibitors effectively inhibit cholesterol synthesis in the liver through stimulation of the low density lipoprotein (LDL) receptors. These drugs are currently.pre-eminent in.the treatmentiof hypercholesterolaemia, except the relatively rarely occurring homozygous familial .hypercholesterolaemia. Therapy with HMG Co A-reductase inhibitors may result in regression of atherosclerotic vascular lesions and several HMG Co A-reductase inhibitors have proven to reduce mortality... Various HMG Co A-reductase inhibitors are-marketed, and are collectively referred to as 'statins'.

We have discovered that statin drugs, in particular (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- (3R,5S)-3,5-dihydroxyhept-6-enoic acid or a pharmaceutically acceptable salt thereof (the AGENT), the calcium salt of which is shown in Fig. 1 below, and atorvastatin produce an improvement in the nerve conduction velocity (NCV) and nerve blood flow in an animal model of diabetic neuropathy. Therefore, statin drugs may be used to improve diabetic neuropathy, whether in type I or type II diabetes.

Therefore we present as a first feature of the invention a method for treating neuropathy in a patient suffering from diabetes comprising administering to the patient a statin drug.

As a preferred feature of the invention we present a method for improving nerve conduction velocity and /or nerve blood flow in a patient suffering diabetic neuropathy comprising administering to the patient a statin drug.

Further features of the invention include use of a statin drug in the preparation of a medicament for use in the treatment of any of the conditions mentioned above.

Examples of statin drugs include, for example, pravastatin (PRAVACHOLTM), lovastatin (MEVACORM), simvastatin (ZOCOR), cerivastatin (LIPOBAYrM), fluvastatin (LESCOLTM), atorvastatin (LIPITORTM) and the AGENT, the structures of which are shown in Figure 1. Preferably the statin drug is atorvastatin or the AGENT. Preferably the AGENT is used at a dose of 5 to 80 mg per day.

The AGENT is disclosed in European Patent Application, Publication No. 0521471, and in Bioorganic-and-Medicinal Chemistry, (1997), 437-444 as an inhibitor of 3-hydroxy-3methylglutaryl CoA reductase (HMG-CoA reductase). Preferably the calcium salt is used as illustrated in Figure 1.

Atorvastatin is disclosed in US 5,273,995; lovastatin is disclosed in US 4,231,938; simvastatin is disclosed US 4,450,171 and.US 4,346,227; pravastatin is:disclosed in US 4,346,227; fluvastatin is disclosed in US 4,739,073; cerivastatin is disclosed in US 5,177,080 and US 5,006,530.

Other compounds which have inhibitory activity against HMG-CoA reductase can be readily identified by using assays well known in the art. Examples of such assays are disclosed in US 4,231,938 at column 6 and W084/02131 at pages 30-33.

It will be appreciated that the statin drug may be administered in accordance with the invention in combination with other drugs used for treating diabetes or the complications of diabetes, such as neuropathy, nephropathy, retinopathy and cataracts. Examples of such treatments include insulin sensitising agents, insulin and oral hypoglycaemics (these are divided into four classes of drug sulfonylureas, biguanides, prandial glucose regulators and alpha-glucosidase inhibitors). Examples of insulin sensitising agents include, for example, troglitazone, rosiglitazone, pioglitazone, MCC-555, (S)-2-ethoxy-3-[4-(2-{4methanesulfonyloxyphenyl} ethoxy)phenyl]propanoic acid and 3- {4-[2-(4-tertbutoxycarbonylaminophenyl)ethoxy]phenyl}-(S)-2-ethoxy propanoic acid. Examples of sulfonylureas are glimepiride, glibenclamide, gliclazide, glipizide, gliquidone and tolazamide.

An example of a biguanide is metformin. An example of an alpha-glucosidase inhibitor is acarbose. An example of a prandial glucose regulator is repaglinide.

Other treatments are known also to improve NCV in diabetic neuropathy and as such these represent preferred combinations of the invention. Examples of such treatments include aldose reductase inhibitors, ACE inhibitors and All antagonists.

The use of aldose reductase inhibitors or ACE inhibitors in improving NCV and treating diabetic neuropathy is disclosed in PCT/GB98/01959. The use of AII antagonists in improving NCV and treating diabetic neuropathy is disclosed in W093/20816.

Suitable aldose reductase inhibitors include, for example, epalrestat, tolrestat, ponolrestat, zopolrestat, AD-5467, SNK-860, ADN-138, AS-3201, zenarestat, sorbinil, methosorbinil, imirestat and.minalrestat.(WAY-121509). Suitable ACE inhibitors include, for example, benazepril, benazeprilat, captopril, delapril, fentiapril, fosinopril, imidopril, libenzapril, moexipril, pentopril, perindopril, pivopril, quinapril, quinaprilat, ramipril, spirapril, spiraprilat, trandolapril, zofenopril, ceronapril, enalapril, indolapril, lisinopril, alacepril, and cilazapril. A preferred ACE inhibitor includes, for example, lisinopril, or a pharmaceutically acceptable salt thereof.

Suitable All antagonists include, for example, losartan, irbesartan, valsartan and candesartan.

A preferred All antagonist is candesartan.

Independent aspects of the present invention include a pharmaceutical combination comprising any one of the statin drugs identified above, preferably the AGENT or atorvastatin, and any one of the named ACE inhibitors identified above, or anyone of the aldose reductase inhibitors identified above, or any one of the AII antagonists identified above. Accordingly, further independent aspects of the present invention include the following: A pharmaceutical combination comprising the AGENT and lisinopril; A pharmaceutical combination comprising atorvastatin and lisinopril; A pharmaceutical combination comprising fluvastatin and lisinopril; A pharmaceutical combination comprising pravastatin and lisinopril; A pharmaceutical combination comprising cerivastatin and lisinopril; A pharmaceutical combination comprising the AGENT and candesartan; A pharmaceutical combination comprising the AGENT, or atorvastatin, and ethoxy-3-[4-(2- {4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid or 3- tert-butoxycarbonylaminophenyl)ethoxy]phenyl} -(S)-2-ethoxy propanoic acid The 'pharmaceutical combination' may be achieved by dosing each component drug of the combination to the patient separately in individual dosage forms administered together or sequentially. Alternatively the 'pharmaceutical combination' may be together in the same unit dosage form.

Therefore, as a further aspect of the invention we represent a pharmaceutical composition comprising a pharmaceutical combination as described herein above together with a pharmaceutically acceptable carrier and/or diluent.

Independent aspects of the present invention include a pharmaceutical composition comprising any one of the statin drugs identified above, preferably the AGENT or atorvastatin, and any one of the named ACE inhibitors identified above, or any one of the aldose reductase inhibitors identified above, or any one of the AII antagonists identified above together with a pharmaceutically acceptable carrier and/or diluent. Accordingly, further independent aspects of the present invention include the following: A pharmaceutical composition comprising the AGENT and lisinopril; A pharmaceutical composition comprising atorvastatin and lisinopril; A pharmaceutical.composition comprising-fluvastatin-and lisinopril; A pharmaceutical composition comprising pravastatin and lisinopril; A pharmaceutical composition comprising cerivastatin and lisinopril; A pharmaceutical composition comprising AGENT and candesartan; and A pharmaceutical composition comprising the AGENT, or atorvastatin, and ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl} ethoxy)phenyl]propanoic acid or 3- tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-(S)-2-ethoxy propanoic acid; and together with a pharmaceutically acceptable carrier and/or diluent.

A preferred pharmaceutical composition of the invention comprises the AGENT or atorvastatin and an ACE inhibitor (including any one of the ACE inhibitors specifically named above, in particular lisinopril), together with a pharmaceutically acceptable carrier and/or diluent.

A preferred pharmaceutical composition of the invention comprises the AGENT or atorvastatin and an aldose reductase inhibitor (including any one specifically named above), together with a pharmaceutically acceptable carrier and/or diluent.

A preferred pharmaceutical composition of the invention comprises the AGENT or atorvastatin and an AII antagonist (including any one specifically named above and preferably candesartan), together with a pharmaceutically acceptable carrier and/or diluent.

The pharmaceutical compositions.of the present-invention-may be administered in a staiidard manner for example by oral or parenteral administration, using conventional systemic dosage forms, such as a tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions, sterile injectable aqueous or oily solutions or suspensions. These dosage forms will include the necessary carrier material, excipient, lubricant, buffer,:bulking agent, antioxidant, dispersant or the like. In particular, compositions for oral administration are preferred.

The dose of a-statin drug, an aldose reductase inhibitor, an AII antagonist or an ACE inhibitor which can be administered in accordance with the present invention depends on several factors, for example the age, weight and the severity of the condition under treatment, as well as the route of administration, dosage form and regimen and the desired result, and additionally the potency of the statin drug, aldose reductase inhibitor, AII antagonist and ACE inhibitor employed in the composition. In addition, account should be taken of the recommended maximum daily dosages for the ACE inhibitors.

Prolonged administration of an ACE inhibitor at a therapeutically effective dose may be deleterious or give rise to side effects in certain patients, for example it may lead to significant deterioration of renal function, induce hyperkalemia, neutropenia, angioneurotic oedema, rash or diarrhoea or give rise to a dry cough. Administration of an ARI may also give rise to deleterious effects or side effects at the dose required to inhibit the enzyme aldose reductase sufficiently to produce a significant beneficial therapeutic effect. The present invention lessens the problems associated with administration of an ARI or an ACE inhibitor alone and/or provides a means for obtaining a therapeutic effect which is significantly greater than that otherwise obtainable with the single agents when administered alone. Furthermore, diabetic neuropathy involve a complex mechanism or number of mechanisms, which initiate a cascade of biochemical alterations that in turn lead to structural changes. These may result in a diverse patient population. The present invention therefore provides the additional advantage that it allows tailoring of treatment to the needs of a particular patient population.

The combination of a statin, preferably atorvastatin or the AGENT, with and ACE inhibitor, preferably lisinopril, is either additive or. synergistic in effect in the treatment of neuropathy, in particular NCV or nerve blood flow, in diabetic pateients.

The combination of a statin, preferably atorvastatin or the AGENT, with and AII antagonist, preferably candesartan, is.either additive or synergistic in effect inthe treatment of neuropathy, in particular NCV or nerve blood flow, in diabetic pateients.

A unit dosage formulation such as a tablet or capsule will usually contain, for example, from 1 mg.to. 100 mg of the statin drug, or/and from 0.1 mg to 500 mg of an aldose reductase inhibitor, or/and from 0.1 mg to 500 mg of an ACE inhibitor. Preferably a unit dose formulation will contain 5 to 80 mg of the statin drug, or/and 0.1 to 100 mg of an aldose reductase inhibitor, or/and 0.1 mg to 100 mg of an AII antagonist or/and-0.1 to 100 mg of an ACE inhibitor.

The present invention covers the pharmaceutical combination of (or product containing) the statin and an aldose reductase inhibitor, an AII antagonist or an ACE inhibitor for simultaneous, separate or sequential use in the treatment of diabetic neuropathy. In one aspect of the present invention, the AGENT drug and the aldose reductase inhibitor or AII antagonist or ACE inhibitor is presented in admixture in one pharmaceutical dosage form. In another aspect, the present invention covers the administration of separate unit dosages of the AGENT and aldose reductase inhibitor or All antagonist or ACE inhibitor in order to achieve the desired therapeutic effect. Such separate unit dosages may be administered concurrently or sequentially as determined by the clinician. The present invention also covers an agent for the treatment of diabetic neuropathy comprising a pharmaceutically acceptable carrier and/or diluent and, as active agents, a statin drug, preferably the AGENT or atorvastatin, and an aldose reductase inhibitor or an AII antagonist or an ACE inhibitor in quantities producing a synergistic therapeutic effect.

In another aspect of the invention there is provided a combination of pharmaceutical compositions for combination therapy of diabetic neuropathy, the combination consisting of a pharmaceutical composition comprising the statin drug and a pharmaceutical composition comprising an aldose reductase inhibitor ora pharmaceutical composition comprising an All antagonist or a pharmaceutical composition comprising an ACE inhibitor.

A further aspect of the present invention comprises the use of a statin drug and an aldose reductase inhibitor or an AII antagonist or an ACE- inhibitor in the preparation of a pharmaceutical composition for use in the treatment of diabetic neuropathy.

A further aspect of the present invention is a method for treating diabetic neuropathy wherein a therapeutically effective amount of a statin drug in combination with an aldose reductase inhibitor or an AII antagonist or an ACE inhibitor is administered systemically, such as orally or parenterally. Where the patient to be treated is normotensive, the ACE inhibitor or All antagonist.will.preferably be,administered in amounts below that required to cause a reduction in blood pressure. Where the patient to be treated is hypertensive, the ACE inhibitor or All antagonist will preferably be used in amounts usually employed to treat hypertension.

The effect of a pharmaceutical composition of the present invention may be examined by using one or more of the published models of diabetic neuropathy well known in the art. The pharmaceutical compositions of the present invention are particularly useful for the prevention of, reducing the development of, or reversal of, deficits in nerve function found in diabetic patients, and therefore particularly useful in the treatment of diabetic neuropathy. This may be demonstrated, for example, by measuring markers such as nerve conduction velocity, nerve blood flow, nerve evoked potential amplitude, quantitative sensory testing, autonomic function testing and morphometric changes. Experimentally, studies analogous to those described in Diabetologia, 1992, Vol. 35, pages 12-18 and 1994, Vol. 37, pages 651-663 may be carried out.

A further aspect of the present invention is a method of treating or preventing the development of disease conditions associated with impaired neuronal conduction velocity in a warm-blooded animal (including a human being) requiring such treatment comprising administering to said animal a therapeutically effective amount of a pharmaceutical combination or composition as described above.

A further aspect of the present invention is a method of reversing impaired neuronal conduction velocity in a warm-blooded animal (including a human being) requiring such treatment comprising administering to said animal a therapeutically effective amount of a pharmaceutical combination.orT:composition'.as'described-above...

Dosages of the.AGENT may be administered according to the cholesterol lowering effect desired from a range of 5-80 mg per day in any number of unit dosages.

Suitable dosages of the statins, ACE inhibitors, aldose reductase inhibitors or All antagonists mentioned herein are those which are available commercially, and which may be further reduced as, suggested herein, or as advised.in such. publications as Monthly Index of Medical Specialities (P.O.BOX 43, Ruislip, Middlesex, UK).

The following non-limiting Examples serve to illustrate the present invention.

Example 1 Suitable pharmaceutical compositions of an aldose reductase inhibitor (ARI) include the following: -I0- Tabklt

ARI

Lactose Ph. Eur.

Croscarmellose sodium Maize starch paste w/v paste) Magnesium stearate mg/tabilI 100 182.75 12.0 2.25 Tablt2.

ARI Lactose Ph.Eur. 223.75 Croscarmellose sodium Maize.sac Polyvinylpyrrolidone w/v paste) 2.25 Magnesium. stearate TLab1lt

ARI

Lactose Ph. Eur.

Croscarmellose sodium Maize starch paste w/v paste) Magnesium stearate 93.25 0.75

ARI

Lactose Ph. Eur.

Magnesium stearate 488.5 11- Example 2 Suitable pharmaceutical compositions of an ACE inhibitor include the following: Tablet 1 ACE Inhibitor 100 Corn starch Gelatin Microcrystalline cellulose Magnesium. stearate Tablet 2 ACE inhibitor Pregelatinised starch 82 Microcrystalline cellulose 82 Magnesium stearate 1 Example 3 Capsule mg The AGENT Lactose 42.5 Corn starch 20.0 Microcrystalline cellulose 32.0 Pregelatinised starch 3.3 Hydrotalcite 1.1 Magnesium stearate 1.1 Capsules containing 1, 2.5 or 10mg of the Agent may be obtained similarly using more or less lactose as appropriate., to achieve a fill weight of 105mg.

12- Example 4 Suitable pharmaceutical compositions containing the AGENT and an ACE inhibitor in a single dosage form include the following: Capsule mg The AGENT Lisinopril 10.0 Lactose.. 42.5 Corn starch 20.0 Microcrystalline cellulose 32.0 Pregelatinised starch 3.3 Hydrotalcite. 1.1 Magnesium stearate 1.1 Example A patient requiring treatment for diabetic neuropathy is treated with the AGENT mg) and lisinopril (10 mg). Lisinopril is administered twice daily and the AGENT is administered once daily.

Example 6 Male Sprague-Dawley rats, 19 weeks old at the start of the study, were divided into nondiabetic animals (normal control group) and animals rendered diabetic by intraperitoneal administration of streptozotocin, (40 45 mg/kg, freshly dissolved in sterile saline). Diabetes was verified 24 hours later by estimating hyperglycaemia and glucosuria (Visidex 1 and Diastix; Ames, Slough, UK). Diabetic rats were tested weekly and weighed daily. Animals were rejected if the plasma glucose concentration was 20 mM of if body weight consistently increased over 3 days. Samples were taken from the tail vein or carotid artery after final experiments for plasma glucose determination (GOD-Perid method; Boehringer -13- Mannheim, Mannheim, Germany). After 6 weeks of untreated diabetes, groups of rats were treated for a further 2 weeks with the AGENT, dissolved in the drinking water.

At the end of the treatment period, rats were anaesthetised with thiobutabarbitone by intraperitoneal injection (50 100 mg/kg). The trachea was cannulated for artificial ventilation and a carotid cannula was used to monitor mean systemic blood pressure.

Motor nerve conduction velocity was measured (as previously described by Cameron et al, Diabetologia, 1993, Vol. 36, pages 299-304) between sciatic notch and knee in the herve branch to tibialis anterior muscle, which is representative of the whole sciatic nerve in terms of susceptibility to diabetes and treatment effects.

Sensory conduction velocity-in saphenousnerve was measured between the groin and ankle (as previously described by Cameron et al. Quarterly Journal of Experimental Physiology, 1989, vol. 74, pages 917-926).

Sciatic blood flow was measured by hydrogen clearance microelectrode polarography (as described by Cameron et al., Diabetologia, 1994, vol.37, pages 651-663). The nerve was exposed between the sciatic notch and the knee and the skin around the incision was sutured to a metal ring to form a pool that was filled with paraffin:oil that was:maintained at 35-37°C by radiant heat. A glass-insulated platinum micro-electrode was inserted into the middle portion of the sciatic nerve and polarised at 250mV with respect to a subcutaneous reference microelectrode. 10%Hydrogen was added to the inspired gas, the proportions of nitrogen and oxygen being adjusted to 70% and 20% respectively. When the hydrogen current recorded by the electrode had stabilised, indicating equilibrium with arterial blood, the hydrogen supply was shut off and nitrogen supply was increased appropriately. The hydrogen clearance curve was recorded until a baseline, defined as no systematic decline in electrode current over minutes. To estimate blood flow, clearance curves were digitised and exponential curves were fitted to the data by computer using non-linear regression. The best fitting exponent gave a measure of nerve blood flow.

14- All data expressed as group mean SEM (number of rats used in brackets) Sciatic Nerve Motor Conduction Velocity Control Values Non-diabetical control 8 week diabetic vehicle 64.04 0.46 50.35 0:93 Atorvastatin 9Diabetic 2 weeks of dosing at 20mg/kg 61.53 0.76 (6) Diabetic+ .2 weeks ofdosingat-50mg/kg "-63:'59-'0:69 The AGENT Diabetic 2 weeks of dosing at 20mg/kg 63.34 0.61 (8) Dose response determination 5 groups of 8 rats dose ranged from 0.3-20mg/kg

ED,

0 2.3mg/kg Saphenous.Nerve Sensory Conduction Velocity Control Values Non-diabetic control 8 week diabetic vehicle Atorvastatin Diabetic 2 weeks of dosing at 20mg/kg Diabetic 2 weeks of dosing at 50mg/kg 61.09 m/s 0.67 52.77 m/s 0.79 (6) 59.77 m/s 0.93 (6) 60.72 m/s 0.94 (6) The AGENT Diabetic 2 weeks of dosing at 20mg/kg 60.57 m/s 0.83 (8) Dose response determination 5 groups of 8 rats dose ranged from 0.3-20mg/kg 0.9mg/kg Sciatic Nerve Blood Flow ControlValues Non-diabetic control 8 week diabetic vehicle 17.89 mi/min/l OOg (of nerve tissue) 0.65 8.82 ml/min/100g+ 0.56(10) Aoratain Diabetic 2 weeks of dosing at 50mg/kg 16.96 1.39 mi/min/lOg (6) Th GNT Diabetic 2 weeks of dosing at 20mg/kg 16.19+±0.51 ml/minIOOg (8) Figure 1.

NN

H

3 N N' U 2 C H IN~0- The AGENT 16- OH OH 0 Atorvastatin .Na Fluvastatin 0

H

3

C

CH

3

H

3 C e Lovastatin 17- Simvastatin NaQOC

O

0 HO 0

H

3 C A0

CH)JH.

Pravastatin Na~ 13 'CH 3 Cerivastatin P:\OPERW al\2003 \2359940 28.doc-16/10/03 18- The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step.or group of integers or steps.

Claims (7)

1. A pharmaceutical combination comprising a synergistic amount of HMG CoA 0 reductase inhibitor (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid, or a pharmaceutically acceptable salt thereof, and a synergistic amount of the All antagonist candesartan.

2. A pharmaceutical combination according to claim I comprising the calcium salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsufonyl)amino]-pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid, and the All antagonist candesartan.

3. A pharmaceutical composition comprising the HMG CoA reductase inhibitor [4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] 3,5-dihydroxyhept-6-enoic acid or a pharmaceutically acceptable salt thereof, and the All antagonist candesartan, in admixture with a pharmaceutically acceptable diluent or carrier.

4. A pharmaceutical composition according to claim 3 comprising the calcium salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid, and the All antagonist candesartan, in admixture with a pharmaceutically acceptable diluent or carrier.

A pharmaceutical combination or pharmaceutical composition according to any one of claims I to 4 wherein the HMG CoA reductase inhibitor is present in an amount of 5 to 80 mg and the All antagonist is present in an amount of 0.1 to 100 mg.

6. A pharmaceutical combination or pharmaceutical composition according to any one of claims 1 to 5 for use in the manufacture of a medicament. P \OPER\MAL\2-()6\12359940 Ispa doc- .)7A)6 0

7. A unit dosage formulation comprising a pharmaceutical combination or pharmaceutical composition according to any one of claims 1 to DATED this 1 3 th day of July, 2006 AstraZeneca AB AND The University Court of the University of Aberdeen By DAVIES COLLISON CAVE Patent Attorneys for the Applicant