CA2384797A1 - Medicament combinations - Google Patents

Abstract

The invention relates to a combination of at least one dihydropyridine compound (component A) and an HMG-CoA reductase inhibitor (component B), to the use of this combination for treating cardiovascular diseases, to medicaments containing this combination and to the production of the same.</ SDOAB>

Description

' . ' Le A 33 966-Foreign Countries / Li/kIu/NT

Pharmaceutical combinations The invention relates to a combination of at least one dihydropyridine compound (component A) with an HMG-CoA reductase inhibitor (component B), the use of this combination for the control of cardiovascular diseases, medicaments comprising this combination and their production.
The compounds of component A are well known to the person skilled in the art.
They are calcium antagonists which are especially employed for the treatment of high blood pressure. Lacidipine is described, for example, in GB-A ~2 164 336. The combination of nifedipine with beta-blockers is described in EP-A-0 165 450.
EP-A-0 180 785 discloses the combination of dihydropyridines, such as nifedipine, with ACE inhibitors.
HMG-CoA reductase inhibitors are a class of lipid-lowering agents likewise well known to the person skilled in the art. The abbreviation "HMG-CoA" stands here for "3-hydroxy-3-methylglutaryl-coenzyme A". Statins preferred in the context of this invention as HMG-CoA reductase inhibitors are described, for example, in EP-A-325 130 or US-A-5 177 080.
WO 99111263 discloses the combination of the dihydropyridine calcium antagonist amlodipine with statins or HMG-CoA reductase inhibitors. However, no actual indication is found there of a combination with cerivastatin. The components nifedipine and lacidipine are also not mentioned there.
The present invention relates to the combination of at least one dihydropyridine compound as component A with HMG-CoA reductase inhibitors as component B.
As component A, lacidipine or nifedipine is preferably employed; nifedipine is particularly preferred.

Le A 33 966-Foreign Countries The invention furthermore relates to pharmaceutical preparations comprising these combinations of the components A and B and their production.
S The invention furthermore relates to the use of the combinations according to the invention for the prophylaxis and treatment of cardiovascular diseases.
The dihydropyridines and HMG-CoA reductase inhibitors according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers).
The invention relates both to the enantiomers and the diastereomers or their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated in a known manner into the stereoisomerically homogeneous constituents.
It has now been found that the combinations according to the invention have unexpected valuable pharmacological properties, in particular they are suitable for the prophylaxis and treatment of diseases of the cardiovascular system, such as hypertension, which are not associated with raised lipid levels in the plasma.
Furthermore, the combinations according to the invention are also suitable for the prophylaxis and treatment of cardiovascular diseases, such as hypertension, with simultaneously raised lipid levels.
HMG-CoA reductase inhibitors in the context of the invention in general represent all substance classes mentioned under this term in the prior art. Those preferred under this term are statins, such as are described, fox example, in EP-A-247 633, US-A-5 006 530, EP-A-33 538, US-A-4 346 227, EP-A-22 478, EP-A-491 226, EP-A-325 130 or EP-A-114 02.7 For further details on the statins, reference is made to the articles in Drugs of the Future 1994, 19(6), pages 537 - 541 and 1995, 20(6), pages 611 and 1996, 21(6), page 642, whose respective contents are included fully by way of reference.

Le A 33 966-Foreign Countries A further survey on HMG-CoA reductase inhibitors is contained in Pharmazie in unserer Zeit, 28th year, No. 3, pages 147-152 (1999).
Atorvastatin, cerivastatin, simvastatin, pravastatin, lovastatin, fluvastatin, itavastatin ("NK-104", see EP-A-0304 063) sowie ZD-4522 (see EP-A-521 471; systematic name: (+)-(3R,SS)-bis(7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methane-sulfonylamino)pyrimidin-5-yl)-3,5-dihydroxy-6(E)-heptenoic acid, calcium salt).
Cerivastatin is particularly preferred.
Statins can be present in the form of their esters, e.g. of the C1-C4-alkylesters, or lactones or as carboxylic acids or salts of the carboxylic acid.
With respect to the HMG-CoA reductase inhibitors, the term "salt" within the meaning of the present invention in each case means physiologically acceptable salts of the compounds concerned: these can be, for example, salts with mineral acids, carboxylic acids or sulfonic acids, in particular with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, malefic acid or benzoic acid or alternatively mixed salts thereof. However, they can also be salts with customary bases, for example alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. calcium or magnesium salts) or ammonium salts, derived from ammonia or organic amines such as diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methylpiperidine and mixed salts thereof.
In the case of cerivastatin, the sodium salt (cerivastatin sodium) is particularly preferably employed.

Le A 33 966-Foreign Countries Further preferred HMG-CoA reductase inhibitors are described in EP-A-0 32S 130 and in EP-A-0-491 226, whose contents are hereby included by way of reference.
EP-A-0 32S 130 relates to substituted pyridines, and EP-A-0-491 226 describes substituted pyridyldihydroxyheptenoic acid derivatives and their salts, among them in particular cerivastatin, which is particularly preferred according to the invention.
The combinations according to the invention have a broad and varied spectrum of action. They can be employed, for example, for the treatment andlor prophylaxis of cardiovascular diseases such as arteriosclerosis, stroke, angina pectoris, diseases of the coronary vessels of the heart, in particular of the arterial coronary vessels, heart failure, primary and secondary myocardial infarct, pathological changes in the vascular wall, circulatory disorders, disorders of the microcirculation; fat metabolism disorders such as raised concentration of lipoproteins in the serum and possibly a shift in the lipoprotein contents, raised serum lipids, hyperlipoproteinemia, 1S hyperchloesteralemia, hypertriglyceridemia, raising both of the serum cholesterol and the serum triglycerides combined with raised VLDL (very low density lipoprotein) and raising of the chylomicrons in the plasma, non-insulin-dependent diabetes mellitus (= type 2 diabetes), diabetes, hyperglycemia; metabolic disorders such as disorder of lipid metabolism, deficiency of acidic lipase, storage diseases, in particular fat storage diseases, phytosterolemia, high blood pressure, obesity, thromboses, pancreatitis, constipation (obstipation), functional disorders of the brain, cerebrovascular insufficiency, cerebral circulatory disorders, apoplexy, transitory ischemic attacks (TIA) and fainting.
2S Of particular interest is the use of the combinations according to the inventions in cardiac rusk management, i.e. in the prophylaxis and treatment of diseases which are influenced or caused by more than one risk factor, e.g. artereosclerosis, diseases of the coronary vessels of the heart, in particular of the arterial coronary vessels, raised serum lipids, hypercholesteralemia, hypertriglyceridemia, raising both of the serum cholesterol and the serum triglycerides combined with raised VLDL (very low density lipoprotein) and raising of the chylomicrons in the plasma and syndrome X.

Le A 33 966-Foreign Countries Typical risk factors are the age, the sex, the cholesterol level, the HDL
level, the systolic blood pressure, smoking, glucose intolerance and cardiac hypertrophy.
The combinations of the components A and B according to the invention, in S particular the specific combination of nifedipine and cerivastatin, prove to be surprisingly advantageous in the treatment of hypertension, coronary heart diseases, cardiac insufficiency, brain function disorder, apoplexy, circulatory disorders and disorders of fat metabolism. An example of disorders of fat metabolism which may be mentioned is dyslipidemias, such as occur in diabetics but also in patients who are not suffering from diabetes. In particular, the combinations according to the invention are suitable for the treatment of hypertension in patients having normal lipid levels. They are likewise suitable for the treatment of hypertension which occurs in combination with hyperlipidemia.
In particular, on account of the combination of the antihypertensive with the lipid-lowering action, the combinations according to the invention can be employed not only for the prevention and treatment of apoplexy (such as the classical monotherapy with antihypertentives), but also for the prevention and treatment of cardiac insufficiency and coronary heart diseases.
When using the combinations according to the. invention, a synergistic effect in the action which is not to be expected is observed. The amounts of the components A
and B employed can thus be lowered in comparison with monotherapy.
If appropriate, it may be expedient to supplement the combination of dihydropyridines and HMG-CoA reductase inhibitors according to the invention by addition of one or more further components. Examples which may be mentioned are acetylsalicylic acid, vitamin C, vitamin E, L-arginine and ACE inhibitors.
These other components can be added individually or alternatively together.

Le A 33 966-Forei~ ngn Countries "Hyperlipidemia" should be understood as meaning a raised plasma level of one or more serum lipids. In this respect, the LDL level is of particular importance.
Increased levels are regarded as being 130 mg/dl in patients of over 45 years and over 160 mg/dl in patients of under 45 years.
S
"Dyslipidemia" should be understood here as meaning either hypertriglyceridemia or hypercholesterolemia, but particularly mixed hyperlipidemia, i.e. a disease state having a raised cholesterol level (LDL and total cholesterol) and raised triglyceride level. This can be associated with a decrease in the HDL (high density lipoprotein) cholesterol in the plasma or a disturbed HDL-C/LDL-C ratio.
The combinations according to the invention are furthermore distinguished by a surprisingly good tolerability.
The combinations according to the invention are preferably employed in human medicine, but are also suitable for veterinary medicine, in particular for the treatment of mammals.
The combinations according to the invention can be. administered parenterally or preferably orally.
The active compounds of components A and B can be converted into the customary formulations in a known manner, it being possible for these to be liquid or solid formulations. Examples are tablets, coated tablets, pills, capsules, granules, aerosols, syrups, emulsions, suspensions and juices.
As the combinations according to the invention are highly tolerable and active even in low doses, all sorts of formulation variants can be produced. Thus, on the one hand, there is the possibility of formulating the individual components separately. In this case, the two individual components A and B do not unconditionally have to be taken at the same time, but on the contrary taking at different times can be Le A 33 966-Foreign Countries advantageous to achieve optimal effects. In the case of such a separate administration, it is suggested to combine the formulations of the two individual components, for example tablets or capsules, at the same time next to one another in a suitable primary pack. In the primary pack, the two components are in each case situated in separate containers, which can be, for example, tubes, vials or blister packs. Such separate packaging of the two components in a common primary pack is also described as a kit.
As further formulation variants for the combinations according to the invention, fixed combinations are preferably also suitable. "Fixed combination" should be understood here as meaning those pharmaceutical forms in which the two components are present together in a fixed quantitative ratio. Such fixed combinations can be produced, for example, as peroral solutions, but preferably they are solid oral pharmaceutical preparations, e.g. capsules or tablets.
Various embodiments are conceivable for solid oral pharmaceutical preparations of the fixed combinations. Some principles will be illustrated by way of example below:
A two-layer tablet contains the dihydropyridine compound of component A in the one layer and the HMG-CoA-reductase inhibitor of component B in the other layer.
The dimensions of the two layers and the exact composition can be varied and are different from one another.
As a specific embodiment of the two-layer tablet, it is conceivable, for example, that the second layer is stuck in suitable form onto a formulation known per se, for example a tablet.
A further possibility is a 'Bull's eye' tablet. In this administration form, a tablet formulation of the one active compound contains a hollow in which the other active compound is located in a suitable matrix. Typically, the active compound employed Le A 33 966-Foreign Countries _g_ in the lower amount is located in the hollow, while the remainder of the tablet contains the active compound employed in the higher amount.
A further possibility is a 'covered' tablet, in which a core which contains the one component is surrounded by a jacket which contains the other component.
Preferably, in a covered tablet the jacket has a certain elasticity. For the particularly preferred example of the combination of cerivastatin with adalat, for example, covered tablets would be conceivable in which the core contains the adalat in the form of a tablet having delayed release of active compound, such as a 'laminated tablet' or an 'OROS
tablet' in which the release rate is controlled by an osmotic process and a semipermeable membrane (Remington's Pharmaceutical Science, Editor A.R. Gennaro, Made Publishing Company, Eastern Pennsylvania 18042, 1985 p.
1653).
In the case in which one of the components is to be employed in only very small amounts, it would also be conceivable to apply the component concerned in a coating to an appropriate administration form of the other component. This coating could cover the core completely or be constructed as a partial coating. If appropriate, it may also be of advantage to coat this coating again with a protective lacquer in order to avoid mechanical damage to the active compound-containing layer. By way of example, combination of cerivastatin with nifedipine may again be mentioned here, cerivastatin preferably being incorporated into the coating, for example, on account of the lower amount required, while it being possible for the core to consist of an adalat formulation known per se. In variants of partial coating, the coating is, for example, applied drop by drop, for example with the aid of an adhesive gun, or pressed on using suitable presses. In this case too, a protective coating is advisable.
As a further possibility for coating, an active compound-containing adhesive film is also possible.

Le A 33 966-Foreign Countries Unlike the administration forms indicated above, which have two essentially separate areas, administration forms of the following forms are also conceivable:
The two components could in each case be formulated by themselves in the form of S minitablets or granules and the minitablets and granules concerned could then be filled together into a capsule. It is furthermore possible to process the minitablets or granules concerned with the aid of a common connecting matrix to give a tablet. In such a tablet, the particles concerned are then embedded in the common matrix.
As a variant of this form, the connecting matrix can also contain the one component, while the other component is incorporated therein in the form of particles, e.g.
minitablets or granules. Instead of minitablets or granules, pellets can also be employed.
Pellets are here in general understood as meaning almost spherical particles having dimensions of about 0.4 mm to about 2 mm.
All abovementioned administration forms can be varied in a known manner by the person skilled in the art. If in one administration form the components A and B are in each case present in separate areas, the respective area can contain the component concerned alone, but it is also possible that the one component is admixed to the other component in a greater or lesser amount.
In the abovementioned administration forms, the formulations for the individual components can be varied in a customary manner, in particular the release rate of each component can be controlled by means of the formulation concerned. The abovementioned administration form as a rule allows formulations having different release characteristics for the components concerned to be used.
The combinations according to the invention are dosed up to 3x daily, and those combinations are preferred which allow administration lx daily.
The combinations according to the invention preferably contain 0.01 to 20 mg/kg, in particular 0.1 to 5 mg/kg, of active compound of component A, and 0.001 to Le A 33 966-Foreign Countries 30 mg/kg, in particular 0.005 to 10 mg/kg, of active compound of component B, in each case based on kg of bodyweight of the patient on oral administration.
If appropriate, it may be necessary to depart from the amounts mentioned, namely depending on the bodyweight or the nature of the administration route, on the individual behavior to the medicaments, the manner of their formulation and the time or interval at which administration takes place. Thus in some cases it may be adequate to manage with less than the abovementioned minimum amount, while in other cases the upper limit mentioned has to be exceeded. In the case of the administration of relatively large amounts, it may be advisable to divide these into a number of individual doses over the course of the day.
The active compounds of components A and B are particularly suitable for formulation in a fixed combination in the form of a solid peroral administration form.
It is generally known that the reliability of taking (compliance) with patients is dependent to a decisive extent on the factors number of administration forms per time of taking and size and weight of the (solid peroral) pharmaceutical form.
The number of the various pharmaceuticals to be taken separately should therefore be kept as low as possible (advantage of a fixed combination), and the size and the weight of a solid peroral administration form should be as small as possible with full therapeutic potency in order to make taking as pleasant as possible for the patient.
Fixed combinations can thus be produced in the form of solid peroral pharmaceutical formulations having minimal size and minimal weight. The fixed combinations according to the invention accordingly offer the highest possible patient compliance and thereby improve the safety and reliability of a therapy decisively.
The release of active compound can be controlled by combination of the two components A and B and modification of the composition or of the functionality. For example, the abovementioned timewise decoupling of the onset of action can also be realized in fixed combinations by delayed release of active compound from one component.

Le A 33 966-Foreign Countries The solid peroral administration forms mentioned here are prepared by the general standard processes. Ingredients are those which are pharmaceutically accepted and physiologically acceptable, for example: as fillers cellulose derivatives (e.g.
microcrystallinecellulose), sugars (e.g. lactose), sugar alcohols (e.g.
mannitol, sorbitol), inorganic fillers (e.g. calcium phosphates), binding agents (e.g.
polyvinylpyrrolidone, gelatin, starch and cellulose derivatives), and all further excipients which are needed for the production of pharmaceutical formulations with the desired properties, e.g. lubricants (magnesium stearate), disintegrants (e.g.
crosslinked polyvinylpyrrolidone, sodium carboxymethylcellulose), wetting agents (e.g. sodium lauryl sulfate), release-delaying agents (e.g. cellulose derivatives, polyacrylic acid derivatives), stabilizers, flavorings and color pigments.
Liquid formulations are likewise prepared by a standard method using pharmaceutically customary excipients and contain the active compound or the two active compounds either in dissolved or suspended form. Typical administration volumes of these pharmaceutical preparations are 1 to 10 ml. Examples of excipients in these liquid formulations are: solvents (e.g. water, alcohol, natural and synthetic oils, e.g. medium-chain triglycerides), soiubilizers (e.g. glycerol, glycol derivatives, wetting agents (e.g. polysorbate, sodium lauryl sulfates), and further excipients which are needed for the production of pharmaceutical formulations with the desired properties, e.g. viscosity-enhancing agents, pH corngents, sweeteners and flavorings, antioxidants, stabilizers and preservatives.
?5 The main constituents of the coverings of capsule formulations are, for example, gelatin or hydroxypropylmethylcellulose.
Pharmaceutical excipients such as are familiar to the person skilled in the art are also described, for example, in the following handbook: "Handbook of Pharmaceutical Excipients", Wade, A. & Welter, P.J., American Pharmaceutical Association, Washington, 2nd edition 1994.

Le A 33 966-Foreign Countries Examples Component A:
1. Nifedipine in doses of 5 mg to 90 mg, preferably in doses of 20 to 60 mg.
2. Lacidipine in doses of 1 mg to 16 mg, preferably in doses of 2 mg to 8 mg.
Component B:
1. Cerivastatin in doses of 0.05 mg to 3.2 mg, preferably in doses of 0.1 mg to 1.6 mg.
2. Simvastatin in doses of 2.5 mg to 160 mg, preferably in doses of 10 mg to 40 mg.
3. Pravastatin in doses of 2.5 mg to 160 mg, preferably in doses of 10 mg to 40 mg.
4. Fluvastatin in doses of 2.5 mg to 160 mg, preferably in doses of 20 mg to 80 mg.
5. Lovastatin in doses of 2.5 mg to 160 mg, preferably in doses of 10 mg to 80 mg.

Le A 33 966-Foreign Countries Example 1 Numerous "fixed dose" combinations can be prepared from granules comprising cerivastatin on the one hand and granules comprising nifedipine on the other hand, such as tablets or capsules which on the one hand contain, for example, 0.1, 0.2 or 0.4 mg of cerivastatin and on the other hand, for example, 20, 30, 50 or 60 mg of nifedipine. The individual granules are described firstly and then a typical example of a "fixed dose" combination.
The formulation comprising cerivastatin (component B) is composed as follows.
Percentages in the context of the invention represent percentages by weight Example 2 Cerivastatin 0.01 % to 5 %
Binder a 0% to 20%
Excipients f 70% to 99%
?0 e~ Binders employed are all customary, pharmaceutically acceptable binders, e.g.
polyvinylpymolidones, gelatin, starch and cellulose derivatives (natural or synthetic). Polyvinylpyrrolidones are preferred, in particular polyvinylpyrrolidone 25.
0 Further excipients which can be employed are all customary pharmaceutical excipients, i.e., for example, as fillers cellulose derivatives (e.g.
microcrystalline cellulose), sugars (e.g. lactose), sugar alcohols (e.g.
mannitol, sorbitol), inorganic fillers (e.g. calcium phosphates) and all further excipients which are needed for the production of pharmaceutical formulations with the desired properties, e.g. lubricants (e.g. magnesium stearates), disintegrants (e.g. crosslinked polyvinylpyrrolidone, sodium carboxymethylcellulose), ~ Le A 33 966-Foreign Countries wetting agents (e.g. sodium lauryl sulfate), stabilizers, flavorings and color pigments.
Lactose, mannitol and microcrystalline cellulose are preferably used as fillers.
Reference is made to WO 98/57917 for the production of these cerivastatin-containing granules.
An example of the composition of the granules thus obtained is indicated in Example 4 of WO 98/57917.
The nifedipine-containing formulation (component A) is composed as follows.
nifedipine 5-35% preferably IO to 30% m/m excipient Ian 5-20% preferably 10 to 25% m/m excipient IIb> 50-85% preferably 55 to 75% m/m flow-regulating agent's0.3-1.5% preferably 0.6 to 0.9%
m/m lubricantd> 0.3-1.5% preferably 0.6 to 0.9%
m/m a> This group includes fillers such as cellulose derivatives (e.g.
microcrystalline cellulose), sugars (e.g. lactose), sugar alcohols (e.g. mannitol, sorbitol) and inorganic fillers (e.g. calcium phosphates, magnesium carbonates). Lactose is preferably employed.
b~ This group includes binders such as methylcelluloses, hydroxypropylcelluloses, hydroxypropylmethylcelluloses and polyvinyl alcohols. A mixture of hydroxypropylcellulose types L and M in a ratio of 2.5:1, in particular 1.7:1, is preferably employed.

' Le A 33 966-Foreign Countries This group includes lubricants such as uncompressed Aerosil, synthetic aluminum silicates, synthetic hydrotalcides, dried aluminum hydroxide gels, kaolin and calcium silicates. Uncompressed Aerosil is preferably employed.
d) This group includes substances such as calcium stearates, magnesium stearate, zinc stearate, stearic acid and sodium stearyl fumarate. Magnesium stearate is preferably employed.
The substances of the nifedipine-containing formulation are granulated using a suitable amount of water, it also being possible to admix some of these substances to the granules without them being granulated. .
With respect to the lubricant, it is the case that as a rule this substance is added to the granules completely without some of it being concomitantly granulated. Instead of water, a solution or suspension can also be used which contains some of the excipients I and/or II.
Before tableting or filling into capsules or other further processing, all powders contained in the formulation are preferably mixed.
The cerivastatin (component B) and the nifedipine (component A) containing granules can then be processed, for example, to give two-layer tablets.
A two-layer tablet is then composed by way of example and preferably in the 2~ following way:
Two-layer tablet containing 0.4 mg of cerivastatin and 60 mg of nifedipine.

Le A 33 966-Foreign Countries L_ ayer I
Cerivastatin 0.40 mg Polyvinylpyrrolidone 3.60 mg sodium hydroxide 0.20 mg Mannitol 167.70 mg crosslinked polyvinylpyrrolidone8.40 mg magnesium stearate 2.70 mg weight of layer 1 = 180.00 mg L. ayer 2:
Nifedipine 60.00 mg Lactose 34.68 mg uncompressed Aerosil 1.92 mg Hydroxy-propyl-cellulose 126.00 mg type L

Hydroxy-propyl-cellulose 75.36 mg type M

magnesium stearate 2.04 mg weight of layer 2 = 300.00 mg total weight of the tablet480.00 mg

Claims (10)

claims

1. A combination of a dihydropyridine calcium antagonist as component A with HMG-CoA reductase inhibitors as component B.

2. A combination as claimed in claim 1, characterized in that it contains nifedipine or lacidipine as component A.

3. A combination as claimed in either of claims 1 or 2, characterized in that it contains atorvastatin, cerivastatin, simvastatin, pravastatin, lovastatin, fluvastatin, itavastatin or ZD-4522 as component B.

4. A combination as claimed in claim 1 of nifedipine with cerivastatin.

5. The use of the combination as claimed in one of claims 1 to 4 for the production of medicaments for the treatment of cardiovascular conditions.

6. The use as claimed in claim 5 for the production of medicaments for the treatment of hypertension in the case of plasma lipid levels which are not raised.

7. The use as claimed in claim 5 for the production of medicaments for the treatment of hypertension with simultaneous hyperlipidemia.

8. A medicament comprising a combination as claimed in one of claims 1 to 4 and, if appropriate, one or more further suitable components.

9. A process for the production of medicaments as claimed in claim 8, characterized in that the components A and B are converted into a suitable administration form using excipients and vehicles and, if appropriate, using further components.

10. A kit, which in separate containers in a single pack in one container contains an efficacious amount of component A, as defined in one of claims 1 to 4, in a pharmaceutically acceptable vehicle and in a second container an efficacious amount of component B, as defined in one of claims 1 to 4, in a pharmaceutically acceptable vehicle.