AU602867B2 - Prostacyclines, their analogues or prostaglandines and thromboxane antagonists for the treatment of thrombotic and thrombo-embolic illnesses - Google Patents

Abstract

Combination products containing a prostaglandine (PG), a prostacycline (PC) or a prostacycline analogue (PCA) and a thromboxane receptor antagonist (TXAA), suited for joint use in the treatment of forms of thrombotic or thrombo-embolic illnesses.

Description

p AM -A 59.q- 3 16 WELTORGANISATION FOR GE~ST E P c r Irnernatianales BU r INTERNATIONALE ANMELDUNG VEROFFENTLIC NQ H TADIE INTERNATIONALE ZUSAMM.ENARBEIT AUF DEM GEBIET DES PATENWESENS (PCT) (21) Internationales Aktenzeicben: PCT/DE86/00260 (81) Bestiinmungsstaaten: AT (europ~isches Patent), AU, BE (europfiiscbes Patent), CH (europ~isches Patent), (22) Internationales Anmieldedatum: 20. Juni 1986 (20.66.86) DE (europiiisches Patent), DK, FR (europaisches Patent), GB (europliiscbes Patent), IT (europgis! hes Patent), JP, LU (europiiisches Patent), NL (europ 'Isches (31) Priorilitsnlktenzeicben: P 35 26 361.8 Patent), SE (europliiscbes Patent), US.

(32) Priorititsdatum: 19. Juli 1985 (19.07.85) Veroffentlicht Prioritatsland: DE Mit iniernationalem Recherchenberich.

(71) Anmelder (far alle Bestimmungsslaaten ausser US): SCHERING AKTIENGESELLSCHAFT BERLIN UNi) BERGKAMEN [DE/DE]; MOllerstrasse 170 178, D-000 Berlin 65 12MP19V (72) Erfinder;und JP 12!A r Erfinder/Anmelder (nur ftir US) STORZEBECHER, Claus-Steffen JDE/DEJ; Brigittenstrasse 6a, D-1000 Berlin 46 WIll', Werner, Georg [DE/DE]; Motzstrasse 25, D-1000 Berlin 30 RADOCH EL, I AUSTRAIAk~N Bernd [DE/DEJ; Gollanzstrasse 132, D-1000 Berlin 28 1987 SKUBALLA, Werner [DE/DE]; Ohvenstrasse 23, D-1000 Berlin 28 VORBRUGGEN, Helmut

TOFC

[DE/DE]; Wilkestrasse 7, D-1000 Berlin 27 a ET NI (54)Title: PROSTACYCLINES, THEIR ANALOGUES OR PROSTAGLANDINES AND THROMBOXANE ANTA- GONISTS FOR THE TREATMENT OF THROMBOTIC AND THROMBO-EMBOLIC ILLNESSES (54) Bezeichnang: PROSTACYCLINE, IHRE ANALOGE ODER PROSTAGLANDINE UND THROMBOXANAN- TAGONISTEN ZUR BEHANDLUNG VON THROMBOTISCHEN UND THROMBOEMBOLI- SCHEN KRANKHEITSBILDERN (57) Abstract Combination products containing a prostaglandine a prostacycline (PC) or a prostacycline analogue (PCA) and a thromboxane receptor antagonist (TXAA), suited for joint use in the treatment of forms of thrombotic or thromboembolic illnesses.

(57) Zusamnmenfassung Kombinationserzeugnisse enthaltend emn Prostaglandin ein Prostacyclin (PC) oder cmn Prostacyclinanalogon (PCA) und cinen Thromboxanrezeptorantagonisten (TXAA) sind zur gemneinsamen Verwendung bei thrombotischer und thromboembolischer Krankheitsbilder gecignet.

This document contains the itiednefs irade undc~T SectiOn 49 and is correct for

SCHERING

PROSTACYCLINS, THEIR ANALOGUES OR PROSTAGLANDINS AND THROMBOXANE ANTAGONISTS FOR THE TREATMENT OF THROMBOTIC AND l"HROMBO-EMBOLIC SYNDROMES T E The invention relates to a combination product for combined use in the treatment of thrombotic and thrombo-embolic syndromes with conditions of increased intravasal platelet activation and hence an increased tendency towards platelet aggregation and platelet adhesion and an increased tendency towards blood coagulation, containing a prostacyclin, a prostacyclin analogue or a prostaglandin (PC/PCA/PG) and a thromboxane receptor antagonist (TXAA).

The invention also relates to the use of a PC/PCA/PG in combination with a thromboxane receptor antagonist for administration for: prophylaxis and therapy of coronary heart diseases, coronary thrombosis, cardiac infarction, peripheral arterial disease, diabetic vascular changes, arteriosclerosis and thrombosis, apoplexy, prophylaxis and therapy of ischaemic attacks of the CNS system, migraine, shock therapy, inhibition of bronchoconstriction, inhibition of gastric acid secretion; further possible uses of the combination are cytoprotection of the mucuous membrane of the stomach and intestine, cytoprotection in the liver, kidney and pancreas, reduction in the pulmonary vascular resistance and pulmonary blood pressure, promotion of renal blood flow, use instead of heparin or as an adjuvant during dialysis or haemofiltration, preservation of conserved blood plasma, especially conserved blood platelets, inhibition of labour pains, treatment of pregnancy toxaemia, increase in cerebral blood flow etc.; the combination product can additionally be used as an antiallergic and as an antiproliferative active substance.

The combination can also be administered, together with calcium antagonists, thromboxane synthetase inhibitors, typical anticoagulants, such as heparin, coumarin or aspirin and corresponding active substances, with phosphodiesterase inhibitors, with angiotensin converting enzyme (ACE) inhibitors, with vasodilating active substances, in particular with betareceptor blockers, anti-inflammatories, antipyretics and antiallergics etc.

It is already known that prostaglandin E 1 prostacyclin and prostacyclin analogues are used for the treatment of acute and chronic thrombotic and thrombo-embolic diseases [Information on the Use of Prostavasin R) from Sanol Schwarz GmbH; Moncada. Br. J. Pharmacol. 76/1, 3-31 (1982); and S.2 S i 1 1 1 1 1 1 1 1 i- Schillinger, T. Krais and G. Stock, New Drug Annual: Cardiovascuar Drugs, Raven Press, being printed].

Besides having the advantages of these treatment forms, which consist of potent inhibition of all stimulators of platelet aggregation, these therapies are limited by the cardiovascular side effects, in particular the marked reduction in blood pressure.

For TXAA, no adequate detection of the action has been carried out for this therapy principle in the clinical investigations to date.

It is to be considered as insufficient to achieve better antiaggregation principles via an increase in the plasma levels of the endogenous prostacyclin in combination with a TXAA CChan, and A. Ford-Hutchinson, Europ. J. of Pharmacol. 110, 323-328, (1985)3, especially since dosing and any reliable and reproducible increase at all in the endogenous prostacyclin is impossible. Moreover, with endogenous prostacyclin there is not the possibility of separating desirab- actions from side effects of the prostacyclin, which exists when synthetic PC/PCA/PG is used.

It has now been found, surprisingly, that the side effects typical of PC/PCA/PG and the inadequate activity of TXAA can be avoided or compensated if the PC/PCA/PG and TXAA are used in combination in the treatment of the abovementioned syndromes. Whilst the platelet-inhibiting antithrombotic and antithrombogenetic action of both classes of active substance are mutually potentiated, the cardiovascular side effects of the PC/PCA/PG are reduced as a result of the reduction in the amounts of the individual active substances which is possible in the combination. The therapeutic range of the individual active substances is thereby increased.

It is possible to use amounts by weight of prostacyclin/prostacyclin analogue/prostaglandin and of thromboxane receptor antagonist which are greatly reduced on their combined administration in comparison with the required dosages previously used for the individual active compounds.

The PC/PCA/PG and TXAA are used in combination in one dose unit or separately and simultaneously or sequentially in a weight ratio of essentially about 1 1 to 1 :10,000 in the same vehicle, a tablet or an oily ~v solution, such as a benzyl benzoatelcastor oil mixture).

Sequential treatment is of particular importance in as much as in those treatments in which a decrease in the PC/PCA/PG action occurs or is to be expected (TachyphyLaxie, ESinzinger, H. and S. Reiter, ProstagL. Leukotr.

and edicne__/3, 281-288 such a reduction in action can be prevented by alternate gradually increasing and gradually decreasing therapy with PC/PCA/PG and TXAA.

Possible compounds of the prostacycLi n/prostacyc Lin anaLogue/prostagLandin series which are suitable for the use according to the invention are all the substances which have aggregation-inhibiting properties on blood plate- Lets and are described, for example, in: R. C. NickoLson, M. H. Town and H. Vorbrflggen, Med. Res. Rev. 5 (1985), B.

I. R. Whittle and S. Moncada, Progress in Medicinal Chemistry 21_ 236 (1984), P. A. Aristoff in Advances in ProstagLandin, Thromboxane and Leukot ri ene Research Vol. 14, 1985, p. 309, and B. RadicheL and H. Vorbr~ggen, in Advances in Prostaglandin, Thrornboxane and Leukotriene Research Vol 14, 1985, p.

2 6 3 and in EP 0011591, 0055208, 0069692, 0086404, 0099538 and 011 9949 as well as in DE-OS 34 08 699 and DE-OS 35 10 978.

Examples which may be mentioned are: prostacyclin PGI 2 15-cyclopentyl-o3-pentanor-5(E)-carbacyclin (ONO-4l 483; Prost. and Med..

53, (1983), ((E)-(1S,5S,7R)-7-hydroxy-6-(3S,4S-3-hydroxy-4-methylnona-1,6-diynyl1bicyclo[3.3.o]octan-3ylidenel pentanoic acid (EP 0086404), (5E)-(16S)-13,14-didehydro-16.20-dimethy1-18,18,19,19-tetradebydro-2,3,4trinor-1,5-lnter-m-phenylene-6a-carbaprostalndii 1 2 (DE-Os 3408699), 5-((E)-(1S,5S.6R,7R)-7-h~ydroxy-6-((3S,4RS)-3-bydroxy-4-methyl-l-octen-6ynyllbicycloE3.3.0loctan-3-ylidenempetaloic acid (iloprost, EP'6011591), r o '4 7-(EI)-(1S.SS,6S.7R)-7-bydroxy-6-((3S.4 S)-3-hydroxy-4--methylnona-1,6diyny1]bicyclo[3.3.0Jactan-3-ylidene-S-oxaheptanoic acid (EP 0099538), dihydroxy-15-cyclohexyl-16,17,18,19,20-pentanorlprostadienoic acid (CG 4305, Arzn. Forsch. 1983, 1240) and the corresponding sodium salt (CG 4203, Drugs Future 9 494, (1984)), B-thiaiminoprostacyclinCHoe 892, Frost. and Med. 10, 231 (1983)), 9-methylcarbacyclin Org. Chem. 48, 534 (1983)), E)-(lS,5S,6S7R)-7-hydroxy-6-I(3S,4S)-3-bydroxy-4-methylnona-1,6diynyllbicyclot3.3.Ojoctan-3-ylidene-3-.oxapentanoic acid ,EP 0119949), (Z)-(lS.SS,6S.7R)-7-bydroxy-6-E(3S,4S)-.3-bydroxy-4-methylnona.-l,6diynyllbicycloE3.3.0loctan-3-ylidenej-3--oxa-S-fluoropentanoic acid (EP 0099538), 7-oxo-16-miethyl-18,19-didehydro-PGI 2 (DE-.OS 3 035 454), 7-oxo-P01 2 (DE-0S 3 035 454), prostaglandin E 1 6-ketoprostaglandin

EV,

(5Z,13E)-(9R,11R,15S)-9-chlor9-15-cyclohexyl-11,15--dibydroxy- 16,17,18,19,20-pentanor-5,13-prostadienoic acid (DE-OS 3 510 978), &.nd 17S,20-dimethyl-trans-2,3-didehydro-PGI, ('ONO 1206, Drugs Future 7, 116 (1982)) Instead of the prostanoic acids mentioned, it is also possible to use physiologically acceptable salts thereof with inorganic or organic bases, such as, for example, sodium hydroxide, potassium hydroxide, tris-ChydroxymethyL)-aminomethane, gLucamine, N-methyLglucamine, morphoLine, Lysine or argi nine..

K

Possible thromboxane receptor antagonists are all the compounds which have a sufficient affinity for thromboxane receptors and have no thromboxaneagonistic activity or a thromboxane-agonistic activity which'is only insignificant in the dose range used, such as described, in: J5 5017-315; US 4472-586-A; US 4263-207; US 4394-515-A; US 4282-365; BE-883-713; 7093-962; J6 0004-154-A; EP--43-292; EP--82-646-A; DE 3346-047-A; WO 8400-754-A; US 4474-804-A; DE 3401-986-A; DE 3127-343; BE-897-763-A; -EP--74-861; AU 8425-607-A; EP-78-668; DE 3339-019-A; and EP-137-426-A and by N. H. Wilson and R. L. Jones in: Advances in ProstagLandin, Thromboxane and Leukotriene Research 14, 420-423 (1985), and by K. Stegmeier et aL. in: Thrombosis Research 35, 379-395 (1984).

Examples which may be mentioned are: 4-[2-(Benzenesulphonamido)ethyllphenoxyacetic acid (BM 13 177) 1K. Stegmeier et al in Thrombosis Research 35., 379-395, 1984].

(morpholinyl)-3-oxocyclopentyll-4-heptenoic acid (All 23848) (Brit. J.

Pharinac. (1985), 86, 259.

1Bf,2zc(5Z_), 3c,4B1-7.-r-2-(Phenyamino)carbonyl1hydrazinomethYl1- 7-oxabicyclot2.2.llhept-2-ylI-5-heptenoic acid (SQ 29.548) (Prostcaglandins 29, 785 (1985)).

4-.[2-(4-Chorobenzenesulphonamido)ethy11bernzeneacetic acid (EM 13 505) (Intern. Conf. Leulcotrienes and Prostanoids in Health and Disease, Tel- Aviv, Oct.1985, p Z~2a,2B,(Z) ,3cL,4ci-7-13-[[[(Phenylamino)carbonyllhydrazonolmethyl]bicy clo[2.2.ljhept-2-yll- (EP 045) and 7-8L(1S,2S,3S ,4R)-3-[1-(phenylthioureidoimino)ethyllbicyclo[2.2A11heptan-2-yij3-5-heptenoic acid (EP 092) (both substances R. A. Arrnstong et al in Brit J. Pharmacol. 84, 595-607, 19851.

Dibenzo~b,fjthiepine-3-methanol 5,5-dioxide (L 640035) [C-C Chan in Europ. J. Pharmacol 110 323-328, 19851.

*1

VTQ

N

7 -3-Chlorophenyl)-N2-[[7-[((3-chlorophenyl)aminolsulphonyl]-3,4-dihydro- 2(1H)-isoquinolinyllsulphonyll-3,4-dihydro-2.7(1H)-isoquinolinedisulphonamide (SKF 88046) B.M. Weichman et al in Prostaglandins Leukottrienes and Medicine 167-175, 19841.

The PC/PCA/PGi are employed in amounts which are clearly below the amounts dtherwise used for inhibition of intravasal platelet aggregation.

When iloprost is used as the PCA, as a rule 10 1,000 yg, preferably 50 250 pg, per day will be sufficient according to the present invention.

Administration can be effected, for example, enterally or parenterally, inhalatively or also transdermally or locally.

In the case of intravenous infusion of iloprost, for example, amounts of about 50 150 ug per day are required.

In the case of oral administration, about 125 250 ug per day are employed.

One dose unit of iloprost contains about 100 pg/ml as a stock solution for dilution in customary infusion excipient solutions for intravenous administration.

For oral administration, one dose unit contains 25 50 Vg, and in sustained release formulations 25 250 pg, as a tablet, coated tablet, capsule, pill, suspension or solution, which can be prepared in the usual manner with the additives and excipient substances customary in galenics.

Systems such as skin plasters or suppositories, for example, are possible for local, topical or transdermal administration.

According to the invention, biologically equivalent amounts of other prostacyclin analogues or prostaglandins can also be employed.

According to the present invention, the thromboxane receptor antagonists are employed in amounts which.are as a rule below the amounts hitherto u.d in human studies ERiess, E. Hiller, B. Reinhardt, C. BraUning in: Thrombosis Research 35, 371-378, 19843. In general, 100 2,000 mg/day, preferably 200 800 mg/day, BM 13 177 or 1 100 mg/day, preferably 2 mg/day, AH23848 or SQ 29548, or a biologically equivalent amount of another thromboxane receptor antagonist are sufficient.

-9 -7 2 IIIIlli ~le N The TXAA can be administered, for example, enteraly or parenterally, inhalatively and also transdermaLLy or locaLLy.

Tablets, coated tablets, capsules, pills, suspensions or solutions, in particular, are possible for the preferred oral administration, and these can be prepared in the usual manner with the additives and excipient substances customary in galenics.

Transdermal systems, such as skin plasters, for example, can be used for local administration.

One dose unit for oral or parenteral administration contains about 50 300 mg, or as a sustained release formulation 100- 1,000 mg, BM 13 177/day or a biologically equivalent amount of another thromboxane receptor antagonist.

Combined treatment with PCA and TXAA is carried out, depending on whether the pathological process is acute, subacute or chronic, for a few days up to weeks or months, the PCA and TXAA being administered in one dose unit or separately and simultaneously or sequentially.

The following examples are intended to illustrate formulation: Example 1 Composition of a combination tablet the galenical Amount/tablet Emg3 1. Ioprost 0.01 0.05 (as a solution in ethanol, 2. BM 13 177 50.0 250.0 3. Lactose 34.99 174.95 4. Maize starch 10.0 50.0 Polyvinylpyrrolidone 2500 3.0 15.0 6. Stearic acid 2.0 10.0 100 500.00 mg 4G-

S

Constituents 3, 4 and 5 are sieved and mixed and the mixture is granulated with the solution of 1. After drying, 2 and 6 are mixed in successively and the compressed mass is pressed to circular tablets with a diameter of 11 mm.

Example 2 Composition of combination tablet Amount/tablet [mg] 1. Iloprost 0.02 0.05 (as a solution in ethanol, 2. SQ 29 S48 4.0 10.0 3. Lactose 65.98 164.95 4. Maize starch 20.0 50.0 Polyvinylpyrrolidone 2500 6.0 15.0 6. Stearic acid 4.0 10.0 100 250.00 mg Constituents 3, 4 and 5 are sieved and mixed and the mixture is granulated with the solution of 1. After drying, 2 and 6 are mixed in successively and the compressed mass is pressed to circular tablets with a diameter of 11 mm.

-LCL---

I 5 r Example 3 omposition of a combination tablet Amount/tablet Emg] 1. Iloprost 0.02 0.05 (as a solution in ethanoL, 2. AH 23 848 1.0 3. Lactose 68.98 172.45 4. Maize starch 20.0 50.0 Polyvinylpyrrolidone 2500 6.0 15.0 6. Stearic acid 4.0 10.0 100 250.00 mg Constituents 3, 4 and 5 are sieved and mixed and the mixture is granulated with the solution of 1. After drying, 2 and 6 are mixed in successively and the compressed mass is pressed to circular tablets with a diameter of 11 mm.

Example 4 Composition of a combination tablet Amount/tablet Emg] 1. Iloprost Na salt 0.0104 0.052 (dissolved in aqua dest) (S 0.05 mg iloprost) 2. BM 13 177 50.0 250.0 3. Lactose 34.99 174.95 4. Maize starch 10.0 50.0 Polyvinylpyrrolidone 2500 3.0 15.0 6. Stearic acid 2.0 10.0 100 500.0 mg Constituents 3, 4 and 5 are sieved and mixed and the mixture is granulated

I'

4 with the solution of 1. After drying, 2 and 6 are mixed in successively and the compressed mass is pressed to circular tablets with a diameter of 11 mm.

Example 5 Composition of a combination tablet Amount/tablet Emg] 1. Iloprost 0.33 1.66 as an inclusion compound with 0.05 mg iloprost) or 6-cyclodextrin, 3% (w/w) 2. BM 13 177 50.0 250.0 3. Microcrystalline cellulose 35.67 178.34 4. Maize starch 12.0 60.0 Stearic acid 2.0 10.0 100 500.0 mg instituents of the recipe, with the exception of the stearic acid, are e:d and are mixed for 15 minutes. Stearic acid (sieved) is added and mixed with the other constituents of the formulation for a further 3 minutes.

The compressed mass is pressed to circular tablets with a diameter of 11 mm.

PHARMACOLOGICAL FINDINGS 1. Platelet function in vitro (human PRP) BM 13 177 (BM in the text) and iloprost are tested against the stimulators U 46 619 (9,11-dideoxy-9tt-11a-methanoepoxy-PGF 2 stable

TXA

2 agonist) and ADP in their action on platelet aggregation and platelet shape change and the IC 50 values are determined.

Thereafter, the action of a combination of the two substances on aggregation (U 46 619 and ADP) is tested in various concentrations CLS~' 1 1 11

Y

Sin i P s hN in several independent experiments; in particular, the combination of low dosages and dosages of the two substances in the region of the IC 0 y values is tested.

Method Platelet aggregation and shape change are measured as photooptical phenomena in stimulated PRP samples (platelet rich plasma). The shape change is recorded here as an increase in the density of the sample by transition from the discoid dormant shape of the platelet into a spherocytic shape with the formation of pseudopodium-like membrane developments and is shown on a recorder. The aggregation is recorded photometrically as the decrease in density due to clumping and "precipitation" of platelet aggregates and is shown on a recorder.

Results Iloprost inhibits, as a function of the concentration, platelet aggregation induced by U 49 619 and shape change. The IC 50 for the inhibition of aggregation is 1.3 2.6 nM, and for the inhibition of shape change the IC 50 is 0.52 1.3 nM.

The 2nd wave of aggregation induced by ADP is inhibited as a function of the concentration, with an IC 50 of 0.26 0.65 nM.

BM 13 177 inhibits, as a function of the concentration, the platelet aggregation induced by U 46 619 and the shape change. The IC 50 for the aggregation is 1.65 6.6 M, and that for the shape change is 1.65 3.3 PM.

The 2nd wave of aggregation induced by ADP is inhibited as a function of the concentration, with an IC 50 of. 0.33 0,66 PM.

1 a: Combination of thromboxane receptor antagonist and iloprost The platelet aggregation induced by U 46 619 and the platelet shape change, and the 2nd wave of aggregation induced by ADP are greatly inhibited with the combination of BM 13 177 with iloprost at concentrations of the two active substances which are in the threshold or subthreshold range. The inhibiting effects of the two active substances potentiate each other here (see Table).

Tables Example 1: Aggregation by 100 ng/ml U 46 619 Active substance Concentration Inhibition 1 BM 13 177 2 Iloprost 1+2 0.66 pM 0.1 ng/ml Example 2: Shape change by 50 ng/ml U 46 619 Active substance Concentration 1 BM 13 177 2 Iloprost 1 2 0.66 yM 0.1 ng/mL Inhibition 28% no inhibition 61% Example 3: 2nd wave of aggregation by 0.5 x 10- 6 M ADP Active substance Concentration 1 BM 13 177 2 Iloprost 1 2 0.165 jpM 0.1 ng/ml Inhibition no inhibition no inhibition -u ypC 2. Intravasal platelet aggregation on anaesthetised rats Method The influence on intravasal platelet aggregation is investigated on urethane-anaesthetised rats.

Collagen (100 pg/kg i.v. bolus) produces transitory thrombocytopenia (a temporary decrease in blood platelet concentration), measured by continuous withdrawal of blood from the a. carotis (50 pl/min) and counting of the platelets in a Technicon-Autocounter. The change in collagen-induced thrombocytopenia decrease) in comparison with the starting value 2nd collagen injection) serves as a measure of the inhibition of intravasal platelet aggregation.

Results Iloprost (0.1 0.33 1.0 yg/kg/min) inhibits collagen-induced thrombocytopenia as a function of the dose. BM 13 177 inhibits thrombocytopenia in the lowest dosage (0.5 mg/kg/min) by 27 6 (MV SE), an effect which cannot be increased by increasing the dose (1.0 2.0 mg/kg/min). The combination of a threshold dose of iloprost (0.1 ug/kg/min with the lowest dose of BM 13 177 tested mg/kg/min) produces a significantly 0.05; Lord test) more powerful inhibition of 45 2% in respect of the individual doses.

3. Mesenteric arteriole thrombosis on anaesthetised guineapigs Method A mesenteric loop is prepared for vital microscopy on anaesthetised guineapigs. After electrical lesion of an arteriole, ADP is applied topically, under control conditions and after administration Sof the substance, until a thrombogenic dose is discovered (occlusion by a platelet thrombus).

Parameters: Increase in the thrombogenic ADP concentration against the initial value; i.v. infusion of iloprost, i.v. injection of BM 13 177.

i *y A J 'T i: :i D "Results On the electrically predamaged mesenteric arteriotes of anaesthetised guineapigs, BM 13 177 (25 mg/kg significantly increases, by about a factor of 4, the ADP concentration required to trigger off occluding platelet thrombi.

Iloprost increases the thrombogenic ADP concentration by a factor of 2.8 in the threshold dose of 0.1 Vg/kg/min i.v.

A combination of BM 13 177 (25 mg/kg followed by an i.v.

infusion of iloprost (0.1 pg/kg/min) increases the thrombogenic ADP concentration by a factor of 12.

On an experimental model for arterial platelet-induced thrombosis, a combination of the TXA 2 antagonist BM 13 177 and the prostacyclin analogue iloprost Leads to a potentiated antithrombogenetic action.

4. Jugular vein thrombosis in anaesthetised rats Method By loading the jugular vein of urethane-anaesthetised rats with a metal stamp cooled to -150C (200 g, 2 min), the vessels are predamaged. The thrombus which grows at this point within 3 hours is quantified by determinations of its Hb content (difference between the damaged and undamaged vascular segment) (Hb content, moist weight).

Infusion of the test substances starts 15 min before the vein is damaged and is continued until the end of the experiment.

Results 1 O The infusion of iloprost in a dosage which is not significantly effective as an individual dose (30 ng/kg/min, in combination with a dose of BM 13 177 which is also ineffective as monotherapy mg/kg, i.v. bolus 50 g/kg/min, gives rise to a significant reduction in the Hb content of the thrombi to the values of undamaged controls.

I _.xiL~~l;i

I'~PLC

BM 13 177 does not have an antithrombotic action as a monotherapy in the jugular vein thrombosi's model on rats. The combination with a dose of iLoprost which has no haemodynamic or antiaggregatory i action completely suppresses thrombus growth.

Blood pressure of spontaneously hypertensive (SH) rats Method The behaviour of the blood pressure and heart rate under infusion of the test substances is observed on conscious SH rats in which a vein catheter is implanted for administration of the substance and an artery catheter is implanted for measurement of the blood pressure.

Iloprost in a threshold dose of 0.3 pg/kg/min (20% reduction in the diastolic blood pressure) and a high dose of BM 13 177 of 2 mg/kg/min (see platelet inhibitior in vivo, 27% inhibition at 2 mg/kg i.v. infusion) are infused together for 20 minutes (n 6 animals).

Result The haemodynamic changes of drop in blood pressure and increase in heart rate caused by iloprost are only slightly influenced by BM 13 177.

Whilst the maximum reduction in blood pressure under iloprost is not influenced by BM 13 177, the action subsides more rapidly.after the end of the infusion under the combination treatment.

An intensification in the anti-hypertensive action of iloprost by BM 13 177 must not be expected, even at high dosages of BM 13 177.

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ABSTRACT

Combination products containing a prostaglandin a prostacyclin (PC) or a prostacyclin analogue (PCA) and a thromboxane receptor antagonist (TXAA) are suitable for joint use on thrombotic and thrombo-embolic syndromes.

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Claims (12)

1. A combination product for combined administration in cases of thrombotic or thrombo-embolic syndromes, containing an effective amount of a compound (hereaftor designated PC/PCA/PG) selected from the group consisting of prostacyclins (PC), prostacyclin analogues (PCA) and prostaglandins (PG) and an effective amount of a thromboxane receptor antagonist hereafter designated (TXAA).

2. The product according to claim 1, characterized in that the PC/PCA/PG and TXAA are in a weight ratio of 1:1 to 1:10,000.

3. The product according to claim 1 or claim 2, characterized in that the PC/PCA/PG and TXAA are present Se together in one dose unit.

4. The product according to any one of claims 1 to 3, characterized in that a PC/PCA/PG dose unit contains 25-250 pg iloprost; 5-[(E)-(1S,5S,6R,7R)-7-hydroxy-6-[(E)-(3S,4RS)- 3-hydroxy-4-methyl-5-octen-6-inyl] bicyclo[3.30] octan-3- ylidene] pentanoic acid or a biologically equivalent amount of another PC/PCA/PG. The product according to any one of claims 1 to 4, S characterized in that a TXAA dose unit contains 50-1,000 mg BM 13 177 (as hereinbefore defined); 4-[2-(benzenesulphonamido) ethyl] phenoxyacetic acid or a biologically equivalent amount of another TXAA.

6. A method for the treatment of thrombotic or thrombo-embolic syndromes in a subject which comprises administering to said subject an effective amount of a compound selected from the group consisting of prostacyclins (PC), S A L o 0232e/RAP prostacyclin analogues (PCA) and prostaglandins and an effective amount of a thromboxane receptor antagonist (TXAA).

7. The method according to claim 7, characterized in that the PC/PCA/PG and TXAA are in a weight ratio of 1:1 to 1:10,000.

8. The method according to claim 7 wherein the PC/PCA/PG and TXAA are administered in one dose unit.

9. The method according to claim 7 wherein the PC/PCA/PG and TXAA are administered in separate dose units, either simultaneously or sequentially. S* 10. The method according to any one of claims 7 to 9, characterized by administering 25-250 pg of iloprost as the PC/PCA/PG or a biologically equivalent amount of another PC/PCA/PG.

11. The method according to any one of claims 7 to characterized by administering 50-1,000 mg of BM 13 177 as the TXAA or a biologically equivalent amount of another TXAA. 0*

12. A method for the treatment of thrombotic or thrombo-embolic syndromes in a subject, which comprises the sequential administration to said subject of an effective amount of a compound selected from the group consisting of prostacyclins prostacyclin analogues (PCA) and prostaglandins and an effective amount of a thromboxane receptor antagonist (TXAA).

13. A combination product containing PC/PCA/PG and TXAA substantially as herein described with reference to any one of the Examples thereof.

14. A method for the treatment of thrombotic or thrombo-embolic syndromes in a subject, substantially as herein A 023 2e/RAP described with reference to any one of the Examples of said method. DATED this 3rd day of August, 1990. SCHEF-ING AKTIENGESELLSCHAFT By Its Patent Attorneys ARTHUR CAVE Fv CO. .0 0 L NT O' U T p- I i n INTERNATIONAL SEARCH REPORT International Application No PCT/DE 86/00260 I. CLASSIFICATION OF SUBJECT MATTER (if several classification symbols apply, Indlcate ill) According to International Patent Classification (IPC) or to both National Classificatlon and IPC Int.Cl.4A 61 K 31/557; 61 K 31/557:31/18) II. FIELDS SEARCHED Minimum Documentation Searched 7 Classlfication System I Classlfcation Symbols Int.C1. 4 A 61 K Documentation Searched other tha M!inimum Documentation to the Extent that such Documents are Inciuded In the Fields Searched III. DOCUMENTS CONSIDERED TO BE RELEVANT* Category Citation of Document, with Indication, where appropriate, of the relevant passags Relevant to Claim No. 1 X CH, A, 637298 (THE WELLCOME FOUNDATION) 29 July 1983, see claims 1,4,5,11,14; 1-4,7,9,12 page 2, column 2, last paragraph; page column 1, lines 24-31,53-60 Special categories of cited documents: 1e later document published after the international filing date document defining t nert w or priority date and not in conflict with the application but document defining the generel state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention earlier document but published on or after the international document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or Involve an inventive step which is cited to establish the publication date of another document of particular relavance; the claimed Invention citation or other special reason (as specified) cannot be considered to involve an Inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published prior to the International filing date but in the art. later than the priority date claimed document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the international Search Date of Mailing of this International Search Report 01 October 1986 (01.10.86) 31 October 1986 (31.10.86) International Searching Authority Signature of Authorized Officer European Patent Office Form PCT/ISA/210 (second sheet) (January SS) 1_ I ANNEX TO THF INTERNATIONAL SEARCH REPORT ON INTERNATIONAL APPLICATION NO. PCT/DE 86/00260 (SA 13642) This Annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP file on 10/10/86 The European Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent document cited in search report CH-A- 637298 Publication date Patent family member(s) Publication date 29/07/83 None For more details about this annex see Official Journal of the European Patent Office, No. 12/82 i INTERNATIONALER RECHERCHENBERICHT gnternationales Aktenzoichen PCT /DE 86 /00260 1. KLASSIFIKATION DES ANMELDUNGSGEGENSTANDS (bet mehreren Klassifikationssymbalen sind alle arizugelpenl 6 Nach der Internationalen Patentkclassilikation (IPC) oder nach der natianalen Klassifikatian und der IPC tnt C1 4 A 61 K 31/557;//.(A 61 K 31/557.31/18) 11. RECHERCHIERTE SACI4GEBIETE Recherchierter Mindestpriifstaff7 Klassifikatianssystem Klassifikationssymbale Int. Ci.4 A 61 K Recherchierte nicht zumn Mindestprufstoff gehorende Veroffentlichungen, saweit diese unter die recherchierten Sachgebiete fallen 3 III. EINSCHLAGIGE VEROrFENTLICHUNGEN 9 Art* Kennzeichnung der Verbffentlichung 11 .soweit erforderlich unter Angabe der malggeblichen Teile 12 Cetr, Anspruch Nr. 3 X CH, A, 637298 (THE WELLCOME FOUNDATION) 29. Juli 1983, siehe Anspriiche 1,4,5,11,14; 1-4,7-9,12 Seite 2, Spalte 2, letzter Absatz; Seite Spalte 1, Zeileri 24-31-, 53-60 *Besandere Kategorien von angegebenen Vero ffentl ichu ngen 10 Veraffentlichung. die den alittemeinen Stand der Technik Spatere Verbffentlichung. die nach demn internatianalen An. definiert, aber nicht als besanders bedeutsamn anzusehen itt meldedatum ader dem PrioritStsdatumn veroffentlicht worden "E"51ers okuen, asjedoch enst am oder nach den inierna. it und mit der Anmeldung nicht kollidiert, sondern nur zuin tinalen Dokmentdat effnlctwrnis Verstbndnis des der Et findung zugrundeliegeinden Prinzips tianlenAnmededtumverafenlict waden1stoder der ihr zugrundeliegenden Thearie angegeben ist Verboffentl ichu ng. die geeignet ist. einen Priaritatsanspruch X'Vrfetihnvobsnde Beungdebaspc- zweifelhaft erscheinen zu latten. oder durch die das Verdf. Verffntlung an ih besnerer atedeusndeiser beaSpruc- fentlichungsdatum elner anderen im Recherchenbericht ge. t ridn annctasnuae u n~drshrTtg nariten Wroffentlichung bctegt werden soil oder die aus eineti keit beruhend betrachtet wverden anderen besanderen Grund angegeben ist (wie ausgeluhrit) Veroffentlichung von besanderer Bedeu tung; die bepnspruch. Veroffentlichung, die sich auf etne mundlicthe offenbarung. te Erfindung kann nicht als auf erfinderischer Taigkeit be. eine Benutzung, eine Ausiellung oder andere Malfnahmen ruhend betrichtet wverden, wenn die Veroffentlichung mit beziehseiner ader mehreren anderen Veroffentlichungen dieser Kate, beziehtgorie in Verbindung gebracht wird und diese Verhindung fur Verdffenitchunig. die var demn internatianalen Anmeldeda. eimen Fachmann naheliegend ist turn, aber nach demn beanspiuchten Priaritatsdlatum veroffent. eofnlcug i igie esle aetaii t licht warden ist VrfetihndeMtle esle aetaii s IV, BESCHEINIGUNG Datum dess Abschiusses der internatianalen Recherche, 1. Oktober 1986 Inter natianale Recherchenbeharde Europiisches Patentamt Absendedasum des internatianalen Recfserchenberichs Forniblatt PCT'ISA/210 (Blatt 21 (Jaruaf 19B5) 1~ I ANHANG ZUM INTERNATIONALEN RECHERCHENBERICHT tYBER DIE INTERNATIONALE PATENTANNELDUNG NR. PCT/DE 86/00260 (SA 13642) In diesem Anhang sind die Mitglieder der Patentfamilien der im obengenannten internationalen Recharchenbericht ange- ftihrten Patentdokumente angegeben. Die Angaben iiber die Familienmitglieder entsprechen dem Stand der Datei des Europdischen Patentamts am 10/10/86 Diese Angaben dienen nur zur Unterrichtung und erfolgen ohne Gew~hr. Im Recherchenbe- richt angefiihrtes P atentdokument Datum der Verbffent- lichung Mitglied(er) der Patentfami lie Datum der Verbffent- lichung CH-A- 637298 29/07/83 Keine FUr nahere Einzelheiten zu diesem. Aiharig siehe Amtsblatt des Europdischen Patentamts, Nr. 12/82