WO1992015283A1

WO1992015283A1 - Parenteral emulsion

Info

Publication number: WO1992015283A1
Application number: PCT/DK1992/000061
Authority: WO
Inventors: Anette MÜLLERTZ; Tomas Tage Hansen
Original assignee: Novo Nordisk A/S
Priority date: 1991-03-01
Filing date: 1992-02-28
Publication date: 1992-09-17

Abstract

The parenteral emulsion, which comprises water, lipids, glycerol and phospholipids as the four main constituents is characterized by the fact that the weight ratio between the lipid and the phospholipids is 18:1 to 30:1, that the concentration of the lipid is between 10 and 30 % w/w, and that the lipid contains long chain acyl radicals and other acyl radicals. In this manner the concentration of phospholipids can be reduced considerably below 1.20 % w/w, which is an advantage both from a therapeutic and an economic point of view.

Description

PARENTERAL EMULSION

This invention relates to a parenteral emulsion consisting essentially of water, lipids, glycerol and phospholipids.

To the best of applicant's knowledge no commercial parenteral emulsions of this type are known which contain less than around 1.20% w/w phospholipid, which functions as an emulsifier. A reduction of the phospholipid concentration would be a desideratum. In the first place, the tendency towards generation of phospholipid vesicles containing exclusively or almost exclusively phospholipid would be reduced, if the concentration of phospholipids could be reduced considerably below 1.20% w/w. In the second place infusion of the commercial emulsions generates chylomicrons which are not directly compatible to the genuine chylomicrons in the blood stream, but which could be made more compatible or compatible to those, if the concentration of phospholipids could be reduced considerably below 1.20% w/w. Reference is made to a later part of this specification, in which the composition of chylomicrons are discussed in more detail.

So far efforts to reduce the phospholipid concentration of the commercial parenteral emulsions have been in vain. It has turned out that a reduction of the phospholipid concentration to e.g. 0.9% w/w in parenteral emulsions with around

20% soy oil generates an unstable parenteral emulsion, i.e. a parenteral emulsion with larger particles and/or a parenteral emulsion which separates into two phases on standing. Documentation will be presented later in this specification.

Thus, the purpose of the invention is the provision of a stable parenteral emulsion of the above indicated kind, in which the concentration of the phospholipids is reduced considerably below 1.20% w/w. Now, surprisingly it has been found that the purpose of the invention can be fulfilled, if the lipid is selected from a specified category of lipids, which does not comprise triglycerides with only long chain fatty acid radicals, e.g. soy bean oil, if the weight ratio between the lipid and the phospholipid falls within certain, specified ranges, and if the concentration of the lipid falls within certain specified ranges. Thus, the parenteral emulsion according to the invention consisting essentially of water, lipids, glycerol and phospholipids and wherein the concentration of the lipid is between 10 and 30% w/w, and the lipid contains long chain acyl radicals and other acyl radicals, is characterized by the fact that the weight ratio between the lipid and the phospholipids is 18:1 to 30:1.

In this specification with claims "radicals" is to be understood as the three acyl radicals attached to the structure

CH₂-0-

I

CH-O-

I CH₂-0-

in the lipid at the three positions indicated. By long chain acyl radicals is understood acyl groups with 14-24 C-atoms. By medium chain acid radicals is understood acyl groups with 6-13 C-atoms, and by short chain acyl radicals is understood acyl groups with 2-5 C-atoms. If not anything to the contrary is indicated, it is to be understood that the acyl radicals can be saturated or unsaturated, and branched or with straight chains. Also, as appears from the following, the lipids can be randomized or structured.

Furthermore, it has been found that the parenteral emulsion according to the invention is considerably cheaper than the prior art parenteral emulsions, because the phospholipid is by far the most expensive constituent of the parenteral emulsion.

The reason why substitution of the soy oil (with exclusively long chain radicals) with lipids containing both long chain radicals and other acyl radicals makes it possible to reduce the concentration of phospholipid and yet maintain a stable parenteral emulsion is not completely understood.

It appears from EP 211 258 and DE 3032300 that it should be possible to produce parenteral emulsions with a concentration of phospholipids below 1.20% w/w, but our experiments have shown that such parenteral emulsions are unstable.

Also, these prior art parenteral emulsions contain conventional lipids i.e. not the lipids used in the parenteral emulsions according to the invention.

DE-A-3032200, EP-A-0233849, and Patent Abstracts of Japan, vol. 13, number 336, Appl. no. 62-266632 describe parenteral emulsions, which besides the constituents indicated in the preamble of the main claim contain an active component, i.e. carnitin, pregnolone or vitamin K^

WO 90/03786 describes a parenteral emulsion of the type indicated in the preamble of the main claim. However, in the sole example the weight ratio between the lipid and the phospholipids is 8.3, i.e. well outside the interval for this ratio according to the invention.

In order to obtain a stable lipid emulsion the particle size should be less than 400 nm and preferably less than 350 nm. We have prepared the following emulsions, which illustrate the invention in comparison to prior art:

10

The emulsions were prepared with the following ingredients: oil egg lecithin glycerol sterile water

The emulsions were prepared as follows:

The work was performed in an LAF bench, and the microfluidizer was placed in immediate proximity thereof. Argon was bubbled through all liquids constantly. 12 or 9 g of egg lecithin were dispersed in 0.5 I of water by means of an Ultra Turrax mixer. When the foam fell the dispersion was finished.

200 g of oil was added, and dispersion was carried out with an Ultra Turrax mixer.

22.5 g of glycerol was added together with water to a total weight of 1 kg, and dispersion was carried out with an Ultra Turrax mixer.

Homogenization was performed on a microfluidizer (120E, Micro fluidic Corp.). The emulsion was passed through totally 5 times.

The pH value was measured and adjusted to around 9.5. Osmolality and particle size was determined. The emulsion was filled on bottles and autoclaved at 121°C for 25 minutes.

After heat treatment the pH value, the osmolality and the particle size was determined.

The emulsions were stored at 4°C. The above table shows that experiment no. 3 yielded an emulsion, which did not fulfil the stability requirements, vide an earlier section of this specification; both visually and in regard to particle size it was evident that no stable emulsion was formed. Also, the above table illustrates the prior art (experiment 1 ) and the invention (experiment 4). Furthermore, it appears from the above table that an emulsion with 1.2% PL in combination with 20% MLM gives rise to a satisfactory emulsion; this, however, is outside the scope of the invention A preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the phospholipids comprise egg yolk phospholipids and/or soy lecithins. These phospholipids are easily available commercially. A preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the weight ratio between the lipid and the phospholipid is 19:1 to 25:1, preferably 19:1 to 21:1. This weight ratio comes very close to the corresponding weight ratio in the genuine chylomicrons, which is approximately 20:1. A preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the concentration of the lipid is between 20 and 30% w/w. From a process technical point of view it is difficult to manufacture emulsions with a lipid concentration above 30% w/w, and emulsions with a lipid concentration less than 20% exhibit an unwanted low energy content. A preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the total amount of phospholipid is equal to or less than 1% w/w. As previously indicated, a low amount of phospholipids is advantageous from different points of view.

A preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the other acyl radicals in the lipid are short chain radicals. This emulsion provides a better growth of the endothelium cells of the gut mucosa.

A preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the other radicals in the lipid are medium chain radicals. This emulsion provides a better energy substrate.

A preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the lipid exhibits a structure

wherein

1) R, is L, R₂ is M,

2) R, is L, R₂ is S,

3) R₂ is L, R, is M, or 4) R₂ is L, R. is S, where L is a long chain acyl radical,

M is a medium chain acyl radical, S is a short chain acyl radical.

These lipids can easily be produced enzymatically. A preferred embodiment of the parenteral emulsion according to the invention is characterized by the fact that the lipid with the composition indicated has a purity of at least 20% w/w, preferably at least 50% w/w, and more preferably at least 80% w/w. The higher the purity, the more pronounced the claimed effect.

It appears from Carpentiers, Y.A., Intravascular metabolism of fat emulsions: The Arvid Wretlind Lecture, Espen, 1988. Clin.Nutr. (1989) 8: 115-125, that the chylomicrons, which are the natural gut generated lipid transport agents in the blood, exhibit the following composition

From the above it appears that the weight ratio triglyceride:phospholipid (TG:PL) is around 20:1, i.e. a ratio equal to or close to the ratio TG:PL used in the emulsion according to the invention.

Claims

1. Parenteral emulsion consisting essentially of water, lipids, glycerol and phospholipids and wherein the concentration of the lipid is between 10 and 30% w/w, and the lipid contains long chain acyl radicals and other acyl radicals, characterized by the fact that the weight ratio between the lipid and the phospholipids is 18:1 to 30:1.

2. Parenteral emulsion according to Claim 1 , characterized by the fact that the phospholipids comprise egg yolk phospholipids and/or soy lecithins.

3. Parenteral emulsion according to Claims 1 -2, characterized by the fact that the weight ratio between the lipid and the phospholipid is 19:1 to 25:1, preferably 19:1 to 21:1.

4. Parenteral emulsion according to Claims 1 - 3, characterized by the fact that the concentration of the lipid is between 20 and 30% w/w.

5. Parenteral emulsion according to Claims 1 - 4, characterized by the fact that the total amount of phospholipid is equal to or less than 1% w/w.

6. Parenteral emulsion according to Claims 1 - 5, characterized by the fact that the other acyl radicals in the lipid are short chain radicals.

7. Parenteral emulsion according to Claims 1 - 5, characterized by the fact that the other radicals in the lipid are medium chain radicals.

8. Parenteral emulsion according to Claims 1 - 7, characterized by the fact that the lipid exhibits a structure

wherein

1) R, is L, R₂ is M, 2) R, is L, R₂ is S,

3) R₂ is L, R, is M, or

4) R₂ is L, R, is S, where L is a long chain acyl radical,

M is a medium chain acyl radical, S is a short chain acyl radical.

9. Parenteral emulsion according to Claims 1 - 8, characterized by the fact that the lipid with the composition indicated has a purity of at least 20% w/w, preferably at least 50% w/w, and more preferably at least 80% w/w.