CS216164B2 - Method of preparation of the new therapeutic means - Google Patents

Description

The invention relates to a process for the preparation of a new therapeutic. The composition is characterized in that the compound of the general formula

% of the compound of the formula I to I.J. heparin 1: 500 to 70 000.

When in the compound of formula (1), R represents a (C1-C4) alkyl group, the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and isobutyl. Among the compounds of formula (I), preference is given to dihydroergotamine, quinor-O-isopropyl-O10-diidyl-Zyl-methyl-5α-benzylergopeptine and dihydroergovaline. Dihydroergotamine is particularly preferred.

Salts of the compounds of formula I and heparin are pharmaceutically acceptable salts which have no higher toxicity than the free bases or acids. Preferred salts of the compounds of formula I are methanesulfonates, maleates, and tartrates, and preferred heparin salts are sodium, potassium and calcium salts.

Therapeutic compositions are prepared by the process of the invention by treating the compounds of formula I or their salts as solids with polyvinyl pyrrolidone and admixing with heparin or salts thereof.

Way . according to the invention can be carried out as follows:

where it means

R is hydrogen or C1-C4alkyl,

R 1 is methyl, ethyl or isopropyl,

R 2 is an isopropyl, sec-butyl, isobutyl or benzyl group and a

X is hydrogen or methoxy, or salts thereof, to form a solid. polyvinylpynrolidone having a molecular weight of 10 · 100 to 100,000, the proportion of the compound of formula I being 0.1 to 5% by weight, and mixed with heparin, po216164

The compounds of the formula I or their salts are mixed together with polyvinylpyrrolidone in the form of poly-N-vinylpyrrolidone-2 (uncrosslinked) having a molecular weight of 10 000 to 100 000, in particular 11 500 to 40 000, preferably 25 000, optionally together with pharmaceutically acceptable additives, for example with surfactants, are polyethylene glycol esters of fatty acids, in particular polyethylene glycotstearate, as well as with stability enhancers such as acids, in particular methanesulfonic acid, maleic acid, tartaric acid, to achieve a pH of less than 7, preferably about 4 to 5. The compounds should be present in the mixture. 0.1 to 5% by weight, preferably 0.5 to 1.0% by weight. The mixture is dissolved in a suitable solvent, for example a lower alcohol such as methanol or ethanol at an elevated temperature, in particular at a temperature of 30 to 80 ° C, preferably at a temperature of 40 to 70 ° C. After complete dissolution (to form a clear solution), the solvent is evaporated at 50 to 80 ° C, preferably at 40 to 70 ° C, first under normal pressure and then under vacuum. add the remaining polyvinylpyrrolidone or other additives during the evaporation of the solution, and after complete evaporation of the solution, a clear liquid is obtained which solidifies at room temperature (15-25 ° C). In a known manner, the fine powder is dried in a vacuum at about 30 ° C for about 12 hours.

The dried product is mixed with sodium chloride and / or sodium phosphate to achieve isotonicity with blood, as well as with an appropriate amount of heparin or salts thereof, such as alkali metal salts, especially sodium or potassium salts, alkaline earth metal salts such as calcium salt. The mixture obtained is homogenized in a manner known per se. Dissolution of the homogenized mixture in sterile distilled water gives an isotonic injection solution having a pH of 7 to 7.5.

The process according to the invention can also be carried out by dissolving the compound of the formula I or its salt in solid form and the polyvinylpyrrolidone in water and mixing this aqueous solution with the aqueous solution of heparin or its salt, in individual solutions. optionally, sodium chloride and / or sodium phosphate is added to the solution mixtures to achieve isotonicity with blood and / or the required pH, as well as polyvinylpyrrolidone, and the mixture is then freeze-dried.

The novel therapeutic agents prepared by the method of the invention are characterized by extremely favorable antithrombotic properties. This action is achieved when the compounds of the formula I or their salts and the heparin or its salts are administered together or separately, for example in two individual doses (twinpack).

The composition may also be used advantageously for the prophylaxis of postoperative thromboses.

Antithrombořcké favorable effect of the composition was in particular J1255f3 _r j _{n, o} .genové test.

The principle of this assay is based on the external registration of the β-fibrin radiation, which is selectively administered to the thrombotic material of the lower extremity vessels (H. H. Frey et. Al., Med. Klin. 70 / 19-75 / p.). 1553 to 1558, especially page 1555).

A suitable antithrombotic effect is obtained with daily administration of -0.2 to 4 mg, preferably 0.5 to 2 mg, of the compounds of the general formula I and 2000 to 14 000, preferably 4000 to 10 000, of heparin, both compounds - they may be in the form of salts. Especially preferred is a composition comprising -0.5 milligrams of dihydroergotamine methanesulfonate and 5000 µl of J. heparinnatria, administered twice daily.

The invention also relates to galenical formulations of the compositions of the invention which are suitable for parenteral administration, such as injection solutions or suspensions for injection. These galenic forms are prepared using ingredients known per se and methods known per se.

Example ‘Dry mixture for injection

a) Preparation of dihydroergotamine methanesulfonate -a polyvinylpyrrolidone

A 4 L flask was charged with 4.0 g of dihydroergotamine methanesulfonate, 476 g of vinylpyrrolidone (average molecular weight 25,000) and 1600 ml of methanol. The flask is connected to a rotary evaporator. At a bath temperature of 60 ° C, the content is heated to 60 ° C with a rotating flask. This results in a clear solution.

The methanol is distilled off under reduced pressure (about 33.33 kPa) at a bath temperature of 60 DEG C. until a syrupy consistency of the residue is obtained. This mass was transferred to an evaporation mist and left at room temperature for two hours. It is then dried (in a vacuum oven at a temperature of about 30 DEG C. under a pressure of about 0.133 kPa for about 12 hours), grinding and drying.

(b) Dry mixing

480 g of the preparation prepared in accordance with (a) are mixed under -aseptic conditions with an amount of heparinnatrium corresponding to 40 * 000 000 IU with 8 g of disodium hydrogen phosphate in the form of dihydrate and 72 g of sodium chloride, especially purified, and filled into pierceable vials, wherein 105 mg of the mixture is introduced into each puncture vial.

Example 2

A good dry mixture for injection and suspension is obtained when, in Example 1, dihydroergotamine methanesulfonate is replaced with an equivalent amount of 6-nor-6-isopropyl-9,10-dihydro-2H-4-methyl-5α-benzylergopeptine methanesulfonate and dihydrocergovaline methanesulfonate.

Example 3

Freeze-dried mixture for injection

(a) Heparinnatrium equivalent to 5 000 000 IU, 1 g of disodium hydrogen phosphate dihydrate and 9 g of sodium chloride are dissolved in 50 ml of water (suitable for injection).

(h) Dissolve 0,5 g of dihydroergotamine methanesulphonate and 59,5 g of polyvinylpyrrolidone in 500 ml of water (suitable for injection).

c) The solutions prepared according to the invention are mixed and sterile filtered. The filtrate is filled aseptically into ampoules, each ampoule containing 1 ml of solution, and then freeze-dried.

Example 4

Dry mixture for injection

A 4 L flask was charged with 4.6 g of dihydroergotamine methanesulfonate (equivalent to 4.0 g of dihydroergotamine), 476 g of polyvinylpyrrolidone (average molecular weight of 25,000), and 1600 ml of methanol. Attach the flask to a rotary evaporator. At a bath temperature of 60 ° C, the contents are heated to about 60 with a rotating flask. This results in a clear solution.

Sufficient methanol was distilled off from the solution under reduced pressure (about 33.33 kPa) at a bath temperature of 60 ° C until a syrupy consistency of the residue was obtained. This mass is placed in an evaporation dish and left at room temperature for about two hours. Then it is dried (in a vacuum oven at 30 ° C, at a pressure of about 0.133 kPa, for about 12 hours), the product is milled and dried.

(b) Dry mixing

480 g of the preparation prepared according to a) are mixed under aseptic conditions with an amount of heparinnatrium corresponding to 20,000,000 I. heparin, with 8 g of disodium hydrogen phosphate dihydrate and 72 g of sodium chloride especially purified. The mixture is then dissolved in 5000 ml of water (suitable for injection) and sterile filtered. The filtrate is filled under aseptic conditions into ampoules, using 1 ml of solution for each ampoule, and finally freeze-dried.

a) Preparation from dihydroergotamine methanesulfonate and polyvinylpyrrolidone

Claims (6)

A process for the preparation of a new therapeutic composition, characterized in that it has a compound of 10,000 to 100,000, wherein the proportion of the compound of the formula I is 0.1 to 5% by weight, and is mixed with heparin, optionally with its salts at a weight ratio of milligrams of the compound of formula I to I.J., heparin of 1: 500 to 70,000. . 2. The process of claim 1, wherein the mixture obtained by the process of claim 1 is freeze-dried. where it means R is hydrogen or (C1-C4) -alkyl, R 1 is methyl, ethyl or isopropyl, R2 is an isopropyl, sec-butyl, isobutyl or benzyl group; and X is hydrogen or methoxy, or salts thereof, to form a solid with polyvinylpyrrolidone with molecular weight 7 8 3. A process according to claim 1 wherein the compound of formula (I) and the polyvinylpyrrolidone are dissolved in a solvent at a temperature of 30 ° C to B0 ° C for solid preparation. 4. The process according to claim 1, wherein methanol and ethanol are used as solvents. 5. A process as claimed in claim 1, wherein dihydroergotamine is used as the compound of formula (I). 6. Method according to items 1 and 3 to 5, characterized. in that compounds of formula I are used as compounds of the formula I, where they are R is hydrogen or (C1-C4) -alkyl, R 1 is methyl, ethyl or isopropyl, R 2 isopropyl, sec-butyl, isobutyl or benzyl; and X is hydrogen or methoxy, but R 1 is not methyl if. X is hydrogen, R is methyl, and R 2 is benzyl.