WO1993013765A1 - Lecithin-containing solutions with levemopamil - Google Patents

Abstract

An aqueous colloidal solution of levemopamil obtained by the fact that a mixture containing levemopamil hydrochloride, a phospholipid, an isotonic product and water or a buffer solution is prepared and homogenized.

Description

 Solutions containing lecithin with levemopamil

description

A process for the preparation of aqueous lecithin-containing solutions with the active ingredient levemopamil is described, the solutions obtained with the aid of this process and the use of these solutions for the production of medicaments.

A not inconsiderable number of active substances causes problems in the application due to the occurrence of local incompatibilities in the area of the application site. Such side effects are particularly noticeable in the parenteral application of aqueous active ingredient solutions, e.g. recognizable in the form of vein irritation when injected into the bloodstream. Levemopamil is one of these active ingredients (EP 147 707). It is known that the local tolerance of levemopamil can be improved with the help of lipids and phospholipids.

Levemopamil can, on the one hand, as described in DE-A-4015108.3, be solubilized in a fat emulsion, as a result of which the local tolerance, tested by intravenous application to the rat, is improved compared to the aqueous solution.

A simple method has now been found which has clear advantages over the known method.

The invention relates to a process for the preparation of colloidal aqueous levemopamil solutions, characterized in that a mixture of levemopamil salt, a phospholipid and an isotonizing agent is mixed with water and homogenized

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

The amount of phospholipid added to the active ingredient is decisive for achieving good local tolerance. The weight ratio of active ingredient to phospholipid is 1: 4 to 1:20, preferably 1: 4 to 1:10. Weight ratios of active ingredient to phospholipid of 1: 5 to are very particularly preferred Suitable phospholipids are natural (ie derived from natural products) or synthetic phospholipids. Preference is given to neutral and / or zwitterionic phospholipids such as the lecithins (phosphatidylcholines), in particular those which contain unsaturated fatty acid residues such as oleic acid and / or linoleic acid. Highly purified egg and soy lecithins containing at least 80% phosphatidylcholine are particularly preferred.

The use of levemopamil hydrochloride in the lecithin-containing solutions according to the invention leads to pH values in the weakly acidic range (pH approx. 4-4.5). Despite the relatively acidic pH, these solutions are distinguished by a significantly improved local compatibility after intravenous administration compared to aqueous solutions of the same concentration which do not contain any phospholipid.

The local tolerance of the levemopamil hydrochloride solution can be easily increased by increasing the pH up to 7.0. However, the long-term storage stability of the pH-neutral solutions is worse than that of the weakly acidic solutions, so that the pH-neutral solutions should be stored in a cool place. Another method of improving the storage stability is to freeze-dry the solutions according to the invention. As a result of the very careful removal of the water, a dry preparation (lyophilisate) is formed which can be stored at room temperature. Before use, all that needs to be added is the water removed from the water.

The buffer solution can compensate for the low pH values (pH 4-5) of the levemopamil solution caused by the active ingredient (hydrochloride). Buffers which allow a pH of 5-7 in the finished solution are preferred. Phosphate buffers are very particularly preferred. Alkaline pH values above pH 7 are less suitable because the stability of the auxiliary (lecithin) is reduced by hydrolysis. Other auxiliary substances, e.g. Antioxidants can be added (2,6-di-tert-butyl-4-methylphenol) and / or heavy metal chelators such as EDTA (ethylenediamine-tetraacetic acid). The quantities used are based on the dosages that can be used in general in other injection preparations.

The isotonicization of the solution to achieve blood isotonicity can be carried out with the abovementioned buffer or with sodium chloride, but also with other salts, but preferably with carbohydrates such as sucrose and / or maltose. Glycerin is also suitable. The salts or the carbohydrates become the buffer solution in quantities added, which in the finished application solution give Os olarities of about 280 to 400 mOsmol / kg.

After the entire mixture of active ingredient, phospholipid, isotonizing agent and water or buffer solution has been prepared, the batch is homogenized. Preference is given to processes which bring the particle sizes of the colloidal solution to values below 0.2 micrometers (on average), so that the entire formulation can be sterile filtered (so-called sterilization filtration with a 0.2 micrometer filter).

It has proven expedient to have the homogenization run in two steps. In the first step, a suspension in which the average particle sizes are still in the range of several micrometers is produced using simple dispersing devices which cause the coarse agglomerates to be broken up by knives running at high speed. This suspension is then further homogenized using suitable methods. High-pressure homogenizers (which are widely used for the production of emulsions) are preferred, but also filtration processes in which the suspension is pressed under suitable pressure through suitable membrane filters (extrusion). Both processes allow a gentle reduction of particle sizes to mean values of less than 0.2 micrometers. The finished solutions can thus be sterile filtered, which means that sterilization filtration can take place, which is very important for a pharmaceutical form which is to be administered parenterally. The reduction in particle sizes is still necessary to achieve adequate storage stability. Colloidal solutions with particle sizes in the micrometer range tend to sedimentation and / or flocculation and, moreover, cannot be administered parenterally because of possible embolisms.

After homogenization and filling (e.g. in ampoules), the finished colloidal solution can be autoclaved in the final container by known methods (typically 20 min at 120 ° C.) without flocculation in the colloidal solution. This sterilization in the final container ensures that the finished dosage form is sterile.

Animal experiments have shown that the local tolerability of the formulations is dependent on the weight ratio of active ingredient: lecithin. Solutions in which approximately equal amounts by weight of active substance and phospholipid were present showed an improvement in the local tolerance compared to a purely aqueous solution in animal experiments (rats), but were significantly less tolerable than the formulations of the method according to the invention in which the weight ratio is preferably 1: 4 to 1:10 lies. A sufficient amount of phospholipid is therefore necessary to achieve optimal tolerance.

Compared to the fat emulsion formulation of DE-A-4015108.5, the method according to the invention has the advantage of a significantly lower amount of lipid, which must be used for good local tolerance. While the weight ratio of active substance: lipid in the case of the emulsion is 1:11, this value can be reduced to about 1: 6 in the process according to the invention without differences in local tolerance being detectable in animal experiments. As a result, in the case of the method according to the invention, an unnecessarily high lipid load on the patient can be avoided.

The following examples illustrate the invention.

example 1

1.375 g levemopamil hydrochloride, 7.500 g soy lecithin S 100 (from Lipoid, Germany) and 10 mg 2,6-di-tert-butyl-4-methylphenol were mixed with 150 ml 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 were added, and the mixture was comminuted to a cloudy suspension with an Ultra-Turrax® dispersing rod for 10 minutes and then im The flask was filled with buffer solution to a total volume of 250 ml and the mixture was then homogenized in the high-pressure homogenizer for 45 min at 50 ° C. and 600 bar. The transparent, slightly opalescent colloidal solution was passed through a sterile filter (0.2 micrometer The ampoules were then sterilized in an autoclave for 20 minutes at 120 ° C. The average particle size after autoclaving was 0.082 micrometers (measured by photon correlation spectroscopy). The pH was 6.32.

Example 2

The preparation was carried out as in Example 1, but with egg lecithin E 100 (from Lipoid, FRG; same amount as in Example 1). The mean particle sizes after autoclaving were 0.099 micrometers, the pH was 6.18.

Example 3

The preparation was carried out as in Example 2, but with a buffer solution which contained 43.15 g of maltrose monohydrate instead of sucrose. The mean particle sizes after autoclaving were 0.089 micrometers, the pH was 6.05. Example 4

The preparation was carried out as in Example 3, but without the addition of the phosphate buffer substances. The mean particle sizes after autoclaving were 0.109 micrometers, the pH was 4.15.

Example 5

The preparation was carried out as in Example 2, but without the addition of the phosphate buffer substances. The mean particle sizes after autoclaving were 0.086 microns, the pH was 4.07.

Example 6

The preparation was carried out as in Example 2, but without the addition of the phosphate buffer substances and with 26.0 g glycerol instead of saccharose. The mean particle sizes after autoclaving were 0.046 micrometers, the pH was 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 average particle sizes were 0.063 micrometers, the pH was 6.33.

Example 8

Levemopamil hydrochloride was dissolved in water at a concentration of 5.50 mg / ml.

Example 9

The formulations of Examples 2, 7 and 8 were administered intravenously at 6 times a day at a dose of 15 mg levemopamil hydrochloride per kg body weight to 6 rats at a rate of 0.6 ml / min. Formulation 8 was only applicable for 2 days, formulation 7 was applicable for 6 days until the occurrence of local incompatibilities made further application impossible. In contrast, the formulation of Example 2 could be administered to the animals over 28 days without local incompatibility reactions occurring.

Claims

Pa en claims 1. A process for the preparation of colloidal aqueous Levemopamil solutions, characterized in that a mixture of a Levemopamil salt, a phospholipid and an Isotoni¬ sierungsmittel mixed with water and homogenized. 2. The method according to claim 1, characterized in that the mixture of levemopamil salt, phospholipid and Isotoni¬ sierungsmittel a buffer is added. 3. Solution obtainable according to claim 1 or 2.