SI9300029A - Lecithin-containing solutions with levemopamil - Google Patents

Description

(57) A colloidal aqueous levopopamil solution, obtained by mixing a mixture of levopopamyl hydrochloride, phospholipid, is mixed with an isotonizing agent and water or buffer solution and homogenized, is described. The use of this solution in the preparation of medicaments is also described.

Sl 9300029 A

Knoll Aktiengesellschaft

Lecithin-containing solution with levemopamil

Description

A process for the preparation of aqueous, lecithin-containing solutions of the active substance levopopamil using this process of obtaining the solution and the use of these solutions in the preparation of medicaments is described.

Not a small number of active substances cause problems with the use, with the occurrence of local intolerances in the area of application. Such side effects are particularly noticeable when parenteral use of aqueous solutions of the active substances, e.g. when injected into a blood vessel in the form of venous irritations. These active substances also include levemopamil (EP 147 707). It is known that lipid and phospholipids can improve the local tolerability of levopopamil.

On the one hand, as described in DE-A-4015108.3, levemopamil can be solubilized in a fat emulsion, thereby improving local tolerability tested by intravenous administration in rats compared to aqueous solution.

We have now found a simple process that has obvious advantages over the known processes.

The subject of the invention is a process for the preparation of colloidal aqueous levopopamyl solutions, characterized in that the mixture of levopopamyl salt, phospholipid and isotoning agent is mixed with water and homogenized.

The active substance (levemopamil) is used in the form of its salts. Levemopamyl hydrochloride is preferred. The concentration of the active substance in the finished solution is 1 - 20 mg / ml, preferably 3 - 10 mg / ml. Particularly preferred are concentrations of about 5 mg / ml.

Active substances The added amount of phospholipid is crucial for achieving good local tolerability. The weight ratio of the active substance against phospholipid is 1: 4 to 1: 20, preferably 1: 4 to 1: 10. Particularly preferred are the weight ratios of the active substance against phospholipid from 1: 5 to 1: 7.

Suitable phospholipids are either natural (i.e. obtained from natural materials) or synthetic phospholipids. Preferred are neutral and / or amphoteric phospholipids such as lecithin (phosphatidylcholine), especially those containing residues of unsaturated fatty acids such as butyric acid and / or linoleic acid. Particularly preferred are highly purified eggs and soyalitin containing at least 80% phosphatidylcholine.

The use of levopopamyl hydrochloride leads to the lecithin-containing solutions of the present invention to a pH value in the weakly acidic range (pH about 4 to 4.5). Despite their relatively acidic pH, these solutions are characterized by significantly improved local tolerability after intravenous administration, relative to equally concentrated aqueous solutions containing no phospholipid.

The local transferability of the levopopamyl hydrochloride solution can be slightly increased by raising the pH to 7.0. The long-term storage stability of pH-neutral solutions is worse than that of weakly acidic solutions, so the pH-neutral solutions need to be stored in a cool place. Another method of improving storage stability is to lyophilize the solutions of the present invention. A very gentle soaking of water produces a dry preparation (lyophilisate) which can be stored at room temperature. Prior to use, only the collected water must be re-added.

The buffer solution can compensate for the active substance (hydrochloride) caused by the low pH (pH 4 - 5) of the levopamil solution. Buffers that allow a pH value of 5 to 7 in the final solution are particularly preferred. Phosphate buffers are particularly preferred. Alkaline pHs beyond pH 7 are less suitable because they reduce the stability of the excipient (lecithin) by hydrolysis. Further auxiliaries may be added to the buffer solution, e.g. antioxidants (2,6-di-tert-butyl-4-methylphenol) and / or heavy metal chelators, such as EDTA (ethylenediamine-tetraacetic acid). The amounts used here are oriented to the commonly used dosages in the injectable preparations.

Isotonizing the solution to achieve blood isotonia may be effected with the above buffer or with sodium chloride, but also with other salts, and preferably with carbohydrates such as sucrose and / or maltose. Glycerin is also suitable. Salts, respectively. carbohydrates are added to the buffer solution in amounts that give an approximately usable solution of osmolarity of about 280 to 400 mOsmol / kg.

After preparation of the complete mixture of the active substance, phospholipid, isotonizing agent and water, respectively. buffer solutions, homogenize the nozzle. Methods that reduce the particle size of colloidal solutions to values below 0.2 µm (average) are preferred, so that the entire composition is sterile filterable (so as a disinfectant filtration with a 0.2µτη filter).

It has proved to be meaningful to allow homogenization in two stages to proceed. In the first stage, with a simple dispersion apparatus that causes the crushing of large agglomerates with high-speed knives, a suspension is prepared in which the medium particle sizes are still in the area of several micrometers. This suspension is then further homogenized by suitable methods. High-pressure homogenizers (which are widespread in the preparation of emulsions) are preferred, but also filtration processes in which the slurry under pressure is pushed through suitable membrane filters (extrusion). Both methods allow the particle size to be reduced to a mean value below 0.2 μτη in a gentle manner. The reconstituted solutions are thus sterile filterable, which allows the disinfection filtration to be performed, which is of great importance for the form of the drug to be administered parenterally. Reduction in particle size is further necessary to achieve sufficient storage stability. Colloidal solutions, with particle sizes in the micrometer range, tend to sediment and / or dislodge, and are not parenterally useful because of possible emboli.

After homogenisation and filling (eg into ampoules), the finished colloidal solution can be autoclaved (typically 20 minutes at 120 ° C) by known methods, without precipitating in the colloidal solution. This sterilization in the final container makes aseptic the finished form of the drug.

In animal experiments, the local transferability of the compositions was shown to depend on the weight ratio of the active substance: lecithin. Solutions containing equal masses of active substance and phospholipid even showed an improvement in local tolerability in the animal experiment (rats) compared to pure aqueous solution, but were clearly less tolerable than the compositions of the methods of the present invention in which it lies preferably, a weight ratio of 1: 4 to 1: 10. Sufficient phospholipid is therefore necessary to achieve optimal portability.

Compared to the fat emulsion composition in DE-A-4015108.5, the process, in the sense of the present process, has the advantage that a significantly lower amount of lipid must be used for good local transferability. While the weight ratio of active substance: lipid in the case of an emulsion is 1:11, this value can be reduced to about 1: 6 in the process of the present invention, without demonstrating differences in local transferability in the animal experiment. Thus, in the case of the method of the present invention, the unnecessarily high lipid load of the patient can be avoided.

The following examples illustrate the invention.

Example 1

1.375 g of levopopamyl hydrochloride, 7.500 g of soyalitin S 100 (Lipoid, Germany) and 10 mg of 2, 6-di-tert-butyl-4-methylphenol are mixed with 150 ml of buffer solution (consisting of 550 mg disodium hydrogen phosphate dihydrate, 265 mg of sodium dihydrogen phosphate monohydrate, 43.15 g of sucrose and 100 mg of disodium EDTA in 500 ml of water). The mixture with the Ultra-Turrax® dispersion rod was crushed for 10 minutes in a cloudy suspension and filled to a full volume of 250 ml with a buffer solution. The nozzle was then homogenized in a high pressure homogenizer for 45 min at 50 ° C and 600 bar. The transparent, weak opalescent colloidal solution was filled into ampoules via a sterile filter (0.2 μπι). The ampoules were then sterilized in an autoclave at 120 ° C for 20 min. The mean particle size after autoclaving lies at 0.082 μτη (measured by photon correlation spectroscopy). The pH is 6.32.

Example 2

Preparation was carried out as in Example 1, but with egg lecithin E 100 (Lipoid, Germany, same amount as in Example 1). The mean particle sizes after autoclaving lie at 0.099 μτη, with a pH of 6.18.

Example 3

The preparation was carried out as in Example 2, but with a buffer solution containing 43.15 g maltose monohydrate instead of sucrose. The mean particle sizes lie after autoclaving at 0.089 μτη, with a pH value of 6.05.

Example 4

The preparation was carried out as in Example 3, but without the addition of phosphate buffer. The mean particle sizes lie after autoclaving at 0.109 μτη, with a pH value of 4.15.

Example 5

The preparation was carried out as in Example 2, but without the addition of phosphate buffer. The mean particle sizes lie after autoclaving at 0.086 μιη, with a pH value of 4.07.

Example 6

The preparation was carried out as in Example 2, but without the addition of phosphate buffered substances, as well as with 26.0 g of glycerin, instead of sucrose. The mean particle sizes lie after autoclaving at 0.046 μιη, with a pH of 4.17.

Example 7 (Comparative Example)

The preparation was carried out as in Example 2, but only with 2,063 g of egg lecithin E 100. The mean particle sizes were at 0.063 μτη, the pH being 6.33.

Example 8 (Comparative Example)

Dissolve levemopamyl hydrochloride in water at a concentration of 5.50 mg / ml.

Example 9

The compositions of Examples 2, 7 and 8 were administered once daily at a dose of 15 mg levemopamyl hydrochloride per kg body weight to 6 rats intravenously at a rate of 0.6 ml / min. Composition 8 is only usable for 2 days, Composition 7 is applicable for 6 days, until further use is no longer possible due to the onset of local intolerance. In contrast, animals can be administered the Example 2 composition over 28 days without local intolerance reactions.

For

Knoll Aktiengesellschaft:

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22554-01 / 93-DO-Re.

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Claims (3)

Patent claims A process for the preparation of colloidal aqueous levopopamil solutions, characterized in that the mixture of levopopamyl salt, phospholipid and isotonizing agent is mixed with water and homogenized. Process according to claim 1, characterized in that a buffer is added to the mixture of levopopamyl salt, phospholipid and isotonizing agent. 3. The solution obtainable according to claim 1 or 2. For Knoll Aktiengesellschaft: 22554-01 / 93-D0-Re. Summary Lecithin-containing solution with levemopamil Described is a colloidal aqueous levopopamil solution obtained by mixing a mixture of levopopamyl hydrochloride, phospholipid, mixing with an isotonizing agent and water or buffer solution and homogenizing. The use of this solution in the preparation of medicaments is also described.