LU85127A1 - NEW DRUG ASSOCIATION BASED ON A HYDROGEN ALKALOID OF ERGOT AND HEPARIN - Google Patents

Description

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The subject of the present invention is a new drug combination and pharmaceutical compositions which can be used for the prophylaxis of thromboses, in particular for the prevention of postoperative thromboses.

5 Heparin is a highly sulphated dextrorotatory mucopolysaccharide with specific anticoagulant properties and is commonly used inter alia in the prevention of postoperative thrombosis. It is a natural constituent of various tissues, in particular the liver and lungs, in a variety of mammals and preparations isolated from different natural sources are available on the market, in free form and in the form of a pharmaceutically acceptable salt, for example in the form of various alkali metal and alkaline-earth salts.

Whole heparin, i.e. as obtained directly from various natural sources according to the usual isolation methods, comprises polymer units of non-uniform molecular weight commonly between 6,000 and 20,000, the average molecular weight being 14,000 to 18,000, in which the basic polymer chain consists of residues of D-glucosamine and D-glucuronic acid. The specific chemical and physical constitution, for example the precise degree of sulfation and the characteristics of the molecular weight vary according to the source, that is to say the animal material from which it comes, as well as precise means of isolation. As indicated below, various techniques are known and have been described in the literature for obtaining heparin preparations of lower average molecular weight than whole heparin preparations, for example obtained directly from the source. animal by other means.

It is also known that the administration of heparin in combination with hydrogenated ergot alkaloids exerting a vasoconstrictive effect, in particular dihydroergotamine, has a particular advantage in relation to the prophylaxis of thromboses, especially prevention. post-operative thrombosis (see for example British patent application No. 1 557 331) and heparin / 2 dihydroergotamine therapy is now an effective treatment commonly followed by patients at risk of thrombosis, especially after a serious operation. The administration is generally carried out parenterally, namely by intravenous injection, and various formulations exhibiting, for example, improved stability characteristics compared to simple solutions intended for such use, are described in the literature or are available on the market. (see for example American patent application No. 4,402,949).

In accordance with the present invention it has now surprisingly been found that when a combination therapy as described above is applied, particularly advantageous results are obtained if the heparin is a low molecular weight heparin. It has been found in particular that by using low molecular weight heparin in combination with a hydrogenated ergot alkaloid having a vasoconstrictive effect, in particular dihydroergotamine, in place of the preparations of whole heparin usually used, the therapeutic efficacy, namely the duration of the anti-thrombotic effect, is greatly increased, the daily dose of heparin and hydrogenated ergot alkaloid necessary for effective prophylactic therapy can be reduced accordingly.

The present invention thus has the very great advantage of allowing a significant reduction in the daily medication required for the treatment of patients. As previously indicated, since the treatment is generally carried out by intravenous injection, the present invention therefore also has the advantage of allowing the reduction in the number of daily injections and at the same time substantially reduces the patient's discomfort. This is particularly important in the case of patients undergoing or having undergone a serious operation.

In accordance with the above, the present invention relates, as a medicament, to the combination of: 3 ti) a hydrogenated ergot alkaloid having a vasoconstrictive effect, or a pharmaceutically acceptable acid addition salt thereof, and ii) a low molecular weight heparin or a pharmaceutically acceptable salt thereof this compound.

The invention also relates to a pharmaceutical composition comprising components i) and ii) as defined above.

Component i) of the medicament and the composition of the invention is advantageously a hydrogenated ergot alkaloid of formula R

o "i ο" Γ— | C-NH ---- 15 ^ .Γθ ° Ü)

XX

in which 20 R represents hydrogen or a C1-C4 alkyl group,

R1 represents a methyl, ethyl or isopropyl group, R2 represents an isopropyl, sec.-butyl, isobutyl or benzyl group and X represents hydrogen or a methoxy group, or a pharmaceutically acceptable acid addition salt of this compound .

Component i) is preferably dihydroergotamine, 6-nor-isopropyl-9,10-dihydro-2 'pi-methyl-5'a-benzyl-ergopeptine or dihydroergovaline, or a pharmaceutically acid addition salt Acceptable of these compounds, dihydroergotamine and the acid addition salts of this compound being most particularly preferred. Suitable pharmaceutically acceptable acid addition salts are, for example, methanesulfonates, maleates and tartrates, and, in the case of dihydroergotamine, especially methanesulfonate.

4

By the expression "a low molecular weight heparin" is meant a heparin prepared for example by isolation or depolymerization methods as described below, in order to achieve a significant reduction in the average molecular weight compared to the preparations of whole heparin.

Components ii) as used in the present invention preferably have an average molecular weight of about 10,000 or less, more preferably about 8,000 or less. However, the average molecular weight is preferably not less than about 4,000, more preferably not less than about 5,000, most preferably not less than about 6,000. The especially preferred components ii) thus have an average molecular weight of between about 10,000 and about 4,000, in particular between about 8,000 and about 5,000, for example about 7,000 ± 1,000 or about 6,000 ± 1,000. It is further preferred that the components ii) have a relatively uniform molecular weight, for example with at least 60%, more preferably 80% of polymer units having a molecular weight within the limits of average molecular weight defined above, c ' i.e., a molecular weight of 10,000 or less.

Suitable pharmaceutically acceptable salts of low molecular weight heparins as components ii) are for example the calcium salt and the potassium salt, in particular the sodium salt.

Low molecular weight heparin or the pharmaceutically acceptable salt of this compound used as component ii) can be obtained by known methods, for example by isolating low molecular weight fractions from whole heparin preparations, by example by fractional precipitation and filtration, for example as described in German patent application DOS 29 45 591, or by depolymerization of high molecular weight fractions of whole heparin, for example by chemical scission, as described for example in the Belgian patent N °. 888 864 or in European patent application N °. Alternatively, components ii) can be obtained by a combination of such techniques, for example by separation of low molecular weight heparin from whole heparin preparations, then depolymerization of the remaining heparin fractions by weight higher molecular weight to obtain additional low molecular weight heparin and, optionally, the mixture of the two low molecular weight heparin preparations thus obtained.

When low molecular weight heparin is prepared by chemical cleavage, the residues of the individual chains may undergo certain chemical modifications, in particular de-sulfation. When such modifications take place on the product intended to be used according to the present invention, the components ii) thus produced can, if necessary, be subsequently reconstituted or modified in an appropriate manner according to known techniques, for example in a manner analogous to that described in Belgian patent N °. 888 864.

When the low molecular weight heparin preparations obtained by chemical cleavage are used in the compositions of the invention, they are preferably preparations which have undergone no or essentially no other chemical modification.

Components i) and ii) are advantageously present in a ratio of 1 mg of component i): 300 to 70,000 (for example 500 to 70,000), preferably 300 to 35,000 IU of component ii). The components i) and ii) are more preferably present in a ratio of 1 mg of component i): 1,000 to 20,000 (for example 2,000 to 20,000), especially 1,000 to 10,000 IU of component ii). When component i) and / or ii) is present in the form of a pharmaceutically acceptable salt, the equivalent quantity of salt providing the indicated ratios is used.

As indicated above, the compositions of the invention will generally be administered by injection. For direct application, they will therefore be in liquid form. Although, for example, simple aqueous or hydroalcoholic solutions are possible, they are generally not preferred because, in the absence of stabilizers, components i) and ii) will react to form sparingly soluble salts which precipitate of the solution. Therefore, simple solutions cannot be stored for more than a few hours and therefore have limited practical value.

The preferred compositions according to the present invention are stabilized solutions of the type described in US Pat. No. 4,402,949 already cited, using for example an additional component iii) which is a calcium or magnesium salt of the acid. Pharmaceutically acceptable ethylenediamine tetraacetic (EDTA) as a stabilizer. For such solutions, the solvent medium preferably comprises iv) water and v) a mono- or polyalcohol.

The magnesium or calcium salts of EDTA indicated as component iii) are the mono-magnesium or mono-calcium salts, including the pharmaceutically acceptable poly-metallic salts comprising magnesium or, preferably, calcium with ions monovalent metals, for example sodium or potassium ions. The preferred EDTA salt for use according to the invention is the disodium mono-calcium salt (CaNa2 EDTA) also known as cal ci umti triplex. The dipotassium mono-magnesium salt (MgK2 EDTA) can also be mentioned.

Component iii) is preferably present in an amount between about 1 and about 50 mg, more preferably 1 to 25 mg, most preferably 1 to 10 mg, based on an amount of 5,000 IU of component ii).

When the solvent medium comprises components iv) and v), that is to say as diluent or vehicle, they preferably represent 45 to 72% and 28 to 55% respectively, based on the total volume of the composition .

Preferred components v) are ethanol, propylene glycol, polyethylene glycol (preferably with an average molecular weight of about 400), diethylene glycol, triethylene glycol and glycerol, as well as mixtures of these compounds. More preferably, component v) comprises a mixture 7 a) of ethanol and b) of triethylene glycol or a mixture c) of glycerol and d) of propylene glycol. In such mixtures, a) and b) are preferably present in a weight ratio of 1: 6 to 10, more preferably 1: 8, and c) and d) are preferably present in a weight ratio of 1: 8 to 12, more preferably 1:10.

According to a preferred variant of the invention, the above solutions also contain, as another component vi), a physiologically acceptable anesthetic. The anesthetic components vi) are preferably "acetanilide anesthetics" term by which is meant any member of the class of physiologically acceptable acetaniide derivatives exerting anesthetic activity, including the various known derivatives of 2-amino-N- phenylacetanilide active as anesthetics, and their pharmaceutically acceptable salts. The preferred acetanilide anesthetics are 2- (diethylamino) -N- (2,6-dimethylphenyl) -acetamide (also known as 1idocaine), 2- (butylamino) -N- (2-chloro-6- methyl-phenyl) -acetamide (also known as hostacaine) and the 2- (2-diethylamino-acetamido) -m-toluic acid methyl ester (also known as baycaine). The pharmaceutically acceptable salts commonly used for such acetanilide anesthetics include, for example, hydrochlorides. When component vi) is present, it preferably represents from 1 to 2% by weight of the total weight of the composition.

The solutions of the present invention, for example for injections, suitably have a pH of 4 to 6.

It should be noted that although the solutions, for example as described above, are generally those most suitable and which are preferred, the present invention also includes other suitable forms of compositions containing components i) and ii), such as lyophilized preparations, for example those which are put in solution or in another suitable liquid form, before administration. The compositions of the invention may contain any other desired additive, for example known carriers, diluents, stabilizers, preservatives, colorants and surfactants.

8

The new combination, for example in the form of a pharmaceutical composition as described above, is indicated for use in the prophylaxis of thromboses, in particular in the prevention of post-operative thromboses.

The advantageous properties of the new combination compared to those previously used can, for example, be demonstrated by clinical trials, for example with the aid of the binding test for fibrinogen labeled with iodine 125 described by KH Frey et al. Ced. Klin., 70 (1975), pp. 1553-1558) 3, trial 10 in which an external measurement of the radioactivity of fibrinogen labeled with iodine 125, which is selectively concentrated in the thrombotic material of the leg veins, is carried out in patients.

Patients having to undergo a serious operation, for example a plastic surgery of the hip joint, 15 receive by the parenteral route 100 pci of fibrinogen marked with iodine 125 the day before the operation and the legs are measured daily. radioactivity of fibrinogen labeled with iodine 125 during the 2 to 3 weeks following the operation. The fibrinogen injection is repeated 8-10 days after the initial administration if the measured radioactivity is low. A Logic 121 counter is used to record the radioactivity, the counting being carried out according to the method described by Kakkar et al., Lancet, 1 (1970), p.540J. Deep vein thrombosis (DVT) is diagnosed if the count at any site differs by 20% or more from those located at an adjacent point on the same leg or located at an identical location on the other leg, and if this difference persists or increases within 24 hours.

In such a clinical trial, the patients are divided into two groups. Group 1 receives 0.5 mg of dihydroergotamine methanesulfonate and 2,500 IU of low molecular weight sodium heparinate (average molecular weight of approximately 7,000 ± 1,000) # 9 administered intravenously once a day as a stabilized solution. Group 2 receives 0.5 mg dihydroergotamine methanesulfonate and 5,000 IU whole sodium heparinate also administered intravenously twice a day as a stabilized solution. The results of Group 1 receiving the composition according to the present invention are compared with those of Group 2 receiving the usual therapy. The reduction in the incidence of PST on the two groups was found to be equivalent.

10 Results comparable to those obtained in the above clinical trial with a daily injection of a single dose comprising 0.5 mg of dihydroergotamine methanesulfonate and 2,500 IU of low molecular weight sodium heparinate (7,000 ± 1,000) , can also be obtained when the dose of low molecular weight heparin is reduced to 1,500 IU.

The daily dose indicated, for the compositions of the invention will therefore be of the order of 1/3 of the daily doses used with the known compositions containing whole heparin or a pharmaceutically acceptable salt of this compound, with in addition a reduction in the usual dose of heparin, for example a reduction to 1,500 IU per day being possible. Thus, the daily dose indicated for component i) will be of the order of approximately 0.2 to approximately 1.5 mg, for example approximately 0.5 mg, and for component ii) from approximately 1,000 to approximately 10,000 IU , for example around 1,500 to around 5,000 IU. If necessary, the daily dose can be administered in divided doses, for example 2 to 4 times a day. However, it is preferably administered in a single dose once a day, for example in the form of a unit dose. If necessary, components i) and ii) can also be administered separately.

i 10

Unit doses suitable for the compositions of the invention, for example for stabilized injectable solutions as described above comprising for example the components iii), iv), v) and, optionally, vi), include ampoules for injection. and disposable syringes containing a predetermined amount of the composition. Such unit doses suitably contain from about 0.2 to about 1.5 mg, preferably about 0.5 mg, of component i) and from about 1,000 (e.g. about 1,500) to about 10,000 IU, preferably about 10 1,500 IU (for example approximately 2,500) to approximately 5,000 IU of component ii). More preferably they contain about 0.5 mg of component i) and about 1,500, about 2,500 or about 5,000 IU of component ii).

The invention also relates to a process for the preparation of a pharmaceutical composition according to the invention, a process in which component i) is intimately mixed with component ii), for example component i) with component ii) in solution in a pharmaceutically acceptable solvent medium. When the solutions are prepared with the additional components iii), iv) and v) and, optionally, vi) as described above, the process is advantageously carried out in stages comprising 1) the preparation of a solution of component i) and, optionally, of component vi) in a solvent medium containing component v); 2) preparing a solution of component ii) and component iii) in a solvent medium containing component iv); 3) the combination of the solutions obtained via steps 1) and 2), and 4) optionally the additional addition of component iv) and / or 30 v).

11

For the preparation of the solutions, the process of the invention is preferably carried out under a protective gas, for example under a CO2 atmosphere. If the pH of the solution obtained is not of the order of 4 to 6, it is preferably adjusted to this order of magnitude, for example by adding an appropriate amount of a pharmaceutically acceptable acid, for example example a pharmaceutically acceptable organic acid. When a pharmaceutically acceptable acid addition salt is used as component i), the added acid will preferably correspond to the salt used. Thus, when component i) is in the form of methanesulfonate, any necessary adjustment of the pH will preferably be carried out by addition of methane sulfonic acid.

The composition obtained can be in the form of a unit dose as described above, for example in the case of injectable solutions, by filling the ampoules after filtration, preferably under protective gas *, for example under carbon dioxide atmosphere.

The present invention also relates to a unitary packaging or packaging system suitable for the simultaneous presentation or administration of the components i) and ii) mentioned above, said components being contained separately in said packaging or packaging system. The components i) and ii) are each advantageously contained in the packaging or packaging system in the form of 25 unit doses, the quantities of components i) and ii) in each * 12 unit dose being, for example, as specified above. , that is to say very particularly comprising about 0.5 mg of component i) and 1,500, 2,500 or 5,000 IU of component ii). The packaging or packaging system preferably contains the instructions for the simultaneous administration of a predetermined quantity of each of the components i) and ii).

The suitable packaging system according to the present invention comprises multiple syringes, for example with two compartments, in which the components i) and ii) are in separate compartments and suitable for administration by simultaneous or immediately consecutive injection of the compounds contained. . Such syringes with two compartments are known.

The following examples illustrate the present invention without in any way limiting its scope.

15 EXAMPLE 1

Process for the preparation of low molecular weight sodium heparinates having an average molecular weight of about 6,000 to about 9,000

1,000 g of whole sodium heparinate having an average molecular weight of 15,000 are dissolved in 6.66 liters of distilled water, the pH is adjusted to 2.7 by adding approximately 145 ml of 25% HCl, and the whole is passed through a folded filter No. 520 b 1/2 (0 320 mm) from the firm Schleicher and Schüll. The filtrate obtained is pumped through a molecular filtration membrane having an exclusion limit of molecular weight units of 10,000 (Pelllicon cassette filter: catalog no. PT GC 00001 from the firm Millipore), at room temperature and protected from light. Conditions . are gathered: 13

Inlet pressure: 3.2 x 105 Pa.

Pressure on the residue: 1.2 x 105 Pa.

Total flow: about 200 ml / min.

Residue flow: approximately 196 ml / min.

5 Flow rate of the filtrate: approximately 4 ml / min.

After pumping for 1 hour, the filtrate is directed to a separate container and is collected. The filtration is stopped after approximately 24 hours. The pH of the filtrate (approximately 1000 - 1200 ml) is readjusted to the pH value of the original whole sodium heparinate solution (approximately pH 7) by addition of approximately 3 ml of aqueous NaOH at 30¾. This solution constitutes FRACTION I.

The pH of the residue is adjusted to 3.5 by adding approximately 10 ml of aqueous NaOH at 30¾ and is filtered for approximately 24 hours under the same conditions as indicated above. The pH of the filtrate (about 800 ml) is adjusted to the pH value of the original whole sodium heparinate solution (about pH 7) by addition of aqueous NaOH. This solution constitutes FRACTION II.

The pH of the residue is adjusted to 4.2 by the addition of approximately 60 ml of aqueous NaOH at 30¾ and is filtered for approximately 24 hours, again under the same conditions as those already indicated more

high. The pH of the filtrate (approximately 500 ml) is adjusted to the pH value

original whole sodium heparinate solution (approximately pH 7). This solution constitutes FRACTION III.

The 3 fractions are then each treated separately as follows:

First of all, the sodium heparinate is precipitated by adding 1.1 volumes of acetone, the oily and viscous precipitate is left to settle overnight and the solvent is removed. The residue is taken up with approximately 3 times its volume of methanol and the whole is stirred thoroughly at approximately 1000 revolutions per minute. The sodium heparinate is then precipitated as a whitish precipitate which is granulated in a mortar with methanol. The suspension obtained is filtered and the residue is dried at 60 ° C. under a pressure of approximately 200 Pa. In the case where the NaCl content is greater than 0.5%, the suspension is reprecipitated according to the same process.

The 3 fractions thus obtained have the following characteristics: / /

S

/ / / / / s

S

/ / / / / / / / Z_ 15

FRACTION__FRACTION FRACTION

I__Π__Lii_

ELEMENTARY ANALYSIS

_C__23.7% __ 24.9% __ 24.4% _ 5 _H_ 3.3% 3.1% 3.2% N 2.9% 2.4% 2.7% O 47.1% 45.9% 46 , 8% 10 S 11.7% 11.9% 11.6%

Na 12.3¾ 11.8¾ 11.3¾

Activity (PTT test), - 'based on standard III, nn + _; IT / nn + CIIT / ~ 75-5 IU / mg ~ 80-5UI / mg 90-5UI / mg

15 of TOMS

20 Anti Xa activity ν <150-10 U / mg 155-10 U / mg 160-10 U / mg 25 Molecular weight ^ 6,000-1,000 v 8,000-1,000 - 9,000-1,000 average _ η- r, <0.5 % <0.5% <0.5% 33 DaCl content? * ’S 16 EXAMPLE 2

Preparation of a stable injectable solution containing 1,500 IU

low molecular weight heparin and 0.5 mq of dihydroergotamine 1) 18.4 kg of propylene glycol and 1.84 kg of anhydrous glycerol are poured into a 50-liter stirrer and the mixture is stirred for 10 minutes under an atmosphere of carbon dioxide. While continuing to stir under a carbon dioxide atmosphere, 0.0286 kg of dihydroergotamine methanesulfonate and 0.426 kg of lidocaine hydrochloride are added to this mixture over 30 minutes to give a solution.

2) 18.4 kg of water (for injections) are poured into a 30 liter agitator and the mixture is stirred for approximately 10 minutes under an atmosphere of carbon dioxide. While continuing to stir under a carbon dioxide atmosphere, 85.71 15 million IU (= approximately 1.7 to 2.5 kg) of sodium heparinate * having a weight is dissolved within 30 minutes average molecular weight of 6,000 * 1,000 and 0.114 kg of CaNa2 EDTA hexahydrate (calcium sodium edetate hexahydrate available commercially under the name calciumtitriplex).

3) To the solution obtained in step 1), the solution obtained in step 2) above is added with stirring and under a carbon dioxide atmosphere. The container in which solution 2) is obtained is then washed with 1 kg of water (for injections) and this water is added to the solution of step 1). The combined solutions are stirred for a further 10 minutes under an atmosphere of carbon dioxide. The pH of the solution is approximately 5.5.

4) The solution is completed with water (for injections) in order to obtain a weight of 42.810 kg (or 40 liters).

5) The solution obtained is prefiltered using a membrane filter (0.2 μm: Ultipor pm Pal 1) and is filtered directly under carbon dioxide in an ampoule filling machine, on a sterile filtration device having a membrane filter (0.2 pm: Ultipor pm P al 1) under a pressure of 1.7 bar.

17

1 ml ampoules are filled under sterile conditions with the solution (filling volume 0.8 ml).

EXAMPLE 3

Preparation of injectable solutions containing 0.5 mg of 5 dihydroergotamine and 2,500 or 5,000 IU of low molecular weight heparin

The process of Example 2 is repeated using the same relative amounts of all the ingredients but using a relative proportion of sodium heparinate (average molecular weight = 6,000 ± 1,000) of 1 and 2/3 for the first step and 3 and 1/3 for the second step.

EXAMPLE 4

Preparation of injectable solutions containing dihydroergotamine and low molecular weight heparin (average molecular weight = 7,000 ± 1,000 and 8,000 * 1,000)

The procedures of Examples 2 and 3 are repeated, but replacing the sodium heparinate with an average molecular weight of 6,000 ± 1,000 by 1) of the sodium heparinate with an average molecular weight of 7,000 ± 1,000 or 2) with the heparin of sodium with an average molecular weight of 8,000 ± 1,000. In each case, the relative proportions of all the ingredients remain the same as for Example 2. The relative proportions of sodium heparinate used are respectively approximately 3,000, approximately 5,000 and approximately 10,000 IU / 1 mg of dihydroergotamine methanesulfonate.

*

Claims (31)

1. As a medicament, the combination of i) a hydrogenated ergot alkaloid having a vasoconstrictor effect, or a pharmaceutically acceptable acid addition salt of this compound, and ii) a heparin low molecular weight, or a pharmaceutically acceptable salt thereof. 2. A pharmaceutical composition, characterized in that it comprises: i) a hydrogenated ergot alkaloid exerting a vasoconstrictor effect, or a pharmaceutically acceptable acid addition salt of this compound, and ii ) a low molecular weight heparin, or a pharmaceutically acceptable salt of this compound. 3. A composition according to claim 2, characterized in that component i) is a hydrogenated rye ergot alkaloid of formula I WH! {- »in which R represents hydrogen or a (4) alkyl group -C4, 4. A composition according to claim 3, characterized in that component i) is dihydroergotamine or a pharmaceutically acceptable acid addition salt of this compound. 5. A composition according to claim 3, characterized in that component i) is 6-nor-6-isopropyl-9,10-dihydro-2'5-methyl-5 '/ x-benzylergopeptine, or dihydroergovaline , or a pharmaceutically acceptable acid addition salt of these compounds. 6. A composition according to any one of claims 2 to 5, characterized in that component i) is the methanesulfonate, maleate or tartrate of a rye ergot alkaloid exerting a vasoconstrictor effect. 7. A composition according to any of claims 2 to 6, characterized in that component ii) has an average molecular weight of about 10,000 or less. 8. A composition according to claim 7, characterized in that component ii) has an average molecular weight of not less than about 4,000. 9. A composition according to claim 7 or 8, characterized in that at least 60¾ of the polymer units of component ii) have a molecular weight of 10,000 or less. - 25 10. A composition according to any one of claims 2 to 9, characterized in that component ii) is the sodium, potassium or calcium salt of a low molecular weight heparin. 11. A composition according to any of claims 2 to 10, characterized in that components i) and ii) are present in a ratio of 1 mg of component i) and 300 to 70,000 IU of compound ii). 12. A composition according to claim 11, characterized in that the ratio is 1 mg of component i) and 1,000 to 10,000 IU of component ii). Λ * 20 * 13. A composition according to any one of claims 2 to 12, characterized in that it is in the form of a solution in a pharmaceutically acceptable solvent medium, further comprising iii) a calcium or magnesium salt d 'Pharmaceutically acceptable EDTA. 14. A composition according to claim 13, characterized in that component iii) is CaNa2 EDTA. 15. A composition according to claim 13 or 14, characterized in that component iii) is present in an amount of from about 1 to about 50 mg based on an amount of about 5,000 IU of component ii). 16. A composition according to claim 15, characterized in that the amount is from about 1 to about 10 mg. 17. A composition according to any one of claims 13 to 16, characterized in that the solvent medium comprises: iv) water and v) a pharmaceutically acceptable mono- or polyalcohol. 18. A composition according to claim 17, 20 characterized in that the component iv) present represents from 45 to 72% based on the total volume of the composition. 19. A composition according to claim 17 or 18, characterized in that component v) represents from 28 to 55% based on the total volume of the composition. , 25 20. A composition according to claim 17 or 19, characterized in that component v) comprises a) ethanol and b) triethylene glycol, or c) glycerol and d) propylene glycol. 21. A composition according to claim 20, characterized in that a) and b) are present in a weight ratio of 1: 6 to 10, or c) and d) are present in a weight ratio of 1: 8 to 12 . 22. A composition according to any one of claims 2 to 21, characterized in that it additionally comprises vi) a physiologically acceptable anesthetic. * 21 23. A composition according to claim 22, characterized in that component vi) is an acetanilide anesthetic or a pharmaceutically acceptable acid addition salt of this compound. 24. A composition according to claim 22 or 23, characterized in that the component vi) present represents from 1 to 2% by weight based on the total weight of the composition. 25. A composition according to any one of claims 2 to 24, characterized in that it is in the form of a unit dose. 26. A composition according to claim 25, characterized in that it is in the form of an ampoule for injection. 27. A composition according to claim 25 or 26, characterized in that it comprises from approximately 0.2 to approximately 1.5 mg of component i) and from approximately 1,000 to approximately 10,000 IU of component ii). 28. A process for the preparation of a pharmaceutical composition according to any one of claims 2 to 27, characterized in that component i) is intimately mixed with component ii), for example component i) with component ii ) in solution in a pharmaceutically acceptable solvent medium. 29. A pharmaceutical composition according to any one of claims 2 to 27 for use in the prophylactic treatment of thromboses, in particular for the prevention of post-operative thromboses. 30. A package or packaging system suitable for essentially simultaneous presentation or administration of a component i) as defined in any of claims 2 to 6 and of a component ii) as defined in any of claims 1 and 7 to 12, said components i) and ii) being contained separately in said packaging or packaging system. R1 represents a methyl, ethyl or isopropyl group, R2 represents an isopropyl, sec.-butyl, isobutyl or benzyl group and X represents hydrogen or a methoxy group, η * 19 * or a pharmaceutically acid addition salt acceptable of this compound. 31. Products and processes in substance as above described with reference to the examples cited.