HU185533B - Process for producing concentrated hydrosoles containing h lipophilic and hydrophilic vitamines - 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

The product obtained by the process according to the invention contains high concentrations of lipophilic and hydrophilic vitamins, is rapidly and completely resorbed, its stability

The present invention relates to a process for the preparation of concentrated hydrosols containing lipophilic and hydrophilic vitamins.

The use of concentrated vitamin hydrosols is of great importance in human therapy. In addition, it is a very valuable product in the large animal husbandry industries; in the treatment of hypovitaminosis diseases in poultry, pigs or other mammals; prevention.

The preparation of concentrated hydrosols containing lipophilic and hydrophilic vitamins is usually hampered by the fact that, by solubilizing relatively large amounts of lipophilic vitamins A, D, and E, in some cases about 5 to 10 types of hydrophilic vitamins, high concentration into the system.

There are relatively few attempts to solve this important problem in the literature.

C. Coles and D. Thomas [J. Pharm. Pharmacol 4, 898 (1952)] and R. Hüttenrauch and L. Klotz (Arch. Pharm. 296, 145 (1963)] solubilized only one ingredient, Avitamin. It has been found that 25% of the detergent suitable for solubilization can be reduced by the use of glycerol, sorbitol and sucrose. However, our teachings do not teach any solubilization of lipophilic and hydrophilic vitamins. 30

No. 2,417,299. U.S. Pat. No. 4,123,123 also relates to the preparation of lipophilic vitamins, in particular vitamin A and vitamin D, in aqueous solution using glycerol and nonionic surfactant. The solution prepared by the process of the invention is a maximum of 35 to 10,000 USP. contains the active compounds in a concentration of 1 unit / ml. By this method, hydrosol containing high concentrations of lipophilic and hydrophilic vitamins which meet today's requirements cannot be produced. 40

According to Hungarian Patent No. 138,791, the hydrophilic and lipophilic vitamins are dispersed in an aqueous solution and the stability of the dispersion is tested with starch syrup or gum arabic and polyhydroxy compound, preferably glycerol, propylene glycol. The disadvantage of this method is that the yellow viscous liquid resulting from the extremely high starch syrup concentration is difficult to handle and the vitamin content of the dispersion is relatively low.

The author of Hungarian Patent No. 149,547 discloses ⁵ θ lipophilic vitamins in an emulsion with an alcoholic zein solution. However, due to its low stability, the emulsion should be transferred to a solid phase after drying at 40 ° C and then sieving. As additives, butylhydroxytoluene as an antioxidant and polyethylene glycols, sorbitol esters, are mentioned as additives. The present invention does not provide a solution for the preparation of a stable hydrosol containing high concentrations of both hydrophilic and lipophilic vitamins.

No. 152,521. U.S. Patent No. 4,123,125 also discloses a process in which the main goal is the solution of θθ lipophilic vitamins. This is achieved, in addition to the use of nonionic emulsifiers, with sugar syrup and ionic wetting agents. The disadvantage of the method is that the concentration of water-soluble vitamins cannot be increased to the present requirements. ⁶⁵

It is an object of the present invention to provide a process for producing a high concentration, stable polyamine solution of high standard, namely a vitamin solution containing all physiologically important lipophilic and hydrophilic vitamins.

In our experiments, in accordance with the above literature data, we found that when solubilizing a mixture of lipophilic vitamins with polyoxyethylene sorbitan oleic acid ester (hereinafter Tween 80), only a relatively greater amount of the non-ionic surfactant was obtained (approximately said hydro). However, this hydrosol becomes unstable when added to the hydrophilic vitamins, clouded by slight changes in temperature or by mechanical stress, and is dense and difficult to handle. The fact that besides lipophilic vitamins nearly 10 kinds of water-soluble vitamins and vitamin-like substances (for example 14-15 w / v% choline chloride) had to be dissolved in solution made the task more difficult. Thus, the total amount of hydrophilic constituents can reach 15-20% v / v, which naturally reduces the amount of water that can be used.

In our experiments, we have found that the above task can be successfully achieved by significantly reducing the amount of surfactant used for dissolution, surprisingly by adding polyhydroxy compounds. The invention is thus based on the discovery that vitamins are dissolved in the presence of a well-defined ratio of polyol to surfactant relative to the total volume of hydrosol.

The discovery is surprising because the no. The Hungarian patent, cited above, states that "the action of non-ionic emulsifiers ... is only slightly affected by polyols such as sucrose, glucose, glycerol and sorbitol". According to the author of the specification, "the effect of nonionic emulsifiers is more or less markedly weakened by the action of polyols". In contrast to these prior data, it has been found that the amount of surfactant used in a 100 ml solution can be reduced to 12-13 g using 4-25 g of polyol and thus obtainable from a stable hydro.

Ploting our experimental results in a phase diagram is a

1. The A-axis of the graph contains g / v% of lipophilic vitamin mixture + Tween-80, B-axis contains g / v% of polyhydroxy compound and C-axis contains hydrophilic substances + g / v% ban. In the area shown in the diagram, the rule underlying the invention prevails.

Accordingly, the present invention relates to lipophilic vitamins, preferably vitamins A, D ₃ - or vitamin E and at least vitamin or vitamin in nature compound or tetszőlees mixture of a hydrophilic, preferably Br Β ₂ -., Β ₆ - B _n - U for the preparation of a stable hydrosol containing vitamin A, panthenol, nicotinic acid amide, folic acid, biotin, choline chloride, carotene, menaquinone, using a nonionic surfactant, a polyhydroxy compound, an antioxidant and / or a preservative consisting of lipophilic vitamin

000,000 - 1,500,000 IU of vitamin A,

100,000-200,000 IU vitamin D ₃ ,

700-1500 IU Vitamin E, and

185 533 of concentrated solutions containing hydrophilic vitamin C or used as vitamin material, depending on animal species, in very small amounts for daily administration of 0.2 to 20 ml

0.10 - 0.20 g Vitamin B, and / or need. 0.20 - 0.30 g Vitamin B ₂ and / or The invention is further illustrated by the following examples. 0.10 - 0.20 g Vitamin B ₆ and / or ₅ bets. 0.001 - 0,002 g Vitamin B ₁₂ and / or 0.6 _ 1.0 g panthenol and / or Example 1 1.0 - 2.0 g nicotinic acid amide and / or Vitamin A 1,400,000 EN 0.01 - 0,025 g folic acid and / or Vitamin Bj 0.14 g 0.033 - 0,005 g biotin and / or IQ Vitamin B ₂ (riboflavin-5- 0.21 g 12 _ 20 g choline chloride and / or -phosphate) 0,0005- 0.0020 g carotene and / or Vitamin B ₆ 0.14 g 2.5 - 3.0 g Vitamin U and / or Vitamin B ₁₂ 0.0014 g 0.01 - 0,025 g menaquinone Vitamin D ₃ 140,000 NE

aqueous solution is prepared in the presence of 4-25 g of polyhydroxy compound and 12-30 g of nonionic surfactant per 100 ml of hydrosol.

In a preferred embodiment of the invention, the polyhydroxy compound is glycerol, sorbitol, sucrose, polyethylene glycol sorbitan fatty acid esters, non-ionic surfactants, sorbitan fatty acid esters, antioxidants and preservatives butyl hydroxybutyrate, used.

In the process of the invention, lipophilic vitamins A, D, E, hydrophilic vitamins B, Β ₂ , Β ₆ , B ₁₂ , U, panthenol, nicotinic acid amide, menaquinone, biotin, folic acid, choline chloride, polyol glycerol, sorbitol, sucrose and polyethylene glycol fatty acid esters, sorbitan fatty acid esters as nonionic surfactants.

Solutions containing the lipophilic and hydrophilic vitamins together are stable at pH 3-6, preferably pH 4-5.5, with a weak acid.

Antioxidants known in the food industry with appropriate redox potential, such as butylhydroxytoluene, butylhydroxyanisole, nor-dihydro-guaracetic acid, propyl gallate, or a mixture thereof with oxycarboxylic acids such as citric acid can be used to prevent oxidation. Use of ascorbyl palmitate is also preferred. The amount of antioxidants is 0.005-0.2%, preferably 0.05%.

The hydrosol can be preserved with preservatives used in human pharmaceutical formulations, such as propyl and methyl paraoxybenzoate or mixtures thereof, or sodium benzoate.

Nitrogen or argon gas may be used as a neutral shielding gas to enhance the stability of the solutions.

An essential advantage of the concentrated hydro sols produced by the process of the invention is that lipophilic vitamins are rapidly and completely resorbed from aqueous solution, while the stability of lipophilic vitamins solubilized in aqueous solution at normal and higher temperatures than in oily solution.

The cosolubilization of the present invention is also suitable for the preparation of human oral and parenteral concentrated polyvitamin compositions.

Prior to human administration, particularly in the case of parenteral administration, the required dilutions should be made.

This is also an additional advantage of the process according to the invention, since there is no need to transport, store, or move high volume diluted solutions. This advantage is particularly useful in veterinary applications. This is where the lipophilic and hydrophilic vitamins come from

Vitamin E 1,050 NE biotin 0.0035 g Vitamin K ₃ 0.0175 g nicotinamide 1.4 g folic acid 0.0175 g Sodium bicarbonate 0.007 g choline chloride 14.0 g panthenol 0.655 g Carotene 0.001 g butylhydroxytoluene 0.01 g Citoromsav 0.625 g nipasol 0.01 g nipagin 0.1 g Tween 80 17.5 g Glycerol 17.5 g Distilled water ad 100.0 ml

Brief description of the solution: In a lipophilic vitamin mixture, butylhydroxytoluene and beta-carotene suspension are dissolved, and Tween 80 and glycerol are added with stirring. In a small portion of the distilled water, the nipaesters are first dissolved by boiling and then dissolved in the still warm solution, the riboflavin phosphate sodium salt, biotin, folic acid, and sodium bicarbonate. All other ingredients are dissolved in the solution cooled to 40 ° C. The two solutions are mixed with vigorous stirring and made up to volume with distilled water. A clear solution is obtained which, after filtration, is placed in vials or plastic containers under neutral inert gas. The solutions should preferably be stored in a cool place protected from light.

Example 2

The 17.5 g of glycerol in Example 1 is replaced with 8.75 g of sorbitol, and the solution is prepared in the same manner as in Example 1.

Example 3

The 17.5 g of glycerol in Example 1 is replaced by 4.375 g of sucrose, and the solution is prepared in the same manner as in Example 1.

Example 4

Vitamin A i 050 000 EN

Vitamin B, 0.14 g

Vitamin B ₂ (riboflavin-5- 0.25 g

-phosphate)

Vitamin B ₆ 0.21 g

Vitamin B ₁₂ 0.0014 g

Vitamin D IU _3105000

Vitamin E 700 NE

-3185,533

biotin 0.0035 g Vitamin U 2.8 g nicotinamide 1.4 g panthenol 0.98 g choline chloride 14.0 g butylhydroxytoluene 0.01 g Citoromsav 0,625 g nipasol 0.01 g nipagin 0.1 g Tween 80 17.5 g Glycerol 17.5 g Distilled water ad 100.0 ml

Example 11

All were carried out as described in Example 1 except that panthenol was omitted from the components.

Example 72

All were performed as described in Example 1, except that the composition contained only choline chloride (18.5 g) as the hydrophilic vitamin or vitamin-like substance.

Brief Description of the Invention Solution: In a lipophilic vitamin mixture, butylhydroxytoluene is dissolved, and Tween 80 and glycerol are added with stirring. In a small portion of distilled water, the nipaesters are first dissolved by boiling and then the riboflavin phosphate sodium salt and biotin are dissolved in the still warm solution. All other ingredients are dissolved in the solution cooled to 40 ° C. The two solutions are mixed with vigorous stirring and made up to volume with distilled water. A clear solution is obtained which, after filtration, is placed in a glass or plastic container under neutral inert gas. The solutions should preferably be stored in a cool place protected from light.

Example 5

The 17.5 g of glycerol in Example 4 is replaced with 8.75 g of sorbitol, and the procedure for preparing the solution is the same.

Example 4.

example

The 17.5 g of glycerol in Example 4 is replaced with 4.375 g of sucrose, and the solution is prepared in the same manner as in Example 4.

Example 7

One proceeds as described in Example 1 is followed with the exception that one of the components omitted Bi and B ₂ vitamin.

Example 8

One proceeds as described in Example 1 is followed with the exception that one of the components B ₆ - Bi ₂ is omitted and vitamin.

Example 9

All were carried out as described in Example 1 except that nicotinic acid amide and biotin were omitted.

Example 10

All were carried out as described in Example 1 except that choline chloride was omitted from the components.

Claims (2)

PATENT CLAIMS 1. A method of lipophilic vitamins, preferably vitamins A, D ₃ - or Evitamint and at least vitamin or vitamins nature of compounds, or any mixture of a hydrophilic, preferably B _r, Β ₂ -, B ₆ -, Bu, Vitamin U panthenol, nicotinic acid amide, for the preparation of a stable hydrosol containing folic acid, biotin, choline chloride, carotene, menaquin using a nonionic surfactant, a polyhydroxy compound, an antioxidant and / or a preservative, characterized in that the lipophilic vitamin is preferably used. 1,000,000 to 1,500,000 IU of vitamin A, 100,000-200,000 IU vitamin D ₃ , 700-100 IU Vitamin E and is preferably used as a hydrophilic vitamin or vitamin-like substance 0.10 - 0.20 g Vitamin B, and / or 0.20 - 0.30 g Vitamin B ₂ and / or 0.10 - 0.20 g Vitamin B ₆ and / or 0.001 - 0,002 g Vitamin B ₁₂ and / or 0.6 - 1.0 g panthenol and / or 1.0 - 2.0 g nicotinic acid amide and / or 0.01 - 0,025 g folic acid and / or 0.003 - 0,005 g biotin and / or 12 - 20 g choline chloride and / or 0,0005- 0.0020 g carotene and / or 2.5 - 3.0 g Vitamin U and / or 0.01 - 0,025 g menaquinone aqueous solution is prepared in the presence of 4 to 25 g of polyhydroxy compound and 12 to 30 g of nonionic surfactant per 100 ml of hydrosol. 2. The process according to claim 1, wherein the polyhydroxy compound is polyethylene glycol sorbitan fatty acid esters, sorbitan fatty acid esters, butoxylic acid, ascorbic acid palmitate, benzoxylic acid, butyl hydroxytoluene, antioxidant and preservative.