DD209734A5 - PROCESS FOR THE PRODUCTION OF CONCENTRATED HYDROSOLES - Google Patents

Abstract

The invention relates to a process for the preparation of lipophilic and hydrophilic vitamins containing concentrated, stable hydrosols using surfactants, antioxidants and / or preservatives, which is characterized in that the lipophilic and hydrophilic vitamins in water, in the presence of 4 to 25 wt ./Vol.% of polyols and 12 to 30% w / v of surfactants (calculated on the total volume of hydrosol) and, optionally, the thus obtained solution is processed into ready-to-administer drug formulations.

Description

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Berlin, October 4, 1983 AP A 61 K / 251 138/6 62 429/11

Process for the preparation of concentrated hydrosols Field of application of the invention

Djte Eriindung relates to a process for the preparation of lipophilic and hydrophilic vitamins containing concentrated hydrosols.

The concentrated vitamin hydrosols play an important role in human therapy. However, they also have important applications in the large-scale farms involved in animal breeding in the treatment or prophylaxis of hypovitaminous diseases in poultry, swine and other mammals.

Characteristic of the known technical solutions

The preparation of lipophilic and hydrophilic vitamins containing concentrated hydrosols is made difficult in most cases by the fact that in addition to the solubilization of relatively large amounts of the lipophilic vitamins A, D and E and in some cases also of ß-carotene about 5 bis 10 different hydrophilic vitamins must be brought into the dissolved system,

Ыап finds in the previous literature few attempts to solve this important task. C. Coles and D. ihomas . Pharm. Pharmacol. £, 898 (1952JJ and R. Hüttenrauch and L. Klotz / Arch. Pharm. 2 ^ 6, 145 (1963 ^ 7 have dealt only with the solubilization of a single constituent, vitamin A. They have

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provides that the required amount of the surfactant suitable for solubilization can be reduced by half by the addition of glycerol, sorbitol and / or sucrose.

However, the results of these authors offer no evidence for the solubilization of lipophilic and hydrophilic vitamins rubbed together containing vitamin mixtures.

US Pat. No. 2,417,299 describes a process for the preparation of lipophilic vitamins, especially vitamins A and D preparations containing aqueous solution, in which glycerol and polyethylene glycol eorbitan monolaurate (Tween 20) are used as solubilizing agents, ¹¹ Ie prepared by this process Solutions, however, can only contain the mentioned lipophilic vitamins in low concentrations (at most 10,000 USP units). The high vitamin concentrations corresponding to today's requirements can not be achieved by this process.

goal of

The aim of the present invention was to devise a new process according to which highly concentrated, stable polyvitamin solutions containing all biologically important lipophilic and hydrophilic vitamins can be prepared,

Presentation of the itVesens of the

The invention is based on the object, suitable means

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for the solubilization of mixtures of lipophilic vitamins.

It has now been found that in the solubilization of mixtures of lipophilic vitamins with the help of polyoxyethylene sorbitan blsäureestern (hereinafter: iween 80) clear solutions (hydrosols) only with the use of relatively large amounts of nonionic surfactants (about 20 to 30 times the Amount of the lipophilic vitamin mixture) can be obtained. But such hydrosols are unstable; surprisingly, however, the amount of nonionic surfactant required was significantly reduced when polyols were added to the mixture in such an amount that the surfactant: poliol ratio was at a total lipophilic concentration Vitamins of 2.0+ 0.5 g / 100 ml (»1 500 000

IU / 100 ml) between 1: 1.25 and 1: 0.25. As the polyols, those organic hydroxy compounds can be used in which all methyl groups are bonded by alcoholic hydroxyl groups, such. Gycin, sorbitol or sucrose. In such, for the purpose of increasing the solubilizing effect applied co-solubilization, the beneficial effect of the compounds used as cosolubilizers (polyols in the present case) can be explained by an immediate influence on the micelle formation. Regardless of whether laminar or spherical micelles are formed, their strength is increased by the incorporation of polyols into the micelles by hydrogen bonding.

The object of the invention based on the above findings is therefore a process for the preparation of lipophilic and hydrophilic vitamins containing concentrated, stable hydrosols using surfactants, antioxidants and / or preservatives, which is characterized in that the lipophilic and hydrophilic vitamins in water , in the presence of 4 to 25 parts by weight / volume of polyols and 12 to 50 parts by weight / volume of surfactants (calculated on the total volume of hydrosol) and, if appropriate, the solution thus obtained is made into ready-to-use pharmaceutical preparations. In the solutions containing the lipophilic vitamins A, D * and E in 100,000 IU / 100 ml total concentration, the surfactant Tween 80 is used in amounts of 0.8 to 1.25 / 100 ml, advantageously 1.1 g / 100 ml. At the indicated vitamin concentration, the polyols (calculated to 100 ml of hydrosol) are advantageously 1.1 g in the case of glycerol in amounts of 0.8 to 1.25 g, and 0.4 to 0.7 g in the case of sorbitol, advantageously 0.66 g and in the case of sucrose from 0.2 to 0.35, advantageously added 0.27 g.

The solutions containing both lipophilic and hydrophilic vitamins show especially at low acid pHs, i. at pH »3 to 6, advantageously 4 to 5» 5 good stability.

In order to protect the solutions against oxidation, the solutions prepared according to the invention may contain antioxidants which are useful in the food industry and have suitable redox potentials, e.g. Butyl-hydroxytoluene, butyl-hydroxyanisole, nor-dihydroguajaressigsäure, propyl gallate, etc. per se or in admixture with hydroxycarboxylic acids, eg. With citric acid, in amounts of $ 0.005 to $ 0.05, preferably 0.01 #.

For preserving the hydrosols, it is possible to use any preservative customary in human pharmaceutical preparations, for example propyl or methyl p-hydroxybenzoate or sodium benzoate.

The stability of the solutions can be achieved by filling in a protective gas atmosphere, e.g. be increased in nitrogen or argon.

Compared with the usual dry vitamin preparations (eg granules), the concentrated hydrosols which can be prepared according to the invention have the significant advantage that the lipophilic vitamins are absorbed more rapidly and more completely from aqueous solutions than from solid preparations and, on the other hand, the stability of the lipophilic vitamins solubilized in aqueous solution at normal and elevated temperatures better than in oily solutions.

The method according to the invention can advantageously be used for the production of polyVitamin preparations which can be administered by human therapy by oral or parenteral route. The preparations which can be used in human therapy can, especially in the case of parenteral administration,

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to be diluted to the desired extent «.

The production of concentrated polyvitaminic surfactants made possible by the present invention has the further advantage over the dilute solutions that the handling, storage and transport of such concentrated solutions is much easier and easier; this advantage can be well utilized especially in the veterinary application, since these concentrated solutions can be administered in very small amounts - daily from 0.2 to 20 ml, depending on the animal species to be treated,

Ausfuhrungabeispiel

The process according to the invention is further illustrated by the following examples, but it should be noted that the invention is in no way limited to the specific content of these examples,

example 1

To prepare 100 ml of concentrated polyvitamin solution, the following materials are used:

vitamin A (in the form of riboflavin) 1 400 000 IiS S vitamin B -5-phosphate) 0.14 vitamin B ₂ G 0.21 S VUtamin о 0.14 0.0014 g vitamin

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Vitamin D- 140 000 IB

Vitamin £ 1 050 IB

Biotin 0.0035 g

Vitamin K 0.0175 g

Nicotinic acid amide 1.4 g

Polyacid 0.0175 g

Sodium hydrogencarbonate 0.007 g

choline chloride (4-hydroxybenzoic acid to 14.0 G panthenol propyl) 0,655 S beta-carotene (4-hydroxybenzoic acid) 0.001 G methyl ester) 0.01 S 0.01 G Butyl-hydroxytoluene water 0.01 O citric acid Propylparaben ο, ι G 17.5 G methylparaben 17.5 G 100.0 ml Tween 80 glycerin distilled

The hydrosol is prepared in the following way:

In the oily mixture of the lipophilic vitamins A, E and D, the butyl-hydroxytoluene and the added in the form of suspension ß-carotene are dissolved, then the Tween 80 and glycerol are added with stirring. Separately, the hydroxybenzoic acid are dissolved under boiling in a part of the distilled water, then in the still warm solution are mixed, the riboflavin-5-phosphate sodium salt, biotin, folic acid and the sodium bicarbonate dissolved · The solution is cooled to 40 ⁰ C and then in it all the remaining ingredients are solved in succession. The two solutions obtained in the above manner are combined with vigorous stirring, and made up to 100 ml with distilled water. It will get a clear solution in this way; this is filtered off, filled in an inert inert gas atmosphere in bottles or plastic containers and expedient stored in a cool place, protected from light.

The hydrosol prepared in the above manner is also

stable after 6 months of storage; the active substance content of the solution shows a loss of at most 0.5 to 2.5 *.

Counterexample to Example 1

A solution was prepared in the composition given in Example 1, with the difference that the glycerin according to Example 5 of US Pat. 299 was added in an amount of 30 wt.% Of the total aqueous solution. In this case no clear, stable hydrosol could be produced even with different variations of the amount and type of surfactants.

Example 2

It was carried out according to Example 1, with the difference that instead of 17.5 S glycerol 8.75 g of sorbitol were used as the polyol.

Example 5

It was carried out according to Example 1, with the difference that instead of 17.5 S glycerol 4.375 S sucrose were used as the polyol.

Example 4

For the preparation of 100 ml of concentrated polyvitamin solution, the following substances are used: Vitamin A 1 050 000 IU

Vitamin B ₁ 0.14 g

Vitamin B ₂ (in the form of riboflavin

5-phosphate sodium salt 0.25 g Vitamin B ₆ 0.21 g

Vitamin B ₁₂

Vitamin D ₅ 10 $

vitamin B

Biotin 5 Vitamin U Nicotinamide Panthenol Choline Chloride

Butyl hydroxytoluene 10 Citric acid 4-hydroxybenzoic acid propyl ester 4-hydroxybenzoic acid methyl ester Tween 80

Glycerin Distilled water too

The hydro sol is prepared in the following way:

In the oily mixture of lipophilic vitamins A, E and D, the butylated hydroxytoluene is dissolved, then the Tween 80 and the glycerol are added with stirring. Separately, the hydroxybenzoic acid esters are dissolved in little distilled water and the riboflavin is dissolved in the still warm solution 5-phosphate-sodium salt and the biotin dissolved. The solution is cooled to 40 ^° C. and then the remaining constituents are dissolved therein one after the other. The two solutions obtained in the above manner are combined with vigorous stirring and made up to 100 ml volume with distilled water. It will get a clear solution; this is filtered off, bottled in an inert protective gas atmosphere in bottles or plastic containers and stored in a lazy place protected from light.

0.0014 G 000 IE 700 IE 0.0035 S 2.8 S 1.4 S 0.98 S 14.0 S 0.01 S 0.625 G 0.01 6 0.1 S 17.5 G 17.5 S 100.0 ml

Counterexample for example 4-

Solutions were prepared in the same composition as in Example 4-, except that the glycerin and Tween 80 were added instead of the amounts indicated therein (17-5 g each) in the following amounts:

a) Glycerol 0.10 g Tween 80 0.35 S

b) Glycerol 0.10 g Tween 80 0.10 g

c) Glycerol 0.12 g Tween 80 0.11 g

In no case were clear, stable hydrosols obtained.

Example 5

Bs was used according to Example 4-, with the difference that instead of 17.5 g of glycerol 8.75 S sorbitol were used as polyol ·

Example 6

It was carried out according to Example 4, with the difference that instead of 17.5 S glycerol 4.375 S sucrose were used as the polyol.

Claims (3)

-10- 4.10.1983 AP A 61 K / 251 138/6 62 429/11 a ariBpruioh A process for the preparation of lipophilic and hydrophilic vitamins containing concentrated stable hydrosols using lysides, antioxidants and / or preservatives, characterized in that the lipophilic and hydrophilic vitamins in water in the presence of calculated on the total volume of the hydrosol 4 bis 25% by weight of polyols and 12 to 30% by weight / volume of nonionic surfactants and, if appropriate, the solution obtained in this way is prepared as ready-to-use pharmaceutical preparations. 2 «method according to item 1, characterized in that one uses glycerol, sorbitol or sucrose as a polyol. 3 · Method according to item 1, characterized in that polyethyleneglycol sorbitan fatty acid esters are used as nonionic surfactants.