EMULSION AND USE OF THE EMULSION AS A PARENTERAL PREPARATION

Abstract: The emulsion has an aqueous, continuous phase and containing as the discontinuous phase the triglycerides 2-oleyl-1,3-di(octanoyl/decanoyl) glycerol, formulated for parenteral use. This emulsion exhibits a better bioavailability than hitherto known parenteral emulsions used as a source for oleic acid.

Description: EMULSION AND USE OF THE EMULSION AS A PARENTERAL PREPARATION The invention relates to an emulsion and a use of the emulsion as a parenteral preparation. The triglyceride 2-oleyl-1 , 3-dioctanoy1 glycerol (2[9-cis-octadecenoyl]-l,3-dioctanoyl glycerol) is described in Am. J. Clin. Nutr. 1987; 45:940-5 and the triglyceride 2-oleyl-l, 3-didecanoyl glycerol (2-[9-cis- octadecenoyl]-l,3-didecanoyl glycerol) is described in F. H. Mattson et al. , Journal of lipid research, 5, 374-77 (1964). Also, an emulsion for enteral use of the first mentioned of the above two triglycerides is described. As the above triglycerides are important as nutrients, especially for diseased humans, there is a need for an emulsion of 2-oleyl-l, 3-di(octanoyl/decanoyl) glycerol, which can be used for parenteral nutrition, and which exhibits a better bioavailability than hitherto known parenteral emulsions used as a source for oleic acid. A very important clinical aspect in regard to the bioavailability is the slower metabolism in comparison to emulsions containing MCT, which are known to cause metabolic acidosis, when infused intravenously. The emulsion according to the invention with an aqueous continuous phase and containing as the discontinous phase the triglyceride 2-oleyl-l,3-di(octanoyl/decanoyl) glycerol, is characterized by the fact that it is formulated for parenteral use. Any worker skilled in the art will know in principle how to compose such formulation. It is to be understood that the term 2-oleyl-l,3-di(octanoyl/decanoyl) glycerol encompasses both the pure 1,3-dioctanoyl triglyceride, the pure 1,3-didecanoyl triglyceride, and furthermore the l-octanoyl-3-decanoyl triglyceride and the 1- decanoyl-3-octanoyl triglyceride, the 2-position of course in all cases being occupied by oleic acid. Surprisingly it has been found that the emulsion according to the invention exhibits a better bioavailability than hitherto known parenteral emulsions used as a source for oleic acid. Moreover, the above-mentioned triglycerides turn out, surprisingly, to be very efficient sources of energy when applied in parenteral nutrition - the oleic acid moiety of the triglycerides being in an optimal position in the molecule in respect to their cleavage by lipoprotein lipase. surprisingly, the above-mentioned triglycerides appear to exhibit physical properties which allow facile formulation of the compounds in liquid products as well as in powdered products exhibiting excellent wetability properties. In the liquid form the products of the invention possess excellent stabilities making sterilization of e.g. parenteral products containing the above triglycerides reliable, easy and safe. The above-mentioned triglycerides are advantageously applied in such emulsions due to their fast conversion by lipoprotein lipase and endothelial lipase and the consequential avoidance of the discomfort and side effects of lipolipaedemia. Arachidonic acid applied in triglycerides of the invention are thus cleared quickly and efficiently thereby providing the essential fatty acid concomitantly with short chain acids useful as energy substrates. A preferred embodiment of the emulsion according to the invention is characterized by the fact that the average diameter of the triglyceride globules is between 5 and 1000 nm, and that less than 5% of the triglyceride globules exhibits a diameter above 5000 nm. This emulsion is well suited as a parenteral emulsion and shows a good bioavailability. A preferred embodiment of the emulsion according to the invention is characterized by the fact that the average diameter of the triglyceride globules is between 5 and 1000 nm, that less than 5% of the triglyceride globules exhibits a diameter above 5000 nm, that the amount of the triglycerides in relation to the amount of the entire emulsion is between 2 and 30% by weight, and that the emulsion contains glycerol to isotonicity and 0.2 - 10% by weight of an emulsifier. This emulsion is very well suited as a parenteral emulsion and shows a superior absorption ability. A preferred emulsifier is a phospholipid. The use of the above-mentioned triglycerides in parenteral nutritional products is further particularly advantageous since the relatively high polarity of the triglycerides favour the stability of their emulsions which are subjected to severe heat treatments during their manufacturing. Use of such emulsion is particularly advantageous for nutrition of severely ill patients e.g. post-operatively. A preferred embodiment of the emulsion according to the invention is characterized by the fact that the triglycerides have a purity of at least 30%, preferably at least 50%, more preferably at least 75%, and most preferably at least 90%. The higher the purity of the triglyceride, the more efficient the absorption of the triglyceride. Also the invention comprises a use of the emulsion according to the invention as a parenteral preparation. EXAMPLE 1 A parenteral feeding product was prepared according to the following formula: Composition for 1000 ml I Lipid 100.0 g II Egg yolk phospholipids (Lipoid E80) 12.0 g III Glycerol 22.5 g IV Water for injection to 1000 ml Production Procedure II was dispersed in 500 ml of IV by a high shear mixer (Ultra turrax) followed by the addition of I and III . . Fianlly water (IV) was added to a total volume of 1000 ml. The whole mixture was further prehomogenized for another 2-3 minutes (ultra turrax) . The pre-emulsion was homogenized in a high pressure homogenizer (MHO Microfluidizer, Microfluidics Corporation, Newton, Mass.). The product was processed 5 times through the Microfluidizer. In order to keep the product temperature below 20 β C the product was passed through an ice slurry by each cycle. The oxidation of lipids was prevented by running the process under Argon and by using liquids saturated with Argon. The product was filled in a suitable package and sterilized in an autoclave at 120°C for 20 minutes. Analytical data pH = 6.5 Osmolality = 285 mOsm/kg water Particle size (d 2 ) = 300 nm Limulus test = < 4 EU/ml EXAMPLE 2 The superiority of the compounds of the invention was illustrated by comparing the rate of their hydrolysis by lipoprotein lipase with the rate of hydrolysis of the non- structured lipid (LLL) and the commercial product Intralipid which contains long chain fatty acids at all positions of the triglyceride molecules. All emulsions were made as described in Example 1. As is apparent from the table below the structured lipid was hydrolyzed at an increased rate thus offering advantages as mentioned above.

Claims: CLAIMS 1. An emulsion with an aqueous, continuous phase and containing as the discontinuous phase the triglycerides 2- oleyl-1,3-di(octanoyl/decanoyl) glycerol, formulated for parenteral use. 2. An emulsion according to Claim 1, wherein the average diameter of the triglyceride globules is between 5 and 1000 nm, and wherein less than 5% of the triglyceride globules exhibits a diameter above 5000 nm. 3. An emulsion according to Claim 2, wherein the amount of the triglycerides in relation to the amount of the entire emulsion is between 2 and 30% by weight, and the emulsion contains glycerol to isotonicity and 0.2 - 10% by weight of an emulsifier. 4. Emulsion according to Claims 1 - 3, wherein the triglycerides have a purity of at least 30%, preferably at least 50%, more preferably at least 75%, and most preferably at least 90%. 5. Use of the emulsion according to Claims 1 - 4, as a parenteral preparation.

Inventors: FROEKJAER SVEN, GODTFREDSEN SVEN ERIK, HANSEN TOMAS TAGE, FROEKJAER, SVEN, GODTFREDSEN, SVEN, ERIK, HANSEN, TOMAS, TAGE
Applicants: NOVONORDISK AS, NOVO-NORDISK A/S
Application year: 1989
Main classification: A61K31
IPC codes: A23D7, A23D9, A23K1, A23L1, A61K9, A61K31, A61P3, C07C69, C11C1, C11C3