DD291696A5 - METHOD FOR PRODUCING WAITER MIXING MEASUREMENTS - Google Patents

Abstract

A process for producing aqueous mixed micelle solutions containing mixed micelles formed from lipoids and salts of bile acids, in which, if desired, active substances hardly soluble or insoluble in water are solubilized, is characterized in that the free bile acids are suspended in an aqueous solution possibly containing isotonizing additives and/or water-soluble active substances at a temperature of 40C to 100C, the lipoids are dispersed in this suspension at a temperature of 40C to 100C and the dispersion obtained is neutralized with bases at a temperature of 0C to 100C, provided that, if necessary, the active substances which are hardly soluble or insoluble in water are dispersed together with the lipoids or solubilized in the mixed micelle solution which does not contain these active substances.

Description

, \

HO

Ri and R ₂ and R ₃ and R ₄ together represent an oxo group, two hydrogen atoms or one hydrogen atom and one hydroxy group, and

X represents a hydroxy group or a grouping of the formula -NH-CH ₂ -CO ₂ H or -NH- (CH ₂ ) ₂ -SO ₃ H.

3. A process for the preparation of aqueous Mischmicellösungen according to claim 1 and 2, characterized in that one uses as lipids phospholipids.

4. A process for the preparation of aqueous Mischmicellösungen according to claim 1 to 3, characterized in that one uses as sparingly soluble in water or insoluble active ingredients in water sparingly soluble or insoluble pharmaceutical active ingredients.

5. A process for preparing aqueous Mischmicellösungen according to claim 4, characterized in that one uses as pharmaceutical active ingredients ß-carbolines.

6. Use of prepared according to claim 4 and 5 aqueous Mischmicellösungen, characterized in that they are used for the preparation of injection solutions.

7. Aqueous Mischmicellösungen, characterized in that they contain ß-carbolines.

8. Aqueous Mischmicellösungen, characterized in that they contain 6-benzoyloxy-4-methoxymethylß-carboline-3-carboxylic acid isopropyl ester.

9. Aqueous Mischmicellösungen, characterized in that they contain 5- (4-chloro-phenoxy) -4-methoxymethyl-ß-3-carboxylic acid isopropyl ester.

10. An aqueous mixed micelle solutions, Sorghum bicolor ·· _w>, characterized in that they contain 5-isopropoxy-4-methyl-ßcarbolin-3-carboxylic acid ethylestei.

11. Aqueous mixed micelle solutions, characterized in that they contain 5- (4-chloro-phenoxy) -3- (3-ethyl-1,2,4-oxadiazol-5-yl) -4-methoxymethyl-ß-carboline.

Fields of application of the invention

The invention relates to a process for the preparation of aqueous Mischmicellösungen containing mixed lipids formed from lipids and salts of bile acids, which are solubilized those, if desired, in water sparingly soluble or insoluble active ingredients.

Characteristic of the known state of the art

Processes for the preparation of such mixed micelle solutions are previously known, for example, from German Patent 2730570.

In the prior art processes, the mixed micelle solutions are prepared by mixing the lipids, the salts of bile acids and optionally the sparingly sparingly soluble or insoluble active ingredients in an organic solvent (e.g.

Ethanol), and the solutions narrows, so that forms a lipid film on the vessel walls, which is detached by means of aqueous solutions. (Biochemistry 19, 19, 60, 60 ff., And 615 et seq., Naturforsch., 32c, 1977, 748ff.).

However, this method is quite complex and can only be transferred to a technically usable scale with considerable expenditure on equipment.

In addition to this preferred method, for example, from Example 3 of the aforementioned patent 2730570 a method is known in which one produces such Mischmicellösungen by mixing the components and stirring the mixture.

However, this process not only has the disadvantage that it lasts several days, but can be seen in the reworking of this example - without active ingredient that in this way only very turbid solutions containing mixed micelles with a mean diameter of about 340 nm.

Clear solutions with mixed micelles of a mean diameter of about 10nm can not be obtained in this way.

Object of the invention

The invention eliminates the disadvantages of the prior art.

Explanation of the essence of the invention

The invention has for its object to provide a process for the preparation of aqueous Mischmicellösungen available.

It has now been found that it is possible to produce such clear aqueous solutions of mixed micelles in a simple manner and a short Zrit by means of a process which is characterized in that the free bile acids at a temperature of 40 ° C to 100 ⁰ C in an optionally isotonizing Suspended additives and / or water-soluble active ingredients containing aqueous solution, the lipids at a temperature of 4O ⁰ C to 100 ⁰ C dispersed in this suspension and neutralized the resulting dispersion at a temperature of ^{0 0} C to 100 ⁰ C with bases, with the proviso in that, if appropriate, the active substances soluble or insoluble in water rc ^{1. are} dispersed together with the lipids or in which the mixed micelle solution is not solubilized.

The method according to the invention can be carried out using the same bile acids as the previously known methods. Suitable bile acids are 5β-cholan-24-acid derivatives of the general formula

HO

Rt and R ₂ and R3 and R4 together represent an oxo group, two hydrogen atoms or one hydrogen atom and one hydroxy group, and

X represents a hydroxy group or a grouping of the formula -NH-CH ₂ -CO ₂ H or -NH- (CH ₂ ) ^ -SO ₃ H.

Examples of suitable bile acids include: cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, glycopoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid and taurochenodeoxycholic acid.

For the preparation of the aqueous Mischmicellösung preferably 1 to 30g and in particular 2g to 15g bile acid per 100g of optionally isotonizing additives and water-soluble active ingredients containing aqueous solution used.

For the preparation of the aqueous Mischmicellösungen the same lipids can be used in der.i inventive method, as in the previously known methods.

Suitable lipids are, for example, monoglycerides, sulfatides, and in particular phospholipids, such as sphingomyelin, plasmalogens, phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phosphatidylinositols and cardiolipins, and also mixtures of these lipids (Dr. Otto-Albert Neumüller: Rompps Chemie-Lexikon : Francksche publishing house, Stuttgart [DE] 2665,3159,3920 and 4045).

For the preparation of the aqueous Mischmicellösungen are preferably 3 to 40% and in particular 5 to 20% Lipoic! used per 100 g of optionally containing isotonic additives and / or aqueous solutions containing aqueous solution. The weight ratio between lipoid and bile acid is preferably 0.1: 1 to 2: 1 and especially 0.8: 1 to 2: 1.

Suitable bases for the preparation of aqueous mixed micelle solutions by the process according to the invention are, on the one hand, alkali metal hydroxides, such as lithium hydroxide, potassium hydroxide and, in particular, sodium hydroxide and, on the other hand, organic nitrogen bases, provided they form physiologically acceptable salts. Such "ickstoffbasen are, for example, ammonia, primary, secondary or tertiary amines, ethanolamine, diethanolamine, piperazine, morpholine, lysine, ornithine, arginine, Ν, Ν-dimethylglucamine, the choline and especially the N-methylglucamine and Trishydroxymethylaminomethan.

Suitable active ingredients which are sparingly soluble or insoluble in water are preferably those whose solubility in water at room temperature does not exceed 2%. Such active ingredients are, for example, crop protection agents, such as sparingly soluble insecticides or herbicides, and in particular sparingly soluble pharmaceutical active ingredients.

In water sparingly soluble or insoluble pharmaceutical active ingredients of the following active ingredient groups are suitable, for example, for the preparation of the medicaments of the invention:

Progestogen-active steroid hormones such as 13-ethyl-17β-hydroxy-18,19-dinor-17a-pregn-4-en-20-yl-3-one (= levonorgestrel), which is an ethyl-ethyl-hydroxy-ethane dinor-na-pregnaAIB-diene ^ Oyn-S-on (= gestoden) or the 13-ethyl-17ßhydroxy-11-methylene-18,19-dinor-17a-pregn-4-en-20yn (desorgestrel), estrogen-active Steroid hormones such as 3-hydroxy-1,3,5 (10) -estratrien-17-one (= ostrone), or 1,9-nor-17a-pregna-1,3,5 (10) -triene-20yn-3 , 17β-diol (ethinyl oestradiol).

Androgen-effective steroid hormones such as 17β-hydroxy-4-androsten-3-one (= testosterone) and its ester or 17β-hydroxy-1α-methyl-5a-androsten-3-one (= mesterolone).

Anti-androgen-active steroid hormones such as 17a-acetoxy-6-chloro-1β, 2β-dihydro-3H-cyclopropad, 2]-pregna-1,4,6-triene-3,20-dione (cypoterone acetate).

Corticosteroids such as the 11β, 17α, 21-trihydroxy-4-pregnene-3,20-dione (= hydrocortisone), the 11β, 17α, 21-trihydroxy-1,4-pregnadiene-3,20-dione (= prednisolone ), the 11ß, 17a, 21-trihydroxy-6a-methyl-1,4-pregnatriene-3,20-dione (= methylprednisolone) and the 6a-fluoro-11ß, 21-dihydroxy-16a-methyl-1,4- pregnadiene-3,20-dione (= Difluocortolon).

Ergolines such as 3- (9,10-dihydro-6-methyl-8a-ergolinyl) -1,1-diethylurea (= ergc! In), which is 3- (2-bromo-9,10-dihydro-6-methyl) 8a-ergolinyl) -1,1-diethylurea (= bromergoline) or the 3- (6-methyl-8a-ergolinyl) -1,1-diethylurea (= terguride).

Antihypertensive agents such as the 7α-acetylthio-17α-hydroxy-3-oxo 4-pregneπ-21-carboxylic acid γ-lactone (= spironolactone) or the 7a-acetylthio-15β, 16β-methylene-3-oxo-17a-pregna-1 , 4-dien-2i, 17-carbolactone = {mespirenone /.

Anticoagulants like the B-l-hexahydro-B-hydroxy ^ -O-hydroxy-methyl-ioctene-e-ynyl-dHl-pentalenylidene-l-pentanoic acid (-loprost).

Psychotropic drugs such as 4- (3-cyclopentyloxy-4-methoxyphenyl-2-pyrrolidone (= Rolipram) and the 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine -2-one (= diazepam).

Carotenoids such as a-carotene and ß-carotene.

Fat-soluble vitamins, such as vitamins of the vitamin A, vitamin D, vitamin E and vitamin K groups.

A particularly preferred group are β-carbolines, as described, for example, in European Patent Applications 234,173 and 239,667. Examples of β-carbolines which may be mentioned are e-benzoyloxy-methoxymethyl-β-carboline-S-carboxylic acid isopropyl ester (= becarnil), isopropyl 5- (4-chlorophenoxy) -methoxymethyl-β-carboline-3-carboxylate ( = CI-PHOCIP), the oleyl S-isopropoxy-methyl-β-carboline-S-carboxylate (= IPMCE) and the 5- (4-chlorophenoxy) -3- (3-ethyl-1,2,4- oxadiazol-5-yl) -4-methoxymethyl-.beta.-carboline (= Phoco). The optimum concentration of active ingredient in the mixed micelle solutions is naturally dependent on the structure of the active ingredient and must be determined by means of the familiar preliminary tests. In general, the concentration of β-carbolines is 1 pg to 40 mg, preferably 100 pg to 10 mg, of active substance per ml of mixed micelle solution. Glycocholic acid and phospholipids are preferably used to prepare the mixed micelles themselves.

If desired, the aqueous mixed micelle solutions prepared by the process according to the invention may contain isotonic additives in order to increase their osmotic pressure. Suitable additives are, for example, inorganic or organic salts or buffer substances, such as sodium chloride, phosphate buffer, citrate buffer, glycine buffer, citrate-phosphate buffer, maleate buffer, etc. mono- or disaccharides, such as glucose, lactose, sucrose, Sugar alcohols, such as mannitol, sorbitol, xylitol or glycerol or water-soluble polymers, such as dextran or polyethylene glycol.

These isotonizing substances are usually added in concentrations such that the resulting aqueous mixed micelle solution has an osmotic pressure of -1000 mosm-optimally 300mosm for injection solutions.

Furthermore, the aqueous Mischmicellösungen may contain additional water-soluble active ingredients to produce combination preparations. Examples of such combination preparations are mixtures of water-soluble and fat-soluble vitamins or preparations which, in addition to corticosteroids, also contain water-soluble antibiotics.

Apart from the conditions listed in claim 1, the preparation of the water-soluble mixed micelle solutions takes place by means of conventional methods, by heating the mixtures with vigorous stirring to the temperatures specified in patent claim 1.

Since the lipids and also some active substances are sensitive to oxidation, the process is expediently carried out under an inert gas atmosphere, such as nitrogen or argon, and the resultant aqueous mixed micelle solutions are stabilized by addition of antioxidants, such as sodium ascorbate, tocopherol or sodium hydrogensulfite.

The process of the invention can be carried out usually within a few minutes, it has the advantage that Mischmicellösungen arise, which are free of organic solvent residues. In addition, the process according to the invention can be carried out with conventional mixing and dispersion techniques (for example, according to the rotor-stator principle), as are customary in pharmaceutical technology (see The Theory and Practice of Industrial Pharmacy, L.Lachman, H.A.

Lieberman, J.L. Kanig, Philadelphia [1970], p.481 or Pharmaceutical Technology, K.H.Bauer, K.H. Frömming and C.Führer, Stuttgart / New York [1986] p. 103), which is a good prerequisite for a reproducible process control, especially under GMP conditions (Good Manufacturing Practices) is given.

After the preparation, the resulting aqueous Mischmicellösung can be sterilized by filtration and / or heat sterilized at 100 ⁰ C to 140 ° C.

The following Alisführungsbeispiele serve to illustrate the method of the invention.

example 1

700 ml 0.02 η acetate buffer of pH 6.0 were heated in a heatable agitator and homogenizer while introducing argon at 80 ⁰ C, is then added under stirring. 54.2g glycocholic acid and stir until a homogeneous suspension is formed (about 5 minutes). Then added to the suspension 90 g phosphatidyl choline (soya lecithin) and 10g Becarnil = 6Benzoyloxy-4-methoxymethyl-ß-carboline 3-carboxylic acid isopropylesterzu and stirred at 8O ⁰ C until the dispersion is homogeneous (about 10 minutes). Thereafter, it is mixed with 20% aqueous sodium hydroxide solution until a pH of 6.0 is reached and immediately receives a clear solution, which is filled with water after cooling, so that a final volume of 1 000 ml is reached. The resulting aqueous Mischmicellösung is sterile filtered.

example

700 ml 0.015m phosphate buffer of pH 7.0 are heated to 80 ° C. in a heatable stirrer and homogenizer with the introduction of argon. Then 47.6 g of cholic acid are added with stirring and stirring is continued until a homogeneous suspension is formed for about 5 minutes). Then added to the suspension so-called phosphatidylcholine (soya lecithin) and stirred at 8O ⁰ C until the dispersion is homogeneous (about 10 minutes). Thereafter, it is mixed with 20% aqueous sodium hydroxide solution until a pH of 7.0 is reached and immediately receives a clear solution. 10 g of becarnil = 6-benzoyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester are stirred into this solution and dissolve rapidly. The resulting solution is filled after cooling with water, so that a final volume of 1000ml is reached. The aqueous Mischmicellösung thus obtained is sterilized at 121 ⁰ C.

Example 3

700 ml of 0.02 N acetate buffer of pH 6.0 are heated to 80 ° C. in a heatable stirrer and homogenizer with the introduction of argon. Then, while stirring, 54.2 g of glycocholic acid are added and stirring is continued until a homogeneous suspension is obtained (about 5 minutes). Then 90 g phosphatidylcholine (Phospholipon 100 L, Fa. Nattermann) and 1,1 g Cl-Phocip = 6-benzoyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester are added to the suspension, and the mixture is stirred until homogeneous at this temperature is. After cooling to 40-50 ⁰ C is neutralized with 20% aqueous sodium hydroxide solution to give a clear solution having a pH of 6.0. After filling to the final volume of 1000 ml, the aqueous Mischmicellenlösung is sterile filtered and can optionally be sterilized at 121 ⁰ C.

Example 4

700 ml of water for injection are heated to 8O ⁰ C in a heated stirrer and homogenizer with the introduction of argon. Then, while stirring, 54.2 g of glycocholic acid are added, and stirring is continued until a homogeneous suspension is obtained (about 5 minutes). Then, 90 g of phosphatidylcholine and 2 g of IPMCE = 5-isopropoxy-4-methyl-β-carboline-3-carboxylic acid ethyl ester are added to the suspension and the mixture is stirred at this temperature until the dispersion is homogeneous (about 10-15 minutes). Then it is mixed with 20% igor aqueous sodium hydroxide solution until a pH of 6.0-6.5 is reached and receives a clear solution which is filled after cooling with water to 1000 ml. The resulting aqueous Mischmicellenlösung is sterile filtered.

Example 5

700 ml of water for injection are heated in a heatable stirrer and homogenizer while introducing argon to 8OX. Then, while stirring, 54.2 g of glycocholic acid are added and stirring is continued until a homogeneous suspension is obtained (approx. 5 minutes). Then, 90 g of phosphatidylcholine and 1 g of phoco = 5- (4-chlorophenoxy) -3- (3-ethyl-1,2,4-oxadiazol-5-yl-4-methoxynethyl-β-carbo! In) are added to the suspension and the mixture is stirred 10-15 minutes), then 20% aqueous sodium hydroxide solution is added until a pH of 6.0-6.5 is reached, and a clear solution is obtained after cooling with Water is made up to 1000 ml and the resulting aqueous mixed micelle solution is sterile-filtered.

Claims (2)

claims: 1. A process for the preparation of aqueous Mischmicellösungen containing Mischmicellen formed from lipids and salts of bile acids, in which, if desired, in water sparingly soluble or insoluble active ingredients are solubilized, characterized in that the free bile acids at a temperature of 4O ⁰ C to 100 ° C. suspended in an optionally isotonizing additives and / or water-soluble active ingredients containing aqueous solution, the lipids at a temperature of 4O ⁰ C to 100 ⁰ C dispersed in this suspension and neutralized the resulting dispersion at a temperature of ^{0 0} C to 100 ^c C with bases with the proviso that it is optionally dispersed in water sparingly soluble or insoluble active ingredients together with the lipids or solubilized in the mixed micelle solution not containing these agents. 2. A process for the production of aqueous Mischmicellösungen according to claim 1, characterized in that the bile acid is a 5ß-cholan-24-acid derivative of the general formula