SE468973B - NEW THERAPEUTIC PREPARATION CONTAINING HYDRATED HYDRATAL CALOIDS AND HEPARIN - Google Patents

Description

The ergot alkaloid component can be reduced to achieve the corresponding effective thrombosis prophylaxis.

Accordingly, the present invention relates to a therapeutic composition by means of which it is possible to substantially lower the dose required for the prophylactic treatment of thrombosis of the combination of a hydrogenated ergot alkaloid with vasoconstrictor effect and heparin. When the combination has been suitably administered by injection, it becomes possible to alleviate the discomfort of the patient by means of the therapeutic preparation according to the invention, even despite only one administration per day. This is especially important for patients recovering from difficult surgeries.

Accordingly, the present invention provides a therapeutic composition comprising i) a hydrogenated ergot alkaloid having vasoconstrictor activity or its pharmaceutically acceptable acid addition salts and ii) a low molecular weight heparin or its pharmaceutically acceptable salts.

As the hydrogenated ergot alkaloid according to i), compounds of the formula I, HN in which R is hydrogen or alkyl having from 1 to 4 carbon atoms, R1 is methyl, ethyl or isopropyl, R2 is isopropyl, sec-butyl, isobutyl or benzyl and X is hydrogen or methoxy, or its pharmaceutically acceptable acid addition salts. Particularly preferred are (i) dihydroergotamine, 6-nor-6-isopropyl-9,10-dihydro-2'8-methyl-5'u-benzylergopeptin and dihydroergovalin or their pharmaceutically acceptable acid addition salts.

In particular, methanesulfonate, maleinate and tartrate are used as salts of the hydrogenated ergot alkaloid.

The dihydroergotamine is especially administered as methanesulfonate.

As the "low molecular weight heparin" according to ii) a heparin is used according to the invention, which is obtained, for example, by means of isolation of the short-chain parts or by cleavage of the chains in the natural heparin. This makes it possible to significantly lower the average molecular weight of the heparin.

The low molecular weight heparin used according to the invention has an average molecular weight of about 10,000 or less, especially about 8,000 or less. Preferably, the average molecular weight is not less than about 4000, especially not lower than about 5000, and most preferably not less than about 6000. Particularly preferred components according to ii) have an average molecular weight of from about 4000 to about 10,000, in particular from about S000 to about 8000, for example about 7000 in 1000 or about 6000 in 1000. It is further preferred that component ii) has a relatively uniform molecular weight distribution, with at least 60%, in particular 80%, of the polymer units having a molecular weight, which is within the above limits, ie. the molecular weight is 10,000 or less.

Suitable pharmaceutically acceptable salts of the low molecular weight heparin as component ii) are the calcium and potassium salts, in particular the sodium salts.

The low molecular weight heparin or its pharmaceutically acceptable 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 described in DE-OS 29 45 595 or by depolymerization of the high molecular weight fractions in the natural heparin, for example by chemical degradation such as e.g. described in Belgian Patent Specification No. 888,864 or European Patent Application No. 27,089. However, component ii) can also be obtained by combining these methods, for example by separating the low molecular weight portions from the natural heparin followed by depolymerization of the remaining high molecular weight portions, whereby a low molecular weight heparin is obtained, which is optionally mixed with the low molecular weight heparin obtained by separation.

According to the invention, a low molecular weight heparin is preferred which has not undergone any or any significant chemical change. Components i) and ii) of the therapeutic composition according to the invention are suitably present in a ratio of 1 mg of component i) to from 300 to 70,000 (for example from 500 to 70,000), preferably from 300 to 35,000, IE (International Units) of component ii). In particular, components i) and ii) are present in a ratio of 1 mg of component i) per 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 the salt corresponding to the stated ratio of components shall be used.

The composition of the invention is conveniently administered by injection. Accordingly, the preparation should be in liquid form. Although it would be possible to prepare a simple aqueous solution or aqueous alcoholic solution, this "path is not recommended, as components i) and ii) in the absence of a stabilizer would react with each other to form a sparingly soluble salt. Thus, such simple solutions without practical value due to their low storage durability.

Preferred compositions correspond to those described, for example, in U.S. Pat. No. 4,092,949 and as additional components iii) contain a pharmaceutically acceptable calcium or magnesium salt of ethylenediaminetetraacetic acid (EDTA) as a stabilizer. The solvent medium preferably contains IV) water and V) a pharmaceutically acceptable mono- or polyalcohol. Recommended calcium and magnesium salts of EDTA as component iii) are the mono-magnesium and mono-calcium salts and they also include pharmaceutically acceptable polymetal salts, which in addition to calcium and magnesium ions contain additional monovalent metal ions, such as sodium or potassium ions.

The preferred salt of the invention is the mono-calcium bis- sodium salt (Ca Na 2 EDTA), which is also known as calcium titriplex. The mono-magnesium bis-potassium salt (Mg K2 EDTA) can also be mentioned here.

Component iii) is preferably present in a proportion of from 1 to 50 mg, especially from 1 to 25 mg, in particular from 1 to 10 mg, based on a proportion of 5000 IU of component ii). Components IV and V in the solvent mixture are preferably present in a proportion of from 45 to 72% and from 28 to 55% calculated on the total volume of the preparation. As component V, ethanol, propylene glycol, polyethylene glycol (average molecular weight about 400), diethylene glycol, triethylene glycol and glycerol and mixtures thereof are preferred. In particular, component V consists of a) ethanol and b) triethylene glycol or c) glycerol and d) propylene glycol. In such mixtures components a) and b) are preferably present in a ratio of from 1 to 6 to 10, in particular 1 to 8 (weight ratio) and components c) and d) are preferably present in a ratio of from 1 to 8 to 12, in particular 1 to 10 (weight ratio). According to 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, especially 2-amino-N-phenyl-acetanilide derivatives or their pharmaceutically acceptable salts, which develop anesthetic action. Preferred acetanilides are 2- (diethylamino) -N- (2,6-dimethylphenyl) -acetamide-2- (butylamino) -N- (2-chloro-6-methyl-phenyl) -acetamide (also known as Hostacain) and 2- (2-Diethylamino- (also known as Lidocaine), acetamido) -m-toluic acid methyl ester (also known as Baycain).

Commonly used salts of these acetanilides are, for example, the hydrochlorides. If component vi) is present, its proportion shall be from 1 to 2% based on the total weight of the preparation. It may also be added that, although solutions as set forth above are best suited for use in the present invention, it is also possible to use other forms of administration. Examples of such other forms are lyophilized preparations which must be reconstituted before administration. The compositions of the invention may further contain additional additives such as carriers, diluents, stabilizers, preservatives, dyes, surfactants and the like.

The therapeutic composition of the invention is used for the prophylaxis of postoperative thrombosis.

The beneficial anti-thrombotic effect of the preparation according to the invention is especially evident in the 1125 test. -fibrinogen- The principle of this test is based on external registration of the radiation from I125-fibrinogen, which is selectively enriched in thrombotic material in the leg veins ¿k.H. Frey et al., Med. Klin. 70 (1975), pages 1553-1558, especially pages 15557.

When comparing, for example, the composition known from DE-AS 25 54 533 and the composition according to the invention, it has been found that the composition according to the invention of i) and ii) when administered once a day in doses of 0.5 mg of dihydroergotamine methanesulfonate and 2500 IU low molecular weight heparin (molecular weight 7000 1 1000), the dose of heparin being even can be reduced to 1500 IU, exhibits the same prophylactic activity against thrombosis, in particular postoperative thrombosis, as when administered three times a day by the composition known from DE-AS 25 54 533.

A recommended daily dose of component i) is from 0.2 to about 1.5 mg, in particular 0.5 mg, and of component ii) from about 1000 to about 10,000 IU, in particular from about 1500 to about 5000 IU. If desired, the composition of the invention may be administered in lower doses 2 to 4 times a day. Preferably, the administration is in a single dose once a day in unit dosage form. On the other hand, however, it is also possible for components i) and ii) to be administered independently of each other.

Suitable unit doses preferably contain for 0.5 mg of component i) about 1500, about 2500 or about S000 IU of component ii). The present invention further relates to a process for the preparation of the therapeutic composition according to the invention. In this case, component i) can be mixed intimately with component ii), or component i) can be dissolved together with component ií) in a pharmaceutically acceptable solvent. If solutions are to be prepared which also contain components iii), iv), v) and possibly also vi), the process can be carried out as described below: 1) Preparation of a solution of component i) and possibly component vi) in a solvent medium containing component v). 2) Barge preparation of a solution of component ii) and component iii) in a solvent medium containing component iv). 3) Combination of the solutions according to 1) and 2) and 4) possible addition of additional proportions of components iv) and / or v).

The process is conveniently carried out in an inert gas atmosphere, for example CO 2 atmosphere, and the pH of the solution obtained is adjusted, for example, by the addition of a suitable pharmaceutically acceptable acid, e.g. methanesulfonic acid (using the methanesulfonate of component i)) of 4 to 6. If other salts of component i) are used, the pH shall be adjusted with the corresponding acids. The preparations thus obtained can be transferred to the desired form of administration. For example, the solutions obtained for injection obtained after filtration can be filled into injection ampoules, suitably under CO 2 gas.

The present invention further relates to the use of the therapeutic composition according to the invention containing components i) and ii) for the prophylactic treatment of thromboses, in particular of postoperative thromboses. Particularly preferred for this is a therapeutic preparation which, in addition to 0.5 mg of dihydroergotamine methanesulfonate, contains 2500, preferably 1500, IU of low molecular weight heparin (average molecular weight 7000 in 1000).

Example 1: Preparation instructions for heparin-sodium fractions in the range from 6000 to about 9000 molecular weight units. 1000 g of heparin sodium with an average molecular weight of about 15,000 are dissolved in 6.66 liters of distilled water and with a pH meter 46 the pH value of this solution is determined. This solution is adjusted to pH 2.7 with approximately 145 ml of 25% hydrochloric acid and filtered on a folding filter No. 520 b 1/2 (ø 320 mm) from the company Schleicher & Schüll. The filtrate is pumped for one hour through a molecular filtration membrane with a nominal cut-off of 100000 molecular weight units under the following conditions and under light protection and filtered thereafter.

Temperature: Room temperature Filter: Pellicon filter cartridge (Cat. No. PTGC 00001 Fa. Milliporel Inlet side pressure: 3.2 X 105 Pa Pressure retent side: 1.2 x 105 Pa Total throughput: m 200 ml / min Flow retentate: W 196 ml / min Flow filtrate: N 4 ml / min.

Once the filtrate stream has been pumped around for one hour, it is passed into a separate vessel and collected therein. Filtering is stopped after about 24 hours. The filtrate, about 1000-1200 ml, is adjusted with the pH meter to the starting value of the heparin sodium solution, ~ pH 7, with about 3 ml of 30% sodium hydroxide solution.

This solution is fraction 1.

The retentate is adjusted with about 10 ml of 30% sodium hydroxide solution to pH 3.5 and filtered once more, under the above conditions, for 24 hours. The filtrate obtained, about 800 ml, is adjusted again with pH meter to the starting value wpH 7. This solution is fraction Z.

The retentate from this filtration is adjusted with about 60 ml of 30% sodium hydroxide solution to pH 4.2 and filtered once more under the above conditions for 24 hours. The filtrate obtained, about 500 ml, is adjusted with pH meter to the starting value mpH 7. This solution is fraction 3.

The three fractions are worked up separately as follows: To the neutralized filtrate is added 1.1-fold volume of acetone and heparin sodium present in the filtrate is precipitated.

The pellet (oily, viscous liquid) is left to stand overnight and the solvent is decanted over it. Over the residue is charged about three times the amount of methanol and proper stirring is performed with a stirrer at about 1000 rpm. As a result, the heparin precipitates in the form of a whitish precipitate, which in connection therewith can be granulated in a mortar under methanol. The suspension thus obtained is filtered off. The residue is then dried at 60 ° C and about 200 Pa in a vacuum drying cabinet. If the NaCl content> 0.5%, a second precipitate is required.

The fractions thus obtained have the following characteristics: Elemental analysis Fraction 1 Fraction 2 Fraction 3 c - 23.74. 24.94 24.44, H 3.3% 3.1% 3.2% N 2.9% 2.4% 2.7% 0 47.1% 45.9% 46.8% S 11.7 % 11.9% 11.6% Na 12.3% 11.8% 11.3% heparin activity (PTT test, according to WHO standard III) Anti-Xa activity weight NaCl content ~ 75i5 IU / mg ~ 80iS IU / mg w90: IU / mg w1S0i10 U / mg ~ 155i10 U / mg m160i10 U / mg -veoøoyooo <0.5% ~ 8000: 1000 <0.5% ~ 9000 : 1000 <0, S% Exemnel 2: Preparation of a stable injection solution containing 1500 IU low molecular weight heparin (molecular weight 6000 + 1000) and 0.5 mg dihydroergotamine 21 šteaëëëllaia: _ëY_êihrê: 4 kg of propylene glycol and 1.84 kg of glycerol anhydrous and the mixture is stirred under CO 2 gas for 10 minutes. With further stirring and CO 2 gas for about 30 minutes, 0.0286 kg of dihydroergotamine mesilate and 0.426 kg of lidocaine hydrochloride are added to the mixture and these substances are dissolved therein. bl š: e @ §tëllaiasfêY_lë§aiaz§a_ë ¥ _ê§: _lêsa9l§krlë: §_h§2ê: ia§: In a 30 liter stirrer, 18.4 kg of water is charged (for injection purposes) and stirring is performed for 10 minutes and C02 -gas. With further stirring under CO 2 gas, 85.71 million μl of low molecular weight heparin (molecular weight 600011000) in the form of the sodium salt (corresponding to 1.7 to 2.5 kg of sodium salt of the low molecular weight heparin with '-68) are added for about 30 minutes. ZS 30 xD -4 0 10 1 with respect to its activity) and 0.114 kg of calcium titriplex (mono-calcium bis-sodium salt of ethylenediaminetetraacetic acid) and these substances are dissolved therein.

The solution prepared according to b) is added under CO 2 gas to the solution prepared according to a). Then the vessel in which the solution b) was prepared is rinsed with 1 kg of water (for injection purposes) and this water is also added to the solution prepared according to a). The combined solutions are stirred for 10 minutes and CO 2 gas (the pH of the combined solutions should be about 5.5) and then brought by adding water (for injection) to a final weight of 42.810 kg ( corresponds to 40 liters of liquid). dl šilzzezies d1) Pre-filtration: The pre-filtration is performed through a membrane filter (0.2 pm - Ultipor pm Pallet). dz) Sterile filtration: the solution prepared and pre-filtered according to c) is filtered directly on the filling machine with CO 2 over a sterilized pressure filtration apparatus with membrane filter (0.2 pm - Ultipor pm Pall) under a pressure of 1.7 bar.

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

Example 3: Preparation of an injection solution containing 0.5 mg of dihydroergotamine and 2500 and 5000 IU of low molecular weight heparin Using the procedure described in Example 2 and the ingredients indicated therein with the exception of replacing the proportion of sodium heparinate with 12/3 and 31/3-fold amount of sodium heparinate (average molecular weight 600011000), the composition given in the title of the example is obtained.

Example 4: Preparation of an injection solution containing 0.5 mg of dihydroergotamine methanesulfonate and low molecular weight heparin (molecular weight 7000 + 1000 and 8000 + 1000).

Using the procedures described in Examples 2 and 3, substituting the sodium heparinate (average molecular weight 600011000) used therein for 1) of sodium heparinate (average molecular weight 700011000) or 2) of sodium heparinate ( average molecular weight 800011000), the composition given in the title of the example is obtained. In all cases, the relative ratios of the constituents are the same as in Example Z.

The relative proportions of the sodium heparinate used are about 3,000, about 5,000 and about 10,000 IU per 1 mg of dihydroergotamine methanesulfonate.

Claims (10)

/ 2 4-68 975- PATENT REQUIREMENTS Therapeutic preparation, preferably in the form of a solution, containing, as essential active ingredients, a hydrogenated ergot alkaloid or its pharmaceutically acceptable acid addition salts and heparin or its pharmaceutically acceptable salts, characterized in that a) the hydrogenated ergot alkaloids have the formula I: R represents hydrogen or alkyl having from 1 to 4 carbon atoms, R 1 represents methyl, ethyl or isopropyl, R 2 represents isopropyl, sec-butyl, isobutyl or benzyl, and X represents hydrogen or methoxy, and b) the heparin is a low molecular weight heparin having an average molecular weight of from 5000 to 8000, components a) and b) being present in a ratio of 1 mg of component a) per 300 to 70,000 IU of component b), and wherein the preparation is furthermore preferably contains a stabilizer in the form of a magnesium or calcium salt of ethylenediaminetetraacetic acid and optionally an anesthetic with an acetanilide structure. Therapeutic composition according to claim 1, characterized in that the hydrogenated ergot alkaloid is dihydroergotamine, 6-nor-6-isopropyl-9,10-dihydro-2'B-methyl-5'a-benzylergopeptin or dihydroergovalin. Therapeutic composition according to claim 1 or 2, characterized in that the hydrogenated ergot alkaloid is in the form of the methanesulfonate, maleinate or tartrate. Therapeutic composition according to any one of the preceding claims, characterized in that the low molecular weight heparin has an average molecular weight of 7000 to 1000. Therapeutic composition according to any one of claims 1 to 3, characterized in that the low molecular weight heparin has an average molecular weight of 6000 in 1000. Therapeutic preparation according to any one of the preceding claims, characterized in that components a) and b) are present in a weight ratio of 1 mg to from 1000 to 10000 IU. Therapeutic preparation according to any one of the preceding claims, characterized in that it contains in a unit dose component a) in a dosage of 0.5 mg and component b) in a dosage of about 1500, about 2500 or about 5000 IU . Therapeutic composition according to any one of the preceding claims, characterized in that the low molecular weight heparin is in the form of its sodium, potassium or calcium salt. A process for the preparation of a therapeutic composition according to any one of claims 1 to 8, which composition is in the form of a solution and contains a stabilizer in the form of a magnesium or calcium salt of ethylenediaminetetraacetic acid and optionally an anesthetic with acetanilide. structure, characterized in that 1) a solution of component a) and optionally the anesthetic with acetanilide structure in a pharmaceutically acceptable mono- or polyalcohol is prepared, and further 2) a solution of component b) and magnesium is prepared or the calcium salt of ethylenediaminetetraacetic acid in a solvent medium containing water, and 3) combine the solutions according to 1) and 2) and 4) optionally to the combined solutions 1) and Z) add additional proportions of water and / or mono- and / or polyalcohols. Use of a therapeutic preparation according to any one of claims 1 to 8 for the manufacture of medicaments which are intended for the prophylactic treatment of postoperative thrombosis.