CH656533A5 - THERAPEUTIC PREPARATION CONTAINING HYDRATED ERGOTAL CALOIDS AND LOW MOLECULAR HEPARINE. - Google Patents

Description

15 The invention relates to a therapeutic preparation which contains a hydrogenated ergot alkaloid with vasoconstrictive action or its pharm, harmless acid addition salts and a low molecular weight heparin or its pharm, harmless salts, and methods for its preparation, according to claims 1 to 9 .

It is known that the administration of natural heparin (mean molecular weight 14,000-18,000) together with a hydrogenated ergot alkaloid which has vasoconstrictive properties, in particular dihydroergotamine, has particular advantages in the prophylaxis of thromboses, in particular postoperative thromboses , (see for example DE-AS 2 554 533) and accordingly the heparin / dihydroergotamine therapy is a valuable and widely used type of treatment for patients with a high risk of thrombosis, in particular as a result of operations. Administration is generally parenteral, i.e. by intravenous injection and various compositions, for example with improved stability compared to conventional solutions for use in the above indication are known from the literature (see US Pat. No. 4,402,929) and commercially available.

According to the invention, it has surprisingly been found that particularly good results are obtained in the prophylaxis of postoperative thrombosis if the heparin-40 component of the combination known, for example, from DE-AS 2 554 533 has a low average molecular weight compared to natural heparin. In particular, it was found that when using low molecular weight heparin together with hydrogenated Ergotalka-45 loids, which have vasoconstrictive properties, especially dihydroergotamine, instead of the known compositions containing natural heparin, the therapeutic utility, i.e. the duration of the antithrombotic effect is dramatically improved, the daily dose of heparin and the hydrogenated ergot alkaloid component for effective thrombosis prophylaxis being reduced accordingly.

The present invention accordingly relates to a therap. Preparation with the aid of which it is possible to substantially reduce the dose of the combination of a hydrogenated ergot alkaloid with vasoconstrictive properties and heparin required for the prophylactic treatment of thrombosis. After the combination is expediently administered by injection, the therapeutic preparation according to the invention reduces the patient's discomfort even as a result of only one administration per day. This is particularly important for patients recovering from major operations.

Accordingly, the present invention relates to a therapeutic preparation containing i) a hydrogenated ergot alkaloid with vasoconstrictive action or its pharm, harmless acid addition salts and

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ii) a low molecular weight heparin or its pharm.

harmless salts.

Compounds of the formula I used in particular as hydrogenated ergot alkaloids according to i) are

wherein

R represents hydrogen or alkyl having 1 to 4 carbon atoms,

Ri for methyl, ethyl or isopropyl,

R2 for isopropyl, sec. Butyl, isobutyl or benzyl and

X represents hydrogen or methoxy,

or their pharm, harmless acid addition salts. _

According to i), dihydroergotamine, 6-nor-6-isopropyl-9,10-dihydro-2'ß-methyl-5'a-benzyl-ergopeptin and dihydrovaline or their pharm, harmless acid addition salts are particularly preferred.

In particular, methanesulfonates, maleinates and tartrates are used as salts of the hydrogenated ergot alkaloids. The dihydroergotamine is administered in particular as methanesulfonate.

According to the invention, a “low molecular weight heparin” according to ii) is a heparin which is obtained, for example, by isolating the short-chain portions or by cleaving the chains of natural heparin. This enables the average molecular weight of heparin to be significantly reduced.

The low molecular weight heparin used according to the invention preferably has an average molecular weight of 10,000 or less, in particular 8000 or less. The average molecular weight is preferably not less than 4,000, in particular not less than 5,000, very particularly not less than 6,000. Particularly preferred components according to ii) have an average molecular weight of 4,000 to 10,000, in particular 5,000 to 8,000, for example 7,000 + 1,000 or from 6000 ± 1000. It is further preferred that component ii) has a relatively uniform molecular weight distribution, for example at least 60%, in particular 80%, of the polymer units having a molecular weight which is within the abovementioned limits, ie the molecular weight is 10,000 or less.

Suitable pharm, safe salts of low molecular weight heparin as component ii) are the calcium and potassium, but especially the sodium salts.

The low molecular weight heparin or its pharm, harmless salts which are used as component ii) can be prepared in a manner known per se, for example by isolating the low molecular weight fractions from natural heparin, for example by fractional precipitation and ultrafiltration as in DE -OS 29 45 591 or by depolymerization of the high molecular weight fractions of natural heparin, for example by chemical degradation as for example in the Belgian patent no. 888 864 or the European. Patent application No. 27 089. Component ii)

but can also be done by combining these processes, for example by separating the low molecular weight fraction from the natural heparin followed by the depolymerization of the remaining high molecular weight fraction, a low molecular weight heparin being obtained which is optionally mixed with the low molecular weight heparin obtained by separation, io According to the invention, a low molecular weight heparin is preferred which has undergone no or no significant chemical change.

Components i) and ii) of the inventive rap. Preparations are expediently present in a ratio of 1 mg of component i) to 300 to 70,000 (for example 500 to 70,000), preferably 300 to 35,000 IU (international units) of component ii). In particular, components i) and ii) are present in a ratio of 1 mg of component i) to 1000 to 20,000 (for example 2000 to 20,000), in particular 1000 to 10,000 IU of component ii). If components i) and / or ii) are present in the form of pharmaceutically acceptable salts,

the equivalent amount of salt should be used, which corresponds to the specified proportions of the components.

The preparation according to the invention is expediently administered by injection. Accordingly, the preparation should be in liquid form. Although it would be possible to prepare a simple aqueous or aqueous alcoholic solution, this route is not recommended since components i) and ii) would react with one another to form a poorly soluble salt in the absence of a stabilizer. Accordingly, such simple solutions are of no practical value because of their low shelf life 35.

Preferred compositions correspond to those described, for example, in US Pat. No. 4,402,949 and contain, as additional component iii), a pharm, harmless calcium or magnesium salt of ethylene-40-diamine tetraacetic acid (EDTA) as stabilizing agent. The solvent medium preferably contains IV) water and V) a pharmaceutically acceptable mono or polyalcohol.

Recommended calcium and magnesium salts of EDTA 45 as component iii) are the mono-magnesium and mono-calcium salts and also include pharm, harmless polymetal salts which, in addition to the calcium and magnesium ions, also contain other monovalent metal ions, such as sodium or potassium ions. The preferred salt according to the invention is the mono-calcium-bis-sodium salt (Ca Na2 EDTA), also known as calcium titriplex. The mono-magnesium-bis-potassium salt (Mg K2 EDTA) should also be mentioned as usable.

Component iii) is preferably present in a proportion of 1 to 50 mg, in particular 1 to 25 mg, very particularly 1 to 10 mg, based on a proportion of 5000 IU of component ii). Components IV and V of the solvent mixture are preferably present in a proportion of 45 to 72% and 28 to 55% based on the total volume of the preparation. As component V, ethanol, propylene glycol, polyethylene glycol (average molecular weight of approx. 400), diethylene glycol, triethylene glycol and glycerol and mixtures thereof are preferred. In particular, component V consists of a) ethanol and b) triethylene glycol 65 or c) glycerin and d) propylene glycol. In such mixtures, components a) and b) are preferably present in a ratio of 1 to 6 to 10, in particular 1 to 8 (weight ratios) and components c) and d)

656 533

are preferably present in a ratio of 1 to 8 to 12, in particular 1 to 10 (weight ratios). In a preferred embodiment, the solutions of components i) and ii) contain, as further component vi), a physiologically acceptable anesthetic. An anesthetic component vi) is preferably an anesthetic with an acetanilide structure. These are acetanilides, in particular 2-amino-N-phenyl-acetanilide derivatives or their pharm, harmless salts which develop an anesthetic effect. Preferred acetanilides are 2- (diethylamino) -N- (2,6-dimethylphenyl) -acetamide (also known as lidocaine), 2- (butylamino) -N- (2-chloro-6-methyl-phenyl) -acetamide (also known as Hostacaine) and 2- (2-diethylamino-acetamido) -m-toluenic acid methyl ester (also known as Baycaine).

The salts of these acetanilides commonly used are, for example, the hydrochlorides. If component vi) is present, its proportion should be 1 to 2% based on the total weight of the preparation.

It is pointed out that while solutions as indicated above are best suited for use in accordance with the present invention, on the other hand there is the possibility of using other forms of administration. Examples of these other forms would be lyophilized preparations that must be solubilized before administration. The preparations according to the invention can also contain further additives such as carriers, diluents, stabilizers, preservatives, dyes, surface-active substances, etc.

The therapeutic preparation according to the invention can be used in the form of a medicament for the prophylaxis of thromboses, in particular of postoperative thromboses.

The favorable anti-thrombotic effect of the preparation according to the invention is particularly evident in the I125 fibrinogen test.

The principle of this test is based on the external registration of the radiation from JI25 fibrinogen, which selectively accumulates in thrombotic material of the leg veins [K.H. Frey et al., Med. Klin. 70 (1975), pages 1553-1558, in particular page 1555].

When comparing the above For example, from compositions known from DE-AS 25 54 533 with the composition according to the invention, it has been found that the composition according to the invention of i) and ii) when administered once daily in doses of 0.5 mg of dihydroergotamine methanesulfonate and 2500 IU of low molecular weight. Heparin (MW. 7000 + 1000), the dose of the low molecular weight. Heparin can even be reduced to 1500 IU, which has the same prophylactic activity against thrombosis, in particular postoperative thrombosis, as the three times daily administration of the composition known from DE-AS 25 54 533.

A recommended daily dose of component i) should be from 0.2 to approximately 1.5 mg, in particular 0.5 mg, and of component ii) approximately 1000 to approximately 10,000 IU, in particular approximately 1500 to approximately 5000 IE. If desired, the preparation according to the invention can be administered in smaller doses 2 to 4 times a day. Preferably, administration is in a single dose, once a day, in a unit dosage form. On the other hand, it is also possible for components i) and ii) to be administered independently of one another.

Suitable unit doses preferably contain about 1500, about 2500 or about 5000 IU of component ii) for 0.5 mg of component i).

The present invention further relates to a method for producing the therap according to the invention. Preparation. Here either a) component i) is intimately mixed with component ii) or b) component i) together with component ii) in a pharmaceutically harmless solvent.

s dissolves or c) 1) a solution of component i) and optionally component vi) in a solvent medium containing component v), further io 2) a solution of component ii) and component iii) in a solvent medium containing the Component iv) is produced and 3) the solutions according to 1) and 2) are combined.

If necessary, further proportions of components iv) and / or v) can be added to the solution according to c).

The process is expediently carried out in an inert gas atmosphere, for example a CO 2 atmosphere, and the pH of the solution obtained is adjusted, for example, to 4 to 6 by adding a suitable pharmaceutically acceptable acid, for example methanesulfonic acid (when using the methanesulfonate of component i)) . If other salts of component i) are used, the pH should be adjusted with the corresponding 25 acids. The preparations obtained in this way can be brought into the desired administration form; for example, the solutions obtained, which are suitable for injection, can be filled into injection ampoules after filtration, expediently with CO 2 gassing. A particularly preferred therapeutic preparation according to the invention contains, in addition to 0.5 mg of dihydroergot amine methanesulfonate, 2500, but preferably 1500 IU, low molecular weight. Heparin (mean molecular weight 7000 + 1000).

35 Example 1

Preparation of a stable solution for injection containing 1500 IU of low molecular weight heparin

(MW 6000 + 1000) and 0.5 mg dihydroergotamine

40 a) Preparation of the dihydroergotamine solution

18.4 kg of propylene glycol and 1.84 kg of glycerol are added anhydrous to a 50 liter stirrer and the mixture is stirred for 10 minutes with CO 2 gassing. With further stirring and CO 2 gassing for about 30 45 minutes, 0.0286 kg of dihydroergot amine mesilate and 0.426 kg of lidocaine hydrochloride are added to the mixture and dissolved therein.

b) Preparation of the solution of the low molecular weight heparin

50 18.4 kg of water (for injection purposes) are placed in a 30 liter stirrer and stirred for 10 minutes with aeration of CO 2. With further stirring and C02 fumigation, 85.71 million IU. low molecular weight heparin (MW 6000 + 1000) in the form of the sodium 55 trium salt (corresponds to 1.7 to 2.5 kg sodium salt of the low molecular weight heparin according to its activity) and 0.114 kg calcium titriplex (mono calcium bis sodium salt of ethylenediamine tetraacetic acid ) added and dissolved in it.

60 c) Mixing the solutions prepared under a) and b)

The solution prepared according to b) is added to the solution prepared according to a) with CO 2 gassing. The vessel in which solution b) was prepared is then rinsed out with 1 kg of water (for injection purposes) and this is also added to the solution prepared in accordance with a). The combined solutions are stirred for 10 minutes with gassing with COi (the pH of the combined solutions should be about 5.5) and then by addition

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of water (for injections) brought to a final weight of 42.810 kg (corresponds to 40 liters of liquid).

d) Filtration dj) Prefiltration: the prefiltration takes place through a

Membrane filter (0.2 | im - Ultipor around Pali). d2) Sterile filtration: the solution prepared and pre-filtered according to c) is filtered directly on the filling machine with C02 using a sterilized pressure filtration device with membrane filter (0.2 µm - Ultipor around Pali) under 1.7 bar pressure.

The sterile-filtered solution is filled into 1 ml ampoules under aseptic conditions (filling volume 0.8 ml).

EXAMPLE 2 Preparation of an Injection Solution Containing 0.5 mg of Dihydroergotamine and 2500 and 5000 IU of Low Molecular Weight Heparin Using the method described in Example 1 and the constituents specified therein, with the exception that the proportion of sodium heparinate is determined by an l2 / 3 and a 373- times the amount of sodium heparinate (mean MW 6000 + 1000) replaced, one arrives at the composition described in the title of the example.

Example 3 Preparation of an Injection Solution

which contains 0.5 mg dihydroergotamine methanesulfonate and low molecular weight heparin (MW 7000 ± 1000 and 8000 ± 1000) using the methods described in Examples 1 and 2, but replacing the sodium heparinate used there (mean MW 6000 ± 1000) by 1) sodium heparin (mean MW 7000 + 1000) or 2) sodium heparin (mean MW 8000 ± 1000), one arrives at the composition mentioned in the title of the example. In any case, the relative proportions of the constituents remain the same as in Example 1. The relative proportions of the sodium heparinate used are approximately 3000, approximately 5000 and approximately 10,000 IU per 1 mg of dihydroergotamine methanesulfonate.

Heparin sodium fractions in the range from 6000 to 9000 molecular weight units which can be used in the above examples can be prepared as described below:

1000 g heparin sodium with an average. The molecular weight of approximately 15,000 is dissolved in 6.66 liters of distilled water and the pH of this solution is determined on the pH meter. This solution is mixed with about 145 ml of 25% hydrochloric acid

10th

adjusted to pH 2.7 and filtered through a pleated filter No. 520 b '/ 2 (320 mm) from Schleicher & Schüll. The filtrate is pumped through a molecular filtration membrane with a nominal cut-off limit of 10,000 molecular weight units under the following conditions under light protection and then filtered.

Temperature: room temperature

Filters: Pellicon filter cassette

(Cat.No. PTGC 00001 Milli-pore)

Inlet pressure: 3.2 • 105 Pa Retentate side pressure: 1.2 • 105 Pa Total flow: ~ 200 ml / min.

Flow rate retentate: ~ 196 ml / min.

15 flow rate of filtrate: - 4 ml / min.

After pumping around for one hour, the filtrate flow is directed into a separate vessel and collected. The filtration is stopped after approx. 24 hours. The filtrate, approx. 1000-1200 ml, is adjusted to the initial value 20 of the heparin sodium solution, pH 7, with approx. 3 ml of 30% sodium hydroxide solution using the pH meter. This solution is the 1st fraction.

The retentate is adjusted to pH 3.5 with about 10 ml of 30% sodium hydroxide solution and filtered again under the conditions given above for 24 hours. The filtrate obtained, 25 approx. 800 ml, is adjusted to the starting value ~ pH 7 on the pH meter. This solution is the 2nd fraction.

The retentate of this filtration is adjusted to pH 4.2 with about 60 ml of 30% sodium hydroxide solution and filtered again under the conditions given above for 24 hours. The filtrate obtained, approx. 500 ml, is adjusted to the initial value ~ pH 7 on the pH meter. This solution is the 3rd fraction.

The three fractions are worked up separately as follows: The neutralized filtrate is mixed with 1.1 times Vo-35 lumen acetone and the heparin sodium contained in the filtrate is precipitated. The precipitate (oily, viscous liquid) is allowed to sit overnight and the supernatant solvent is decanted off. The residue is covered with about three times the amount of methanol and 40 with a stirrer at about 1000 rpm. mixed well. As a result, the heparin accumulates in the form of a whitish precipitate, which can then be granulated in a rubbing pan under methanol. The suspension obtained from this is filtered off. The residue is then dried at 60 ° C. and approx. 45 200 Pa in a vacuum drying cabinet. If the NaCl content is> 0.5%, a second precipitation is necessary.

The fractions thus obtained have the following specifications:

Elemental analysis

Fraction 1

Fraction 2

Faction3

C.

23.7%

24.9%

24.4%

H

3.3

3.1

3.2

N

2.9

2.4

2.7

O

47.1%

45.9%

46.8%

S

11.7%

11.9%

11.6%

N / A

12.3%

11.8%

11.3%

Heparin activity (PTT test,

~ 75 ± 5 IU / mg

~ 80 + 5 IU / mg

-90 + 5 IU / mg based on WHO standard III)

Anti Xa activity

- 150 + 10 U / mg

~ 155 + 10 U / mg

-160 + 10 U / mg

Most common molecular weight

-6000 + 1000

-8000 + 1000

-9000 ± 1000

NaCl content

<0.5%

<0.5%

<0.5%

s

Claims (9)

656 533 PATENT CLAIMS 1. Therapeutic preparation containing i) a hydrogenated ergot alkaloid with vasoconstrictive effect or its pharmaceutically acceptable acid addition salts and ii) a low molecular weight heparin or its pharmaceutically acceptable salts. 2) a solution of component ii) and a magnesium or calcium salt of ethylenediamine-tetraacetic acid is prepared in a solvent medium containing water and s 3) the solutions according to 1) and 2) are combined. 2. Therapeutic preparation according to claim 1, characterized in that a hydrogenated ergot alkaloid is a compound of the formula I, wherein R represents hydrogen or alkyl having 1 to 4 carbon atoms, Ri for methyl, ethyl or isopropyl, R2 for isopropyl, sec. Butyl, isobutyl or benzyl, and X represents hydrogen or methoxy, or their pharmaceutically acceptable acid addition salts used. 3. Therapeutic preparation according to claims 1 and 2, characterized in that the hydrogenated ergot alkaloid dihydroergotamine, the 6-nor-6-isopropyl-9,10-dihydro-2'ß-methyl-5'a-benzylergopeptin or the dihy- droergovalin used. 4. Therapeutic preparation according to claim 1, characterized in that one uses the hydrogenated ergot alkaloid in the form of methanesulfonate, maleinate or tartrate and the low molecular weight heparin in the form of its sodium, potassium or calcium salt. 5. Therapeutic preparation according to claim 1, characterized in that one uses a low molecular weight heparin with an average molecular weight of 10,000 or less. 6. Therapeutic preparation according to claim 1, characterized in that a low molecular weight heparin with an average molecular weight of 7000 + 1000 used. 7. Therapeutic preparation according to claim 1, characterized in that a low molecular weight heparin with an average molecular weight of 6000 + 1000 used. 8. A method for producing a therapeutic preparation according to claim 1, characterized in that either a) component i) is intimately mixed with component ii) or b) component i) is dissolved together with component ii) in a pharmaceutically harmless solvent or c) 1) a solution of component i) in a solvent medium containing a pharmaceutically acceptable mono- or polyalcohol, furthermore 9. A method for producing a therapeutic preparation according to claim 8, characterized in that an anesthetic acetanilide is added to the solution according to 1) of method c).