HU181759B - Process for preparing stable aqueous alcoholic solutions of dihydro-ergotamine or dihydro-ergotoxine methananeor ethane-sulphonate - Google Patents

Description

ethanesulfonate stable aqueous alcoholic solutions

FIELD OF THE INVENTION The present invention relates to a process for preparing stable solutions for pharmaceutical use in aqueous solutions of dihydroergotamine or dihydroergotoxin methane or ethanesulfonate in an aqueous solvent mixture containing a polyhydric aliphatic alcohol and / or a polymer thereof and optionally ethanol.

The dihydro derivatives produced by the catalytic hydrogenation of the corresponding natural rye alkaloids have a very wide range of therapeutic applications based on their favorable pharmacological properties. Particularly, for therapeutic use, ergocristine, ergocornine, α- and β-ergocriptine, and especially the dihydro derivatives of ergotamine, are among the ergotamine alkaloids.

These hydrogenated nutmeg alkaloids are most commonly used in the form of aqueous or aqueous alcoholic solutions of their acid addition salts, in particular their methanesulfonate, for oral administration in the form of drops, said salts of hydrogenated nutmeg alkaloids generally being in the range of 0.1 to 0.5% by weight. , 1-0.2% by weight.

However, in the case of such aqueous and / or aqueous solutions, the stability of the hydrogenated nutmeg alkaloids in the aqueous medium is inadequate due to isomerization and decomposition reactions in the solutions. Hydrogenated mother-rose alkaloids and their acid addition salts tend to undergo acylation in the peptide portion of the molecule in aqueous or aqueous media and to form dihydrolizergic acid amide and dihydrolysergic acid as a result of hydrolysis. In addition, the indole ring may undergo an oxidative change, which is manifested by the yellow coloration of the solutions. These degradation processes may result in the solution not reaching the required stability, i.e. reducing its active ingredient content by more than 10% during the stated shelf life [cf. Kari Thoma, Arzneimittelstability, Frankfurt a.M., 1978],

Numerous attempts have been made to overcome these difficulties and to ensure the stability of hydrogenated nutmeg alkaloids in aqueous media; these have mainly sought to increase the stability of the solution by limiting the water content of the solution and using organic solvents as the solvent. Thus, according to Belgian Patent No. 842,346, hydrogenated mother liquor alkaloids, such as dihydroergotoxin or dihydroergotamine or acid addition salts thereof, are dissolved in a pharmacologically acceptable organic solvent, such as ethanol, propylene glycol, glycerol, . Similarly, according to Hungarian Patent Application No. 171,514, the acid addition salts of hydrogenated nutmeg alkaloids have up to 18, preferably up to 3 carbon atoms, one or more carbon atoms.

-1181759 in a mixture of polyhydric alcohols and their polymers containing up to 40% but preferably not more than 3% water.

Also, the use of organic solvent mixtures having a very limited water content as a solvent is intended to improve the stability of solutions of hydrogenated peptide alkaloids according to Belgian Patent No. 869,560, which proposes a solvent mixture containing one or more alcohols having a dielectric constant below 50, preferably 30 to 46. .

However, these solutions are in many respects unsatisfactory, on the one hand, severely limiting the water content of the solution, since at a preferred water content of up to 3%, the solvent mixture is barely considered as an aqueous alcoholic medium; the stability of the solution is only one quarter of that of a solution containing 3% water, whereas in solutions with a higher water content the alkaloids are significantly degraded even at 20 ° C, as shown in the comparative examples herein. The lack of stability is also indicated by the fact that, as cited, the solutions are preferably prepared in an inert gas atmosphere and stored with the exclusion of air.

While such mixtures of solvent containing at least 60% but preferably at least 97% of mono- and / or polyhydric alcohols can provide a high degree of stability to dissolved hydrogenated kelp alkaloids, these solutions are not at all advantageous from the medical point of view, entailing the ingestion of a significant amount of mono- and / or polyhydric alcohol by the body, which is not desirable in itself, and is particularly detrimental to pediatric use and to the need for regular administration of other drugs during medication, which may include drugs that are completely incompatible with alcohol. Particular attention should be paid to this condition in elderly patients, particularly those requiring medication. Therefore, the current world-wide aspiration is to prepare liquid pharmaceutical compositions for oral administration in aqueous solution. It has already been proposed to stabilize solutions of dihydroergotamine or dihydroergotoxin methane or ethanesulfonate in aqueous alcoholic solutions of more than 50% by using various stabilizers as antioxidants such as ascorbic acid or propyl gallate and chelating agents such as ethylenediaminetetraacetic acid 8. Belgian Patent No. 542). Although solutions of considerable stability can be obtained by this method, they exhibit undesirable degradation of the active ingredient when stored for prolonged periods, as demonstrated by the experiments described below. Therefore, we have sought to enhance the stability of such aqueous-alcoholic solutions of the dihydroergotamine and dihydroergotoxin salts, which are more effective and have excellent pharmaceutical use.

It has been found that the above drawbacks can be overcome and that the dihydroergotamine or dihydroergotoxin2

solutions of methane or ethanesulphonate having a water content of more than 40%, having excellent shelf life of more than 3 years, can be prepared by treating the dihydroergotamine or dihydroergotoxin-methane or ethanesulphonate alcohol and / or a liquid polymer of such alcohol and optionally dissolved in a mixture of 41 to 80% by weight, preferably 41 to 60% by weight, of a monovalent saturated aliphatic alcohol having 2 to 4 carbon atoms and the solvent mixture and 0.05 to 0% stabilizer, 15% by weight of nicotinic acid or nicotinic acid diethylamide and 0.05 to 0.2% by weight of thiourea, glutathione or S-carbamoyl cysteine are added.

Polyethylene glycol ("polyethylene glycol 400") preferably has a molecular weight of up to 380-420, preferably propylene glycol and / or glycerol as the polyvalent alcohol of 2 to 3 carbon atoms with 41 to 80% by weight of water in the solvent mixture. ethanol is preferred as a monovalent aliphatic alcohol having from 2 to 4 carbon atoms. Any of these polyhydric alcohols or alcohol polymers can be used alone with the indicated amount of water, but for mixtures of solvents having a higher water content (50-60%), it is preferable to use mixtures of various alcohols (e.g., propylene glycol and / or glycerol and ethanol). When ethanol or other monohydric alcohols are used in addition to polyhydric alcohols and / or alcohol polymers, the weight ratio of the latter to polyhydric alcohols or alcohol polymers or mixtures thereof may be, for example, 1: 2 to 1: 4.

Of the substances used as stabilizing additives in the solvent mixture, nicotinic acid amide and nicotinic acid diethylamide have not yet been used to stabilize solution formulations. Thiourea alone was first described by R. Dolder, Pharm. Acta Helv. 27, 54, 235 (1952)] to stabilize aqueous vitamin C solutions; Its use as an antioxidant is also mentioned by K. Thoma (Arzneimittelstability, Frankfurt a / M 1978). Münzel and co-workers mention glutathione and cysteine in their list of organic antioxidants in their book "Galenisches Praktikum" (Wissenschaftliche Verlagsgesellschaft m.b.H., Stuttgart 1959); no literature is available on the use of S-carbamoyl cysteine for this purpose. The use of a combination of nicotinic acid amides and sulfur-containing organic compounds as a stabilizer is novel, and no such reference has been found in the literature.

Among the additives used in the present invention as stabilizing agents, nicotinic acid amide and diethylamide also provide less inhibition of epimerization, hydrolysis or oxidation, even in the presence of hydrogenated mother liquor alkaline alcohols, in particular 4.0 and 5.5, preferably 4.5 and 4.5. PH of 5.0.

However, the stabilizing effect of the nicotinic acid amides to be used according to the invention is not limited to stabilizing the pH, but such amides also exhibit a specific stabilizing effect on hydrogenated nutmeg alkaloids, as evidenced by, for example, inorganic or organic acids or bases are used to adjust the pH of such solutions, the stability of the solution is not improved at all, or, on the contrary, deteriorates.

Another additive according to the invention is thiourea, glutathione or thiourea in a concentration of 0.05-0.2% by weight of the solution.

S-carbamoyl cysteine inhibits oxidative staining of the alkaloid solution 10; the use of thiourea in an amount of about 0.1% has proved particularly advantageous for this purpose.

The solutions of hydrogenated nutmeg alkaloids produced by the process according to the invention also exhibit such a high degree of stability against the oxidative effect of air that it is unnecessary to work in an inert gas atmosphere during the preparation of such solutions and to eliminate the air completely. This also offers significant advantages in terms of manufacturing technology.

In order to illustrate the effectiveness of the stabilizing additives used in the process of the invention, comparative experiments were carried out with the solutions described in the already cited Hungarian Patent Specification 25,171,514, designated "Cj" or "E / formulation" (and considered satisfactory for formulation C only). to prepare solutions of the stated compositions and to test their stability on their own and with the addition of the stabilizers of the invention (0.05% nicotinic acid amide and 0.1% thiourea).

To test the stability of each solution is ₃₅ to 50 ° C, 60 ° C, or stored for 10 days at 75 ° C followed by high performance liquid chromatography in the solution undegraded alkaloid levels were determined. The assays were performed by L. Szepesy et al., J. Med. Chromatogr. _40, 149, 271-280 (1978)], a "Liquopump 312" pulse-free pump, a "Liquodet 308" variable wavelength detector (Labor MIM), a "Rheodyne 7120" injector (Rheodyne), and an "HP 3380 S" electronic integrator- 45 (Hewlett Packard) in a Nucleosil 10 Ci ₈ (Chrompack) column; eluting with a 1: 1 mixture of acetonitrile and 0.01 M aqueous ammonium carbonate at a flow rate of 1 mL / min. Detection was performed at 50 to 280 nm. The measurement error for this method is ± 1%.

20 μΐ of each of the solutions to be tested (with an alkaloid concentration of 0.1% for the dihydroergotoxin acid addition salts and 0.2% for the dihydroergotamine acid addition salts) was injected for each assay; the standard solutions, also injected at 20 μΐ, were prepared by weighing 10 mg of dihydroergotoxin-methanesulfonate or 20 mg of dihydroergotamine-60-methanesulfonate into a 10 ml volumetric flask, with acetonitrile and water 1: Dissolve in a 1: 1 mixture and make up to 10 ml with the same solvent mixture. 65

Retention times:

dihydroergocristine methanesulfonate 18.8 minutes dihydroergocornine methanesulfonate 13.5 minutes dihydroergocryptine methanesulfonate 17.0 minutes dihydroergotamine methanesulfonate 11.4 minutes

From the analytical results obtained,

In - = _ kt

Using the formula 1-0 ^- <-t (where t is the number of months from solution preparation to stability test, c _{0 is} the initial alkaloid concentration and c _{t is} the concentration of alkaloid found at test time), k ( month ^-1 ) stability constant; 50 ° C, 60 ° C and 75 ° C for ^c k-value, from which a simple calculation,

100, based on the 2,303 log - ^ - = - k ₂₅ · t relationship, the 0,1054 t = - formula gives the t shelf life of the solution k ₂₅ (internationally accepted standard for shelf life - cf. Kari Thoma, Arzneimittelstability, Frankfurt, M.M., 1978, refers to the time within which the active ingredient content of the solution is reduced by up to 10%.

Comparative experiments yielded the following results:

Preparation C:

(according to Hungarian Patent Application No. 171,514)

Dihydroergotamine metánsztűfonát

Glycerol, anhydrous Ethanol (94% by weight) Propylene glycol Distilled water

25 ° C constant of the above solution:

2.0 g 156.0 g

212.5g

254.5g

375.0 g ~ 37.5 wt%. extrapolated to temperature

K = 4.8 · 10 ^-5 .

Extrapolated k-constant at 25 ° C of a solution of the same composition, but containing 0.05% nicotinic acid: doc and 0.1% thiourea: 2.17 · 10 ^-5 ; dielectric constant 52.5.

Preparation D:

(according to Hungarian Patent Application No. 71 514)

Dih idroergotamine methanesulfonate

Ethanol (94% by weight) Glycerol, anhydrous Distilled water Methanesulfonic acid

25 ° C constant of the above solution:

2.0 g 49.0 g 146.0 g

800.0 g ~ 80% by weight.

Extrapolated to 0.0068 g

-3181759 k = 1.92 10 ^-3 (shelf life: about 4.5 years).

Extrapolated k constant at 25 ° C for a solution of the same composition but containing 0.05% nicotinic acid amide and 0.1% thiourea: 1.03 · 10 ' ³ (shelf life: about 8.5 years); dielectric constant: 75.2.

The results of the above comparative experiments clearly show that the addition of the stabilizing additives of the present invention not only significantly improves the stability of formulation C containing nearly 40% water, but also has an unsatisfactory stability of 80% according to the above cited patent. water-containing dihydroergotamine methanesulfonate solutions can be made to have acceptable stability, with a shelf life of up to 15 days.

The formulations containing the stabilizing additives of the present invention are also provided with dielectric constants of the solutions to illustrate that solutions of 75 having a dielectric constant of well over 50 dielectric constant values as required by Belgian Patent No. 869,560 can be made good by the process of the present invention. too. 25

Further comparative experiments were carried out with the above method to demonstrate that the stability of solutions of dihydroergotoxin and dihydroergotamine methane or ethanesulfonate according to the present invention is significantly higher than the aqueous solution containing more than 50% aqueous which is obviously due to the use of more effective stabilizers of the invention.

In these experiments, the solution of Example 1 of the cited Belgian patent ₃₅ (composition: 0.1 g of dihydroergotoxin methanesulfonate, 15 g of glycerol, 5 g of ethanol,

0.1 g of ethylenediaminetetraacetic acid disodium salt, 0.05 g of propyl gallate, 0.015 g of methanesulfonic acid, made up to 100 ml with distilled water (solution ₄₀ according to example 1 of this description): 0.1 g of dihydroergotoxin methanesulfonate 05 g of nicotinic acid amide, 0.1 g of thiourea, 55.13 g of polyethylene glycol 400 and 44.62 g of distilled water) were compared for stability. 45

The test solutions were allowed to stand at room temperature under filtered light for 6 and 12 weeks respectively, and at 75 ° C for 48 hours and 100 ° C for 3 hours, respectively, in an accelerated test. The results obtained are summarized in the following 50 tables ("baseline value" means the active ingredient content of the solution at the commencement of the study, calculated as the active ingredient of the product):

Comparison of the above figures clearly demonstrates that the stability of the active ingredient in the solution of the claimed stabilizer composition is significantly higher both at room temperature and when heated.

Practical embodiments of the process of the invention are illustrated by the following examples, however, it should be noted that the scope of the invention is in no way limited to the scope of these particular examples. For each of the Examples, hydrogenated walnut alkaloid solutions of the same composition as in the Example, but not containing the stabilizing additives of the present invention, were prepared for comparative stability studies; the stability values obtained with these known solutions according to the test method described above in the table of results of the stability tests are "IA", "2A", etc. .

Example 1

The following substances are used to prepare the solution:

Dihydroergotoxin methanesulfonate 3: 3: 2: 1 Nicotinic acid amide Thiourea Polyethylene glycol 400 Distilled water

1.0 g 0.5 g 1.0 g

551.3 g (= 490 mL) 446.2 g ~ 44.6 wt%.

In a mixture of polyethylene glycol and distilled water, dihydroergotoxin methanesulfonate, nicotinic acid amide and thiourea are successively dissolved at room temperature (15-25 ° C) with stirring. The pH of the solution is between 4.5 and 5.0. After filtration under pressure, the solution is poured into drops.

.A) Comparative Example

The solution was prepared in the same manner as in Example 1, but only as follows:

Dihydroergotoxin methanesulfonate 3: 3: 2: 1 Polyethylene glycol 400 Using distilled water

1.0 g

551.3 g (= 490 mL) 447.7 g ~ 44.8 wt%.

55 Example 2 The Belgian Notified solution: patent To prepare the solution uses the following materials of crimp: solution: 60 Dihydroergotoxine-methane Initial Value: 98.7% 96.8% sulfonate 3: 3: 2: 1 1.0 g 75 °, 48 hours: 97.6% 86.1% nicotinamide 0.5 g 100 °, 3 hours: 98.6% 91.0% thiourea 1.0 g Scattered light, 6 weeks: 90.1% 87.5% propylene 545.7 g (= 525 mL) Scattered light, 12 weeks: 74.5% 59.1%. 65 Distilled water 451.8 g ~ 45.2% w / w.

-4181759

In a mixture of propylene glycol and distilled water, dihydroergotoxin methanesulfonate, nicotinic acid amide and thiourea are dissolved in succession at room temperature (15-25 ° C) with stirring. The pH of the solution is between 4.5 and 5.0. After filtration under pressure, the solution is poured into drops.

In a mixture of propylene glycol and distilled water, dihydroergotamine methanesulfonate, nicotinic acid amide and thiourea are successively dissolved at room temperature (15-25 ° C) with stirring. The pH of the solution is between 4.5 and 5.0. After filtration under pressure, the solution is poured into drops.

Comparative Example 2A)

The solution was prepared in the same manner as in Example 2 but using only the following materials:

Comparative Example 4A)

The solution was prepared in the same manner as in Example 4 but using only the following materials:

Dihydroergotoxin methanesulfonate 3: 3: 2: 1 Propylene glycol Distilled water

1.0 g

545.7 g (= 525 mL) 453.3 g ~ 45.3 wt%.

Dihi droergotamine methanesulfonate Propylene glycol Distilled water

2.0 g

545.7 g (= 525 mL) 452.3 g ~ 45.2 wt%.

Example 3

The following substances are used to prepare the solution:

Dihydroergotoxin methanesulfonate 3: 3: 2: 1 1.0 g

Nicotinic acid amide 0.5 g

Thiourea 1.0 g 30

Glycerol anhydrous 145.0 g

Ethanol (94% by weight) 178.0 g

Propylene glycol 264.0 g

Distilled water 410.5 g ~ 41.1% by weight.

Example 5

The solution was prepared as described in Example 4 using the following materials:

Dih (droergotamine methanesulfonate

Nicotinic acid amide Thiourea Polyethylene glycol 400 Distilled water

2.0 g 0.5 g 1.0 g

551.3 g (= 490 mL) 445.2 g ~ 44.5 wt%.

Comparative Example 5A)

The solution was prepared in the same manner as in Example 5 but using only the following materials:

Dihydroergotoxin methanesulfonate is dissolved in ethanol with stirring, and then a mixture of glycerol, propylene glycol and distilled water in which nicotinic acid amide and

thiourea. The solution pH 4.5-5.0 40 It is. Under pressure after filtration, the solution Dih idroergotamine methane- we put them in drop jars. jlfonat 2.0 g Polyethylene glycol 400 551.3 g Distilled water 446.7 g Comparative Example 3A 45 Dihydroergotoxine-methane Example 6 sulfonate 3: 3: 2: 1 1.0 g Glycerol is anhydrous 145.0 g The solution was prepared as described in Example 4 Ethanol (94% by weight) 168,0g 50 the following materials: propylene 264.0 g Distilled water 412.0 g ~ 41.2 wt%. Dihydroergotoxine-methane sulfonate 3: 3: 2: 1 1.0 g nicotinamide 0.5 g Example 4 55 thiourea 1.0 g Ethanol (94% by weight) 137.0 g To prepare the solution, use use the following materials Glycerol is anhydrous 145.0 g crimp: propylene 264.0 g Distilled water 451.5 g Dihydroergotamine methane 60 sulfonate 2.0 g nicotinamide 0.5 g Example 7

44.7% by weight.

Thiourea Propylene glycol Distilled water

1.0 g

545.7 g (= 525 ml)

450.8 g ~ 45.1% w / w.

weight%.

The solution was prepared as described in Example 4 using the following materials:

-512

18175S

Dihydroergotoxin methanesulfonate 3: 3: 2: 1

Nicotinic acid amide Thiourea ethanol (94% by weight) Glycerol anhydrous Propylene glycol Distilled water

1.0 g 0.5 g 1.0 g

95.0 g

145.0 g 264.0 g

495.0 g ~ 50% w / w.

Propylene glycol 545.7 g (= 525 ml)

Distilled water 451.8 g ~ 45.2% by weight.

In a mixture of propylene glycol and distilled water, dihydroergotoxin methanesulfonate, nicotinic acid diethylamide and thiourea are dissolved in succession at 5 room temperature (15-25 ° C). The pH of the solution is between 4.5 and 5.0. After filtration under pressure, the solution is poured into drops.

Example 8

The solution was prepared as described in Example 2 using the following materials:

Dihydroergotoxine Krafft

nicotinamide

thiourea

propylene

Distilled water

Comparative Example 8A)

1.0 g 0.5 g 1.0 g

545.7 g (= 525 mL) 20

451.8 g ~ 45.2% w / w.

Example 10

The solution was prepared as described in Example 9 using the following materials:

Dihydroergotoxin methanesulfonate 3: 3: 2: 1 Nicotinic acid amide Glutathion Propylene glycol Distilled water

1.0 g 0.5 g 4.1 g

545.7 g (= 525 ml)

448.7 g ~ 44.9% w / w.

The solution was prepared in the same manner as in Example 2, 25 but we use only the following materials: 30 Dihidroergotoxin- ethanesulfonate propylene Distilled water 1.0 g 545.7 g (= 525 mL) 453.3 g ~ 45.3 wt%. Example 9 35 To prepare the solution, glaze: using the following materials Dihydroergotoxine-methane 40 sulfonate 3: 3: 2: 1 1.0 g Nicotinic acid diethylamide 0.5 g thiourea 1.0 g

Example 11

The solution is prepared in the same manner as in Example 9 but using the following materials:

Dihydroergotoxin methanesulfonate 3: 3: 2: 1

nicotinamide

S-carbamoyl-cysteine Propylene glycol Distilled water

1.0 g 0.5 g 2.2 g

545.7 g (= 525 mL) 450.6 g ~ 45.1 wt%.

The stability test of the solutions prepared according to the invention in the manner described in the examples above, as well as the known solutions prepared after each example for comparison, are summarized in the following table:

solutions storage temperature and time Because concentration % k (month ^-1 ) e It consists of xtrapolated k at 25 ° C. (month ^-1 ) Shelf life! time Dielekt- ruined constant 40 ° C 12 weeks 98.6 4.70 · 10 ^-3 First 50 ° C 12 weeks -> 94.7 1.82 · 10 ^-2 5.63 · 10 ^-4 15.6 years 50.6 75 ° C 10 days 89.3 3.40 · 10 ^-1 40 ° C 12 weeks 73.2 1.04 · 10 ^-1 1 / A. 50 ° C 12 weeks 50.6 2/27 · IO ^-1 2.93 · 10 ^-2 3.6 months 50.7 75 ° C 10 days 64.6 1.31 · 40 ° C 12 weeks 98.5 5.04 · 10 ^-3 Second 50 ° C 12 weeks 95.7 1.47 · 10 ^-2 8.71 · 10 ^-4 10.1 years 57.9 75 ° C 10 days 94.6 1.67 · 10 ^-1 40 ° C 12 weeks 62.4 1.57 · 10 ^-1 2 / A. 50 ° C 12 weeks 51.7 2.20 · 10 ^-1 9.02 · 10 ^-2 1.2 months 57.6 75 ° C 10 days 85.4 4.74 · 10 ^-1

-6Continue Table

solutions storage temperature and time Concentrated k concentration (month * ¹ )% 25 ° C Shelf life extrapolated k. time (month * ¹ ) Dielekt- ruined constant 40 ° C 12 weeks 97.0 1.02 10 * ² Third 50 ° C 12 weeks 92.9 2.46 10 ' ² 2.49 · 10 ′ ³ 3.5 years 57.6 75 ° C 10 days 94.4 1.73 10 ' ¹ 40 ° C 12 weeks 90.8 3.22 0 ' ² 3 / A. 50 ° C 12 weeks 83.7 5.93 to * ² 1.19 · 10 * ² 8.9 months 57.5 75 ° C 10 days 92.5 2.34 10 * ¹ 40 ° C 12 weeks 98.3 5.72 10 * ³ 4th 50 ° C 12 weeks 93.8 2.13 10 * ² 6.41 · 10 * ⁴ 13.7 years 57.8 75 ° C 10 days 86.3 4.42 10 * ¹ 40 ° C 12 weeks 96.8 1.08 10 * ² 4 / A. 50 ° C 12 weeks 89.0 3.89 10 * ² 1.31 · 10 * ³ 6.7 years 57.8 75 ° C 10 days 78.7 7.19 10 * ¹ 40 ° C 12 weeks 99.6 1.34 10 ' ³ 5th 50 ° C 12 weeks 97.8 7.42 10 * ³ 7.50 · 10 * ^s 117.1 years 50.5 75 ° C 10 days 87.4 4.04 10 * ¹ 40 ° C 12 weeks 90.1 3.48 10 * ² 5 / A. 50 ° C 12 weeks 74.1 9.99 10 * ² 6.19 · 10 * ³ 1.4 years 50.1 75 ° C 10 days 69.5 1.09 40 ° C 12 weeks 96.1 1.33 10 * ² 6th 50 ° C 12 weeks 90.0 3.51 10 * ² 2.73 · 10 * ³ 3.2 years 59.2 75 ° C 10 days 90.1 3.13 10 * ¹ 40 ° C 12 weeks 95.8 1.43 10 * ² 7th 50 ° C 12 weeks 89.4 3.74 10 * ² 2.95 · 10 * ³ 3.0 years 62.2 75 ° C 10 days 89.5 3.33 10 * ¹ 40 ° C 12 weeks 98.3 5.72 10 * ³ 8th 50 ° C 12 weeks 95.1 1.68 10 * ² 1.00 · 10 * ³ 8.8 years 57.9 75 ° C 10 days 94.0 1.86 10 * ¹ 40 ° C 12 weeks 63.4 1.52 10 * ¹ 8 / A. 50 ° C 12 weeks 52.5 2.15 10 '* 8.63 · 10 * ² 12 months 58.1 75 ° C 10 days 85.5 4.70 10 * ¹ 40 ° C 12 weeks 98.4 5.38 10 ³ 9th 50 ° C 12 weeks 95.4 1.57 10 * ² 9.38 · 10 * ⁴ 9.4 years 57.9 75 ° C 10 days 94.3 1.76 10 * ¹ 40 ° C 12 weeks 98.1 6.39 10 ³ 10th 50 ° C 12 weeks 94.9 1.75 10- ² 1.15 · 10 * ³ 7.6 years 57.6 75 ° C 10 days 93.9 1.89 10 * ¹ 40 ° C 12 weeks 97.3 9.12 10 * ³ 11th 50 ° C 12 weeks 92.6 2.56 10- ² 1.68 · 10 * ³ 5.2 years 57.8 75 ° C 10 days 91.5 2.67 10 * ¹

As can be seen from the data in the table, the solutions prepared according to the process of the invention have very good stability; all solutions meet the practical shelf-life requirement (shelf life of at least 3 years) and in most cases exceed it several times.

However, solutions of the same composition but not containing the stabilizing additives according to the invention (i.e. prepared according to the state of the art) are much less stable, the comparative examples 1A, 2A, 3A and

-7181759 does not meet the practical shelf life requirement, and the solution of Comparative Example 4A has a shelf life less than half of that of the solution prepared according to the invention (Figure 4).

Claims (3)

Patent claims: CLAIMS 1. A process for the preparation of stable solutions of dihydroergotamine or dihydroergotoxin methane or ethanesulphonate in aqueous solution of a polyvalent aliphatic alcohol and / or a polymer of such alcohol and optionally ethanol, wherein the dihydroergotamine or dihydroergotoxin is - or -ethanesulfonate C2-3 saturated polyhydric alcohol and / or such alcohol liquid polimeije calculated total weight and optionally from 2 to 4 carbon atoms, a monovalent saturated aliphatic alcohol and the solvent% by weight, preferably 41 to 80 ₅ 41 to 60 weight% dissolved in water, whereby the to the solution are added a) 0.05-0.15% by weight nicotinic acid amide or nicotinic acid diethylamide and b) 0.05-0.2% by weight thiourea, glutathione or S-carbamoyl cysteine. 2. A process according to claim 1 wherein the polyhydric alcohol is propylene glycol and / or glycerol and the monovalent saturated aliphatic alcohol is ethanol. 3. The process of claim 1 or 2, wherein the alcohol polymer is polyethylene glycol having a molecular weight of from 200 to 500. Responsible for publishing: Director of Economic and Legal Publishing 84.4441 - Zrínyi Printing House, Budapest