JPH0672101B2 - Medicine consisting of hydrogenated ergot alkaloids and heparin - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel pharmaceutical composition useful for preventing thrombosis, particularly postoperative thrombosis, and a method for producing the composition.

Heparin (also called heparic acid) is a highly sulfated dextrorotatory mucopolysaccharide with specific anticoagulant properties, and is widely used especially for preventing postoperative thrombosis. This substance is present in many mammalian species as a natural constituent of various tissues, especially the liver and lungs,
Products isolated from various sources are commercially available in the form of free or pharmaceutically acceptable salts, for example various alkali or alkaline earth metal salts.

Total heparin, or heparin isolated directly from a wide variety of sources, usually has an average molecular weight of 1 over 6000 to 20000.
It consists of a polymer with a heterogeneous molecular weight of 4000 to 18000, the basic polymer chain of which is composed of D-glucosamine residues and D-glucuronic acid residues. The exact chemical and physical make-up, such as the exact degree of sulfation and molecular weight characteristics, will depend on the source, ie the animal material from which it was obtained, and the detailed isolation means. Various techniques for obtaining total heparin products, eg, heparin products having lower average molecular weights than those obtained directly from animal sources, are also described and known in the prior art, as described below.

Further, it is known that administration of heparin together with hydrogenated ergot alkaloids having vasoconstrictor activity, particularly dihydroergotamine, is advantageous for prevention of thrombosis, particularly postoperative thrombosis (for example, British Patent Specification). 15th
57331), heparin / dihydroergotamine therapy has now become a widely used and valuable treatment modality for patients at risk of thrombosis, especially major postoperative patients.
Administration is generally parenteral, such as intravenous injection, and various formulations, such as those for which the above uses are more soluble than simple solutions, are described in the literature and commercially available (e.g., U.S. Pat.No. 4,402,949). reference).

According to this invention, it has been surprisingly found that particularly advantageous results are obtained when the heparin component is a low molecular weight heparin when applying said combination therapy. In particular, the use of low molecular weight heparin in place of the previously used total heparin together with hydrogenated ergot alkaloids having vasoconstrictor activity, especially dihydroergotamine, results in a surprisingly improved therapeutic effect, for example the duration of antithrombotic activity. It has thus been found that the daily doses of both heparin and hydrogenated ergot alkaloid components required for effective prophylactic treatment can be correspondingly reduced.

Therefore, the present invention has the important advantage that the daily dosage required to treat a patient can be significantly reduced. As mentioned above, the procedure is usually performed by intravenous injection,
The invention also has the advantage, at the same time, of reducing the required daily injection rate and thus of substantially reducing patient dissatisfaction. This is especially important for patients who undergo major surgery and then recover.

Accordingly, the present invention provides a pharmaceutical composition comprising a hydrogenated ergot alkaloid, or a pharmaceutically acceptable acid addition salt thereof, and heparin, or a pharmaceutically acceptable salt thereof. Formula (I) (Wherein R is hydrogen or alkyl having 1 to 4 carbon atoms, R ₁ is methyl, ethyl or isopropyl, R ₂ is isopropyl, secondary butyl, isobutyl or benzyl,
X means hydrogen or methoxy), ii) heparin is a low molecular weight heparin having an average molecular weight of about 5000 to about 8000, and i) and iib) are present in the composition in a weight ratio of component i). There is provided a composition, wherein component ii) is present in 300 to 70,000 international units per 1 mg.

Preferred component i) is dihydroergotamine, 6-nor-
Isopropyl-9,10-dihydro-2'β-methyl-5 '
α-benzyl ergopeptin or dihydroergovaline, or a pharmaceutically acceptable acid addition salt thereof,
Of these, dihydroergotamine and its pharmaceutically acceptable acid addition salts are most preferable. Suitable pharmaceutically acceptable acid addition salts are, for example, methanesulfonate, maleate and tartrate, in the case of dihydroergotamine the methanesulfonate is particularly preferred.

The term "low molecular weight heparin" refers to an average molecular weight of about 5,000 to about 8,000 obtained by significantly reducing the average molecular weight as compared to the total heparin product by, for example, an isolation method or a depolymerization method described below.
Means heparin.

It is preferred that the average molecular weight is not less than about 6000, and particularly preferred is, for example, about 7000 ± 1000 or about 6000 ± 1000. Furthermore, component ii) may have a relatively homogeneous molecular weight, for example at least 60%, more preferably 80% of the polymer units have a molecular weight within the above average molecular weight range, for example having a molecular weight of 10,000 or less. desirable.

Suitable pharmaceutically acceptable salts of low molecular weight heparin in component ii) include, for example, calcium and potassium salts, especially sodium salts.

The low molecular weight heparin or pharmaceutically acceptable salt thereof used as component ii) is a low molecular weight fraction separated from the total heparin product by methods known in the art, for example by fractional precipitation and filtration according to DE-A 2945591. Alternatively, it can be obtained by depolymerizing the high molecular weight fraction in total heparin, for example by chemical cleavage as described in Belgian Patent 888864 or European Patent Publication 27089. Alternatively, component ii) is a combination of the above methods, i.e., for example, separating low molecular weight heparin from total heparin product and then depolymerizing the residual high molecular weight heparin fraction to yield lower molecular weight heparin. Then, it can be obtained by combining the two kinds of low molecular weight heparin products obtained as desired.

When producing low molecular weight heparin by chemical cleavage,
Individual chain residues may undergo certain chemical modifications, especially desulfation. If this occurs, in the use according to the invention, the initially prepared component ii) may optionally be reconstituted or otherwise modified by methods similar to those known in the art, for example those described in French Patent 888864. You can

When a low molecular weight heparin product obtained by chemical cleavage is used in the compositions of this invention, it is desirable that it has no or substantially no other chemical modifications.

Component i) and component ii) are component i) 1 mg: component ii) 300
To 70,000 (eg 500 to 70,000) international units (I
U), preferably present in a ratio of 300 to 35000 international units. Furthermore, components i) and ii) are preferably present in a ratio of 1 mg of component i): component ii) 1000 to 20000 (eg 2000 to 20000) international units, 1000 to 10000.
Most preferably it is present in a ratio of international units. Component i)
And / or when ii) is present in the form of a pharmaceutically acceptable salt, an amount of salt sufficient to provide the above ratio is used.

As mentioned above, the compositions of this invention are generally administered in the form of injections. For direct administration, the composition is a liquid. Although simple aqueous or water / alcohol solutions may be used, they are generally not preferred because if no stabilizing measures are taken components i) and ii) react to form sparingly soluble salts and precipitate out of solution. . Therefore, a mere solution cannot be stored for a period of several hours or more, and has little practical value.

A preferred composition of this invention is of the type described in U.S. Pat. No. 4,402,949, wherein a pharmaceutically acceptable calcium or magnesium salt of ethylenediaminetetraacetic acid (EDTA) which acts as a stabilizer is added as an additional component iii). It is a stabilizing solution. In this solution, the solvent preferably consists of iv) water and v) a pharmaceutically acceptable mono- or polyalcohol.

The magnesium and calcium salts of EDTA shown as component iii) are monomagnesium salts and monocalcium salts, including pharmaceutically acceptable polymetallic salts, wherein magnesium and preferably calcium is a monovalent metal ion such as sodium ion. Alternatively, it is contained together with potassium ions. The preferred EDTA salt for use in this invention is monocalcium bis-sodium salt (CaNa ₂ EDTA), also known as Calcium Tate Triplex. Monomagnesium bispotassium salt (MaK ₂ EDTA) can also be used.

Ingredient iii) is approximately 1 in the amount of ingredient ii) 5000 international units.
To about 50 mg, preferably 1 to
More preferably present in the range of 25 mg, 1 to 10
Most preferably it is present in the mg range.

When the solvent consists of components iv) and v) as diluents or carriers, they are preferably present in amounts of 45 to 72% and 28 to 55%, respectively, relative to the total volume of the composition.

Preferred components v) are ethanol, propylene glycol, polyethylene glycol (preferably an average molecular weight of about 40).
0), diethylene glycol, triethylene glycol and glycerin and mixtures thereof.
Furthermore, v) is preferably a mixture of a) ethanol and b) triethylene glycol or c) glycerin and d) propylene glycol. In such a mixture a) and b) are 1: 6
It is preferred that c) and d) be present in a proportion of from 1 to 8 parts by weight, further 1: 8 parts by weight, and in the ratio of from 1: 8 to 12 parts by weight, even 1:10 parts by weight.

In a preferred embodiment, the solution further comprises component vi)
A physiologically acceptable anesthetic can be included as
The anesthetic component vi) is preferably an “acetanilide anesthetic”, which means any of a series of physiologically acceptable acetanilide derivatives which have an anesthetic activity and which are known to have various known anesthetic activities. Amino-N-phenylacetanilide and its pharmaceutically acceptable salts are included. A preferred acetanilide anesthetic is 2- (diethylamino)-
N- (2,6-dimethylphenyl) acetamide (known as lidocaine), 2- (butylamino) -N
-(2-chloro-6-methylphenyl) acetamide (known as hostacaine) and 2- (2-diethylaminoacetamido) -m-toluic acid methyl ester (known as baicaine). Examples of such pharmaceutically acceptable commonly used salts of acetanilide anesthetic include its hydrochloride. If component vi) is present, its amount is preferably 1 to 2% by weight, based on the total weight of the composition.

It is known that the acetanilide derivative as described above has the action of improving the stability of the preparation (the above-mentioned US Patent No.
No. 4402949 Col. 4, lines 8-16. See European Patent Application Publication No. 28813 (May 20, 1981)).

For example, an injectable solution suitably has a pH of 4 to 6 in the present invention.

Of course, although solutions are generally the most commonly used and preferred, eg, as described above, other suitable forms of the present invention, consisting of components i) and ii), such as solutions or other suitable liquid forms prior to administration, are also contemplated. Also included are freeze-dried preparations and the like. The compositions of this invention may further contain desired additives such as carriers, diluents, stabilizers, preservatives, colorants and surfactants known in the art.

The composition of the present invention is used for prevention of thrombosis, particularly postoperative thrombosis.

The compositions of this invention have advantageous properties over previously used compositions. This is for example Frey (Med.Kli
n. 70: 1533-1558, 1975), as demonstrated by clinical studies using the I ¹²⁵ -fibrinogen uptake test.
There it was selectively concentrated in thrombotic substances in the leg veins
Radioactivity from I ¹²⁵ -fibrinogen is measured externally to the patient.

In this test, major surgery, such as total hip
Patients undergoing replacement (total hip replacement) were given I ¹²⁵ -fibrinogen 100uci parenterally the day before surgery, then daily in the legs for 2 and 3 weeks.
¹²⁵ radiations were scanned. If the count rate is low,
Fibrinogen injections were repeated 8-10 days after the first dose. The radioactivity was recorded using a Logik 121 counter / rate meter, and the counting was carried out according to the technique of Katzker et al. (Lancet, Vol. 1, p. 540, 1970). Deep vein thrombosis (DVT) if the counts at any site differ by 20% or more from the counts at the adjacent position of the same leg or at corresponding positions on the other leg, and the difference persists or increases over the next 24 hours I diagnosed.

In the above clinical experiment, patients aged 40 or older who underwent abdominal surgery for 60 minutes or longer were divided into two groups. Average age
In the first group consisting of 97 patients (37 males, 60 females) aged 59.1, 0.5 mg of dihydroergotamine methanesulfonate and low molecular weight sodium heparinate (average molecular weight of about 7,000 ±
1000) 2500 international units were intravenously injected once daily in the form of a stabilizing solution. A second group of 103 patients (30 males, 73 females) with an average age of 61.4 years was treated with 0.5 mg of dihydroergotamine methanesulfonate and 5000 international units of total sodium heparinate in the form of a stabilizing solution twice daily. It was injected intravenously. At least 7 days in both groups, average 8.7 days in group 1, second group
Treatment continued for an average of 8.3 days in the group. The results of the first group to which the composition of the present invention was administered and the second group to which the known therapeutic method was applied were compared. It was found that the reduction of DVP frequency in both groups was equal.

Detailed results are as follows.

Number of patients with thrombosis: 1st group: 4 persons 2nd group: 14 persons Thrombus site in case of occurrence: 1st group One calf: 3 persons One thigh: 1 person 2nd group One calf ... … 4 people Both calves …… 6 people One thigh ………… 2 people One calf is the same thigh ……………… 1 Both calves and both thighs ………… ............ 1 person Similar results were obtained with 0.5 mg of dihydroergotamine methanesulfonate and low molecular weight sodium heparinate (7000 ± 1
000) In the above clinical trial consisting of an injection of 2500 IU once a day, it was also obtained when the low molecular weight heparin dose was reduced to 1500 IU.

Therefore, a suitable daily indicated dose of the composition of the invention is of the order of 1/3 of the daily dose of a known composition consisting of total heparin or a pharmaceutically acceptable salt thereof, and in addition to conventional heparin It is also possible to reduce the dose to, for example, 1500 international units per day. That is, the indicated daily dose of component i) is about 0.2 to about 1.5 mg, for example 0.5 mg, and component ii) is about 1000 to about 10,000 international units, for example about 1500 to about 5000 international units. If desired, the daily dose can be administered as divided doses, for example 2 to 4 times daily. However, it is preferable to administer a once-a-day dose, eg in a unit dose form. Alternatively, if desired, components i) and ii) can be administered separately.

Suitable unit dosage forms of the compositions of this invention, such as the stabilized injectable solutions described below, contain, for example, components iii), iv), v) and optionally vi), ampoules for injection and disposable syringes containing a fixed amount of the composition. Is included. Such unit dosage form comprises about 0.2 to about 1.5 mg, preferably about 0.5 mg of component i) and about 1000 (eg about 1500) to about 10,000, preferably about 1500 (eg about 2500) of component ii). It is suitable to include about 5000 international units. Further, about 0.5 mg of component i) and about 1500, about 2500 or about 500 of component ii).
It is preferred to include 0 international units.

Further, the invention comprises a composition of the invention, which comprises making component i) an intimate mixture with component ii), for example by dissolving component i) with component ii) in a pharmaceutically acceptable solvent. To provide a manufacturing method of. The above components iii), i
When a solution is made using v), v) and optionally vi), this method preferably comprises: 1) preparing a solution of component i) and optionally component vi) in a solvent consisting of component v). , 2) component ii) and component ii in a solvent consisting of component iv)
a multi-step consisting of dissolving i) to produce a solution, 3) combining the solutions obtained in steps 1) and 2) above, and 4) optionally further adding components iv) and / or v) Can be implemented as a law.

In the production of the solution, the method of the present invention can be carried out by protective gasification of the solution, for example CO ₂ gasification.
If the pH of the resulting solution is outside the pH range of 4 to 6,
The above range can be adjusted, for example, by adding an appropriate amount of a pharmaceutically acceptable acid, for example, a pharmaceutically acceptable organic acid. When a pharmaceutically acceptable acid addition salt is used as component i), the acid added should correspond to that used to form the salt. That is, when the component i) is a methanesulfonic acid salt, the necessary pH adjustment is preferably carried out by adding methanesulfonic acid.

The resulting composition is filled into an ampoule after passing, for example, in the case of an injectable solution, as described above.
Protected with CO ₂ gasification and stored in unit dose form.

Furthermore, the present invention relates to the prevention of thrombosis, which comprises administering to a subject in need of treatment a sufficient amount of said component i) and said component ii) to prevent thrombosis, especially postoperative thrombosis. A method for preventing postoperative thrombosis is provided.

Suitable daily doses of components i) and ii) in the above method are as described above, components i) and ii) being preferably administered simultaneously in the form of said pharmaceutical composition.

The invention further provides a pack or dosing device suitable for substantially simultaneous delivery or administration of said component i) and said component ii), wherein components i) and ii) are contained in said pack or dosing device. Provide a pack or device.
Ingredients i) and ii) are preferably included in the pack or dosing device in unit dosage form, respectively, wherein the amount of ingredients i) and ii) in each unit dosage form is about 0.5 mg of ingredient i).
And component ii) preferably consisting of 1500, 2500 or 5000 international units. It is also desirable that the pack or dosing device be provided with instructions for co-administering a predetermined amount of components i) and ii).

Suitable dosing devices according to the invention include components i) and i
Included are multi-chambers, for example two-chamber syringes, suitable for simultaneous or direct sequential administration of the ingredients by injection, i) contained in separate chambers. Such multi-chamber syringes are known in the art.

The present invention enables the following methods.

(A) In the subject in need of treatment, a sufficient amount of the above-mentioned component i) and the above-mentioned component to prevent thrombosis, particularly postoperative thrombosis.
A method for preventing thrombosis, especially for preventing postoperative thrombosis, which comprises administering ii).

(B) Ingredient i) is administered at a daily dose rate of about 0.2 to about 1.5 mg, and ingredient ii) is administered at about 1000 to about 10,000 international units of 1
The method according to (a) above, which is administered at a daily dose rate.

(C) The method according to (b) above, wherein component i) is administered at a daily dose rate of about 0.5 mg, and component ii) is administered at a daily dose rate of about 1500 to about 5000 international units.

Examples of the present invention will be shown below.

Example 1 Preparation of low molecular weight sodium heparinate having an average molecular weight of about 6000 to about 9000.

Dissolve 1000 g of total sodium heparinate having an average molecular weight of 15,000 in 6.66 liters of distilled water and add about 145 ml of 25% HCl to adjust the pH.
Adjust to 2.7 and pass the whole amount through a folding filter 520 ^b 1/2 (0.320 mm) made by Schreichel & Schür. The obtained liquid was designated as a molecular weight exclusion limit of 10,000 (Pericon
Filter, pass through a molecular permeation membrane (catalog number PT / GC00001, Millipore Company) at room temperature with a pump. The usage conditions are as follows.

Inlet pressure: 3.2 × 10 ⁵ Pa Residual pressure: 1.2 × 10 ⁵ Pa Total flow rate: Approx. 200 ml / min Residual flow: 196 ml / min Liquid flow: Approx. 4 ml / min After pumping for 1 hour, liquid Direct the flow of to another container and collect. Stop after about 24 hours. 30% NaOH in liquid
About 3 ml of the aqueous solution was added to the initial pH value of total sodium heparinate (about p
Readjust to H7). This solution is called Fraction I.

Adjust the pH to 3.5 by adding about 10 ml of 30% NaOH aqueous solution to the residue,
Repeat for about 24 hours under the same conditions as above. Liquid (approx. 800 m
Re-adjust to the initial pH value (about pH 7) of the total sodium heparinate solution by adding aqueous NaOH solution to l). This solution is called Fraction II.

Adjust the pH to 4.2 by adding about 60 ml of 30% NaOH aqueous solution to the residue,
Repeat for about 24 hours under the same conditions as above. Liquid (about 500m
l) is the initial pH value of the total sodium heparinate solution (about pH 7)
Readjust. This solution is called Fraction III.

The above three fractions were separately subjected to the following steps.

First, sodium heparate is precipitated by adding 1.1 volumes of acetone, and the oily, viscous precipitate is left to stand overnight to be precipitated, and the solvent is decanted off. Cover the residue with about 3 volumes of methanol and stir the whole well at about 1000 rpm. As a result, heparin sodium salt settles as a whitish precipitate,
This is granulated in a mortar under methanol. The resulting solution is passed and the residue is dried at 60 ° and a pressure of about 200 Pa. If the NaCl content is greater than 0.5%, reprecipitation by the same method is required.

The three fractions thus obtained have the following characteristics.

Example 2 Low molecular weight heparin 1500 international units / dihydroergotamine
Preparation of 0.5 mg injectable solution.

1) Propylene glycol 18.4kg and anhydrous glycerin
Pour 1.84 kg into a 50 liter stirred container and add CO ₂ to the mixture.
Stir for 10 minutes while gasifying. 0.0286 kg dihydroergotamine methanesulfonate and lidocaine hydrochloride
0.426 kg is dissolved in the above mixture with stirring and CO ₂ gasification for a further 30 minutes.

2) Inject 18.4 kg of water (for injection) into a 30-liter stirring container and stir for about 10 minutes while CO ₂ gasification. Average molecular weight 6
000 (name in commercial calcium Tate Replenisher try) 0.114Kg heparin sodium 85.71 × 100 million in international units of ± 1000 (about 1.7 to 2.5 kg) and CaNa ₂ EDTA ₆ dihydrate, further with ₂ gasification stirring and CO 30 It takes a minute to dissolve in the water.

3) Add the solution obtained in step 2) above to the solution obtained in step 1) with stirring and CO ₂ gasification. The container obtained with the solution 2) is washed out with 1 kg of water (for injection), and this is also added to the solution of step 1). The solutions are combined and stirred for 10 minutes with CO ₂ gasification. The pH of the solution is about 5.5.

4) Add water (for injection) to the solution to make a weight of 42.810 kg (or 40 liters).

5) The obtained solution was pre-filtered with a membrane filter (0.2 μm, Ultipol nm Pal) to obtain a membrane filter (0.2 μm).
m, Ultipol nm Pal)
Pass directly into the ampoule filling machine at 1.7 bar in the presence of CO ₂ . The solution is filled under aseptic conditions into 0.8 ml of 1 ml ampoules.

Example 3 0.5 mg dihydroergotamine and low molecular weight heparin i) 250
0 and ii) Production of an injectable solution consisting of 5000 international units.

First sodium heparate (average molecular weight 6000 ± 1000)
1/3 was used in the second experiment and 3.1 in the second experiment
The procedure of Example 2 was repeated using the same relative proportion amounts of each component, except at a relative proportion of / 3.

Example 4 Preparation of an injectable solution consisting of dihydroergotamine and low molecular weight heparin of average molecular weight i) 7000 ± 1000 and ii) 8000 ± 1000.

The procedures of Examples 2 and 3 are repeated using 1) sodium heparinate with an average molecular weight of 7000 ± 1000 or 2) sodium heparinate with an average molecular weight of 8000 ± 1000 instead of sodium heparinate with an average molecular weight of 6000 ± 1000. In each case, the relative proportions of the components are the same as in Example 2. The relative proportion of sodium heparate used was about 30 each.
00, about 5000 and about 10,000 international units / dihydroergotamine methanesulfonate 1 mg.

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Claims (10)

[Claims] 1. A pharmaceutical composition comprising a hydrogenated ergot alkaloid, or a pharmaceutically acceptable acid addition salt thereof, and heparin, or a pharmaceutically acceptable salt thereof, wherein a) the hydrogenated ergot alkaloid has the formula: (I) (Wherein R is hydrogen or alkyl having 1 to 4 carbon atoms, R ₁ is methyl, ethyl or isopropyl, R ₂ is isopropyl, secondary butyl, isobutyl or benzyl,
X means hydrogen or methoxy), b) heparin is a low molecular weight heparin having an average molecular weight of about 5000 to about 8000, and a) and b) are 1 mg of component a) in the composition in a weight ratio.
To component b) is present in the amount of 300 to 70,000 international units. 2. The hydrogenated ergot alkaloid is dihydroergotamine, 6-nor-6-isopropyl-9,10-dihydro-2 ′ β-methyl-5 ′ α-benzyl ergopeptin or dihydroergovaline. The pharmaceutical composition according to claim 1. 3. The pharmaceutical composition according to claim 1 or 2, wherein the hydrogenated ergot alkaloid is methanesulfonate, maleate or tartrate. 4. The average molecular weight of low molecular weight heparin is 7,000 ± 10.
The pharmaceutical composition according to claim 1, which is 00. 5. The low molecular weight heparin has an average molecular weight of 6000 ± 10.
The pharmaceutical composition according to claim 1, which is 00. 6. Component a) and component b) are the same as component a) 1 mg
The pharmaceutical composition according to claim 1, wherein component b) is present in a ratio of 1000 to 10000 international units. 7. A pharmaceutical composition according to claim 1 which forms a unit dose form containing 0.5 mg of component a) and b) 1500; 2500 or 5000 international units of component b). 8. The pharmaceutical composition according to claim 1, wherein the low molecular weight heparin is a sodium salt, a potassium salt or a calcium salt. 9. The pharmaceutical composition according to claim 1, which is used as a pharmaceutical useful for preventive treatment of postoperative thrombosis. 10. Component a) Formula (I) (Wherein R is hydrogen or alkyl having 1 to 4 carbon atoms, R ₁ is methyl, ethyl or isopropyl, R ₂ is isopropyl, secondary butyl, isobutyl or benzyl,
X means hydrogen or methoxy) and a hydrogenated ergot alkaloid of the formula b) and component b) intimately admixing a low molecular weight heparin with an average molecular weight of about 5000 to about 8000, or a pharmaceutical composition of component a) and component b) together. Or a pharmaceutically acceptable mono- or polyalcohol solution of component a) (which may optionally co-exist with an acetamylide anesthetic), and 2) ethylenediamine. Prepare a water-containing solvent solution of component b) in the presence of magnesium or calcium tetraacetate salt, and 3) mix the solutions prepared in 1) and 2) above, and 4) mix in 3) if desired. Water and / or
Alternatively, a method for producing a pharmaceutical composition by the step of optionally adding a mono- and / or polyalcohol.