IE912918A1

IE912918A1 - Use of mixed micelles

Info

Publication number: IE912918A1
Application number: IE291891A
Authority: IE
Original assignee: Hoffmann La Roche
Priority date: 1990-08-17
Filing date: 1991-08-16
Publication date: 1992-02-26
Also published as: ZA916314B; CA2049374A1; JPH04244021A; EP0471309A1; AU8178791A

Abstract

The use of mixed micelles for the preparation of oral administration forms of vitamin K1.

Description

Vitamin K-deficiency haemorrhages in neonates (3-5 days old) have in recent years been diagnosed more and more frequently thanks to new diagnostic possibilities. At the same time, since 1980 late vitamin K-deficiency haemorrhages have been observed more and more frequently in infants (3-8 weeks old) who have hitherto appeared healthy.

An effective treatment of this disorder has, in the absence of suitable administration forms, been possible only with great risk for the neonates.

Hitherto, vitamin Ki for administration to neonates has been solubilized with the aid of synthetic solubilizers such as e.g.

Cremophor EL, Tween and Pluronics. When administered parenterally these synthetic micelle formers can occasionally cause various side effects such as e.g. allergic reactions, anaphylactic shock or haemolysis.

In the scope of the present invention it has surprisingly been found that a safe and effective treatment with vitamin Ki by the oral route can be achieved in the form of aqueous mixed micelle solutions.

The invention is accordingly concerned with the use of mixed micelles for the manufacture of peroral administration forms of vitamin Kj, especially for use in neonatology.

As the mixed micelles there can be used aqueous solutions of cholanic acid salts and phospholipids which are known, for example, from DE-OS 2 730 570.

As cholanic acids there come into consideration for the solutions in accordance with the invention trihydroxycholanic acids such as cholic acid, glycocholic acid and taurocholic acid, and dihydroxycholanic acids such as deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, chenodeoxy acid, glycochenodeoxycholic acid and taurochenodeoxycholic acid. Glycocholic acid is preferred. As Grn/4.7.91 - 2 cholanic acid salts there come into consideration especially alkali salts such as the sodium salt.

Example of phospholipids are phosphatides such as phos5 phatidylcholines, glycerol ether phosphatides, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, plasmologens or sphingomyelins. Phosphtatidylcholines such as soya lecithin and egg lecithin are preferred.

The molar ratio of lipid to cholanic acid salt conveniently lies between 0.8:1 and 1.5:1.

The amount of lipid plus cholanic acid salt in the solution can vary over wide limits and can be e.g. 50-150 mg/ml.

The amount of vitamin Ki in the mixed micelle solutions can also vary over wide limits and can be e.g. 1-100 mg/ml of solution.

The mixed micelle solutions can be manufactured by simply 20 dissolving and mixing the individual ingredients.

In a special embodiment an aqueous mixed micelle solution of a lipid and a cholanic acid salt is firstly prepared and then the vitamin Ki is added.

For example, glycocholic acid is dissolved in purified water Ph.Eur. with the aid of sodium hydroxide and the pH is adjusted to a value of 5.5 with hydrochloric acid. The lecithin is dissolved in the sodium glycocholate solution while stirring and the vitamin Kj is added while stirring.

Purified water Ph.Eur. is added to the thus-obtained vitamin Ki mixed micelle solution, the pH is adjusted to a value of 6.0 with hydrochloric acid and the solution is made up to the final volume with purified water Ph.Eur.

The solution obtained is conveniently filtered through a suitable filter and filled into suitable containers. - 3 The following Example illustrates in more detail the manufacture of oral vitamin Kj preparations in accordance with the invention.

Example Composition of a vitamin Kj preparation for oral administration: Ingredient Per ml Vitamin Kj 10.0 mg Glycocholic acid 54.6 mg Lecithin 75.6 mg NaOH (purest) qs Hydrochloric acid (analytical) qs Water for injection ad 1.0 ml Manufacture: a) 1.5 kg of sodium hydroxide are dissolved in 7.0 kg of purified water Ph.Eur. while gassing with N2 and cooling. b) 21.84 kg of glycocholic acid are suspended in solution a) and brought into solution by the addition of sodium hydroxide (10%) at pH 5.5-6.5. After the glycocholic acid has dissolved completely the pH is adjusted to a value of 5.5 with IN hydrochloric acid. c) 30.240 kg of comminuted lecithin are dissolved while stirring vigorously in the glycocholate solution b) which is heated to 60°C. d) 4.0 kg of vitamin Kj are poured slowly into the mixed micelle 25 solution c) and the mixture is stirred until an almost clear solution is obtained. e) The vitamin K4 mixed micelle solution d) is treated with 265 kg of purified water Ph.Eur. while stirring and cooled to 25°C. - 4 f) The solution e) obtained is adjusted to pH 6.0 with IN hydrochloric acid and made up to the final volume of 400 1 with purified water Ph.Eur. g) The solution f) is filtered through a suitable filter candle (e.g 0.2-1.2 mm) and filled into containers under a N2 atmosphere.

The unexpectedly good activity of the preparations obtainable in accordance with the invention is evident when they are compared with conventional vitamin K4 preparations.

Figure 1 shows the bioavailability of a conventional solution (manufactured with Cremophor EL) and of the mixed micelle solution in accordance with the invention. The bioavailability which is achieved by intramuscular administration of corresponding solutions serves as the reference (100%).

In the case of oral administration of a solution with a synthetic solubilizer (Cremophor EL) the bioavailability of vitamin Kj was only % of the comparable i.m. administered preparation (100%).

On the other hand, with a mixed micelle solution an oral bioavailability of vitamin Ki of 115% of that of the comparable i.m. administered preparation was achieved.

Figure 2 shows the Quick value obtained in the blood of neonates 24 hours after the i.m. injection of a mixed micelle solution of vitamin K4 and after the oral administration of the Ki mixed micelle solution in accordance with the present invention, in each case in comparison to the initial value.

The i.m. form of vitamin Ki was not able to increase the initial Quick value within 24 hours after administration (the most important phase of the activity), on the other hand with the oral administration form the Quick value could be raised within 24 hours from about 55% to 75%, i.e. in the normal range (min. normal range = 70%).

Claims

1. The use of mixed micelles for the manufacture of peroral administration forms of vitamin Kj.

2. The use according to claim 1, in which mixed micelles from cholanic acid salts and phospholipids are used.

3. The use according to claim 2, in which the cholanic acid 10 salt is a glycocholate and the phospholipid is lecithin.

4. The use according to claims 1-3 in neonatology.

5. A commercial pack containing a mixed micelle solution of 15 vitamin Kj together with instructions for the oral administration to neonates.

6. A method of treating vitamin Ki deficiencies in humans wherein mixed micelle solution of vitamin Ki are administered 20 perorally.

7. A method as in claim 6 wherein said mixed micelles are formed from cholanic acid salts and phospolipids. 25

8. A method as in claim 7 wherein the cholanic acid salt is a glycocholate and the phospholipid is lecithin.

9. A method as in claim 6 wherein human neonates are treated.

10. . Use according to claim 1, substantially as hereinbefore described and exemplified.

11. A commercial pack according to claim 5, substantially as hereinbefore described.