AU624107B2 - Emulsion for parenteral administration - Google Patents

Description

To: The Commissioner of Patents 1 fi

PCT

OPI DATE 19/07/89 APPLN. ID 28214 89 PCT NUMBER PCT/SE88/00680 INTERNATIONAL APPLICA (51) International Patent Classificati A61K 31/23, 9/10, 49/00 i onal Publication Number: WO 89/ 05638 29 June 1989 (29.06.89) (43) International Publication Date: (21) International Application Number: PCT/SE88/00680 (22) International Filing Date: 14 December 1988 (14.12.88) (31) Priority Application Number: 8705064-7 (81) Designated States: AT (European patent), AU, BE (European patent), CH (European patent), DE (European patent), DK, FI, FR (European patent), GB (European patent), IT (European patent), LU (European patent), NL (European patent), NO, SE (European patent), US.

Published With international search report.

With amended claims.

(32) Priority Date: (33) Priority Country: 18 December 1987 (18.12.87) (71) Applicnt (for all designated States except US): KABIV- ITP-UM AB [SE/SE]; S-112 87 Stockholm (SE).

(72) Inventors; and Inventors/Applicants (for US only) WRETLIND, Karl, Arvid, Johannes [SE/SE]; Floragatan 2, S-114 31 Stockholm AJAXON, Bengt, Magnus [SE/SE]; Havelvagen 7, S-756 47 Uppsala (SE).

(74) Agents: ONN, Thorsten et al.; AB Stockholms PatentbyrA, Zacco Bruhn, Box 3129, S-103 62 Stockholm

(SE).

(54) Title: EMULSION FOR PARENTERAL ADMINISTRATION (57) Abstract The invention relates to emulsions intended for parenteral administration and containing a hydrophobic phase emulsified in an aqueous phase. In accordance with the invention, a substantial part of the hydrophobic phase contains one or more alkyl esters of pharmacologically acceptable fatty acids, and then particularly ethyl esters. The emulsions can be used for parenteral nutrient supply and as vehicles for pharmacologically active substances or agents, and may also be used for both purposes in combination.

WO 89/05638 PCT/SE88/00680 1 Emulsion for parenteral administration Fat emulsions which are intended, inter alia, for intravenous, nutrient supply and which exhibit insignificant .secondary effects have been available since the beginning of the 1960's (Wretlind, A. Development of fat emulsions, JPEN 5: No. 3, 230.235, 1981). This development work has investigated the effect of emulsions which contain a number of mutually different fats (oliveoil, cottonseed oil, soyabean oil, maize oil, safflower oil, coconut o.il, etc.) and several mutually different emulsifiers (soyabean phospholipids, egg yolk phospholipids, cerebrosides, diglycerides etc.). One characteristic feature common to all of these emulsions is that the fats or oils used comprise triglycerides of fatty acids.

All of the fat emulsions earlier investigated and present day fat emulsions require preparation by homogenization under high pressure. One reason for this is because the fats used have high viscosities. Another drawback with present day fat emulsions is that the fats or oils used can only be cleansed with great difficulty, in a manner to free the glycerides completely from all other substances, such as sterols and unsaponifiable fractions. Several methods have been proposed for cleansing the oils used.

One such method has been described by S.S. Chang (US-A 4 101 673). The method to Chant involves removing a part of the polar, undesirable constituents with the aid of silica gel. Other attempts have been made with the aid of molecular distillation techniques. This latter method has not been found to have any practical value, however.

Consequently, there is a desire in this respect to find compounds other than triglycerides which will enable fatty acids to be administered in the form of emulsions, and optionally in the form of emulsions which are totally WO 89/05638 PCT/SE88/00680 2 free from the so-called unsaponifiable residues present in fats of animal and vegetable origins. Another desire is one of discovering fatty acid compounds which have a lower viscosity than the lipids used hitherto and at present in the preparation of fat emulsions. A lower viscosity would also enable fat emulsions to be prepared in a somewhat simpler fashion, and would also enable emulsions to be prepared with smaller particle sizes of the colloidal suspension than those of conventionally prepared fat emulsions.

The present invention now makes it possible to prepare emulsions which will satisfy the aforesaid desiderata, with the use of alkyl esters, and then preferably ethyl esters of fatty acids deriving from synthetic, animal or vegetable origins. These alkyl esters can be obtained either by esterification of triglycerides with ethyl alcohol or other alcohols in the presence of a catalyst, such as sodium alcoholate and certain zinc compounds. Alternatively, fatty acids can be prepared by complete hydrolysis of triglycerides with sodium hydroxide or potassium hydroxide, whereafter the solution containing the salt compound of the fatty acids is extracted with hexane or some other organic solvent, so as to remove unsaponifiable residues.

The free fatty acids are obtained subsequent to adding hydrochloric acid or some other acid. The free fatty acids can then be converted to ethyl esters or some other alkyl esters in some suitable way, by treating the fatty acids with ethyl alcohol or some other alkyl alcohol having one or two hydroxyl groups capable of esterification. Suitable esters can also be obtained by esterifying synthetic or otherwise produced fatty acids having an even or an odd number of carbon atoms.

The present invention thus relates to an emulsion intendad for parenteral administration and including a hydrophobic WO 89/05638 PCT/SE88/00680 3 phase emulsified in a water phase, this emulsion being characterized in that a substantial part of the hydrophobic phase comprises one or more alkyl esters of pharmacologically acceptable fatty acids. The alkyl esters will preferably comprise low-molecular alkyl esters having 2-4 carbon atoms in the alkyl groups, and then primarily ethyl esters.

The fatty acids are preferably of vegetable, animal or synthetic origins, and will preferably have from 9 to 22 carbon atoms in their carbon chains.

In accordance with one embodiment, the carbon chain of the fatty acids will contain predominantly or exclusively an even or odd number of carbon atoms. This has been found significant with respect to certain usages of the emulsions prepared. For instance, fatty acids having an odd number of carbon atoms will produce a high percentage of glucose when metabolized, a fact which can have significance when using the emulsion for nutrient administration.

The alkyl ester content of the emulsion will suitably be from 5 to 60 percent by weight, calculated on the total emulsion, and preferably from 5 to 30 percent by weight.

Future reference to percentages made in this description and appended claims refers to weight/volume percent unless otherwise stated.

The hydrophobic phase of the emulsion may also include glyceryl esters of fatty acids. The weight ratio of the alkyl esters to the glyceryl esters will then suitably be from 10:1 to 1:10.

The use of ethyl esters or other alkyl esters of fatty acids will afford, inter alia, the following advantages: 1:o homogenization is simplified as a result of the lower viscosity; rri, 1 1 y i l li 1 1 1 1 WO 89/05638 PCT/SE88/00680 4 2:o the lower viscosity will also result in a lower viscosity of the prepared emulsion; 3:o a lower intrinsic weight, thereby enabling a lower specific weight to be obtained with, iodo-emulsions or hydrofluorocarbon emulsions; 4:o ethyl ester results in metabolic properties other than those obtained with triglyceride ester.

It has also been surprisingly found in the case of many substances that, in addition to the aforementioned advantages, these esters are better solvents than triglycerides of animal or vegetable origin. The technique of dissolving pharmacologically active substances in triglycerides, such as soyabean oil, and subsequently preparing the solution to emulsion form with the aid of suitable emulsifiers is known to the art, (for instance from US-A 4 168 308). It has been found, however, that in many cases the solubility of these substances in such oils is so poor that desired concentrations in the final emulsion cannot be reached. It has now surprisingly been found that the solvent prooerties of these alkyv esters, for instance ethyl esters of fatty acids, are totally different from the solvent properties of the triglyceride esters present in the fatty acids animal and vegetable origins. The use, for instance, of fatty acid ethyl esters enables oil-in-water emulsions to be prepared which contain higher quantities of pharmacologically active substance in the hydrophobic phase. The particle size of these emulsions will also be smaller than the particle size of the emulsions based on triglyceride.

Since the particles in an alkyl-ester emulsion are much smaller than the particle size of conventional fat emulsions, there is obtained a much greater specific diffusion surface area, thereby resulting in a more rapid and more powerful effect of the active substance.

WO 89/05638 PCT/SE88/00680 According to one important embodiment of the invention, the present emulsion will thus contain one or more pharmacologically active substances dissolved or dispersed in the hydrophobic phase. These substances, or agents, may be of very different types, as will be made apparent in the following, and the type of active substance used is not intended to limit the scope of the present invention.

Furthermore, the inventive emulsions may contain X-ray contrast agents, particularly in the form of one or more iodized fats or contrast substances for such investigative procedures as datortomography and NMRI (Nuclear Magnetic Resonance Imaging). These substances or agents may be present in a quantity of 1-60 percent by weight, calculated on the whole emulsion.

It will also be apparent that the inventive emulsion has two essential areas of use. The first of these areas is the use of the emulsion as a nutrient source intended for parenteral nutrient supply. The second of said areas is the use of the emulsion as a vehicle for carrying pharmacologically active substances, including X-ray contrast substances or media, these substances being dissolved or dispersed in the hydrophobic phase. The afore-illustrated advantages are thus achieved by the superior solvent properties and solution promoting properties of the ingoing alkyl esters. It will be understood, however, that the two areas of use may also be combined, such that an emulsion intended for nutrient supply can include one or more oharmacologically active substances in the hydrophobic phase.

The inventive emulsions are primarily intended for intravenous administration, particularly when used for nutrient supply. The emulsions, however, can also be administered parenterally in any other manner, the manner in which the emulsions are administered being determined by the effect WO 89/05638 PCT/SE8800680 and function of the pharmacologically active substances included and by the indications or symptoms of the patient.

The compositions prepared in accordance with the invention may also contain various additives, i.e. in addition to the active substance (or substances) and the hydrophilic component, comprising water, optionally with substances dissolved therein, and the hydrophobic component, comprising alkyl esters, and then particularly ethyl esters of fatty acids. These further additives may, for instances, comprise preserving agents, pH-adjusters and agents for achieving a suitable ozmotic pressure. In this respect, one of the most important additives will comprise one or more suitable emulsifiers capable of providing a stable dispersion. A multiple of emulsifying and suspension agents of both natural and synthetic origin can be used in this respect. Examples of such agents include phospholipids deriving from eggs or soyabeans, and polyethylene polypropylene glycol. Many useable emulsifiers are known from the literature and are commercially available, and the person skilled in this particular art will have no problem in selecting one or more agents suitable for the purpose intended.

The emulsion may also contain nutrients dissolved or dispersed in the aqueous phase. Examples of such substances include, for instance, amino acids, glycerol, glucose, fructose, xylitol, sorbitol or other sugars or alcohols, water-soluble vitamins, salts and trace elements. The emulsion may-contain several of these substances at one and the same time. Furthermore, the aqueous phase may also contain water-soluble, pharmacologically active substances.

All of -the particles presert in an invenzive emulsion will have a diameter considerably smaller than 1 micron, thereby obviating the risk of the particles fastening in the WO 89/05638 PCT/SE88/00680 7 capillaries. An emulsion having a particle size of 0.1-0.3 micron can be produced without any great difficulty. This renders the system stable. It has also been found that the inventive emulsions can be prepared in a manner to prevent the particles from forming agglomerates in the blood. The inventive emulsions will withstand being autoclaved and can be stored for long periods without degredation or decomposition. Furthermore, it has been found that the actual vehicle system is well tolerated and will not result in secondary effects, when administered intravenously.

An example of pharmacologically active substances capable of being administered in accordance with the present invention include those which belong to one of the following groups: Centrally active substances: such as active depressants anaesthetics active anagelsics central stimulants Substances having peripheral effect on he neuromuscular system: such as spasmolytics muscle relaxing substances Substances which affect the cardiac and vascular system: such as substances having a vasopressor effect

I

'i WO 89/05638 PCSE8/00680 8 i Substances which affect the resoiratory system: such as asthma treating substances Contrast substances for use in conventional radiology diagnosis, datortomographic and NMRI (Nuclear Magnetic Resonance Imaging) investigations.

Antiobiotic, cytostatic and chemotherapeutical substances.

The list of such substances is indefinite.

Emulsions prepared in accordance with the present invention exhibit a high degree of tolerance in experiments carried out on animals. Ethyl esters of fatty acids obtained from soyabean oil have been examined in infusion experiments on rats. In this respect it was possible to administer 70 ml/kg intravenously at a rate of 0.3 ml/kg/min without the occurrence secondary effects. The volume used corresponded approximately to the energy consumed each minute by the animal concerned. Subsequent to hydrolysis of the ethyl esters, the amount of alcohol administered to the animals in the aforesaid experiments corresponds to only 10 of the total energy requirement of the body.

This supply of alcohol has no appreciable physiological or medicinal significance. In other experiments, rats were given repeated daily infusions of the aforesaid ester emulsion in an amount of 150 ml/kg over a planned trial period of 14 days. No secondary effects were observed. The animals exhibited a normal weight increase. The amount administered exceeded 40% of the energy requirement of the animals.

The emulsion itself was prepared in a conventional manner, i.e. a manner well known to the skilled person from, for instance, the aforecited literature. Thus, the hydrophobic 9 WO 89/05638 PCT/SE88/00680 phase, the emulsifier and the aqueous phase can be mixed together to form a "coarse emulsion", which is then homoa genized in some suitable apparatus to a suitable particle size with regard to the hydrophobic phase. Those substances intended to be in solution or dispersion in the hydrophobic phase, and/or the aqueous phase are normally first dissolved in respective phases prior to mixing said phases together. Subsequent to homogenization, the emulsion is poured into suitable containers and then sterilized.

As will be understood, it is imperative that the quality of the emulsion ingredients is such as to be free from pharmacological complaint, and that this quality is sustained through the whole of the process of preparation.

Thus, the components must be free from contaminants capable of causing harmful secondary effects, such as pyrogens, and must also be protected from the harmful effect, for instance, of oxidation, prior to, during and subsequent to the process of preparation, all of which is well known to the person skilled in this art.

The invention will now be described with reference to a number of examples.

Example 1 100 g of soyabean oil were mixed with 1 liter of absolute alcohol. It was found that the oil did not dissolve, but lay in a layer beneath the alcohol. Sodium alcoholate was then added in an amount corresponding to 0.25 g metallic sodium. A clear solution was obtained after 20-30 minutes, subsequent to trans-esterification of the soyabean oil taking place. Three volumes of water were added and the resultant oil layer was then isolated and washed with some small volumes of water. The resultant oil comprised the ethyl esters of the fatty acids of the soyabean oil.

WO; 89/05638 PCT/SE8800680 The viscosity of the ethyl esters is significantly lower than the viscosity of the original soyabean oil. The specific weight is also lower than the specific weight of corresponding triglyceride.

50 g of the ethyl esters were mixed with 6 g phospholipids, 12.5 g glycerol and water to a volume of 500 ml. 1 M NaOH was added to obtain a pH between 7 and 10.5, whereafter the mixture was homogenized in a conventional manner, e.g. in a Moulin-Gaulin homogenizer. The resultant emulsion was heat sterilized at 120'C for 20 minutes. Subsequent to being analyzed for control purposes, the emulsion was ready for intravenous administration. The measured particle size was 0.15-0.30 micron.

The emulsion was administered in quantities of 150 ml per kilogram and day to rats under a planned 14 day course of administration. The rats exhibited a good increase in weight. No signs of secondary effects were observed. The amount administered corresponded to about 40 to 50 of the energy requirements of the rats.

ExamDle 2 100 g of oil (soyabean oil, safflower oil, olive oil or some other vegetable or animal oil) were mixed with 2 liters of 0.2 M NaOH and 0.5 liter of hexane while slowly stirring the mixture. The hexane fraction was separated, subsequent to all fat having been saponified. The aqueous solution was neutralized with 1 liter of 0.5 M HC1. The resultant layer of free fatty acids was separated and washed with water. Subsequent to having removed all water with water-free sodium sulphate, the fatty acids were esterified with ethyl alcohol or some other alkyl alcohol in a manner similar to that described, for instance, by C.H. Rogers (A method for manufacturing oenanthylate. J.

Amer. Pharmaceut. Assoc. Sci. Ed. Vol 12:503-506, No. 6, 1923.) WO 89/05638 PC/SE8/00680 11 The esters obtained were used to prepare fat emulsion. The ingredients used were as follows: Ethyl esters of fatty acids 100 g Egg yolk phospholipid 12 g Glycerol 25 g Sterile and pyrogen-free water to an amount of 1000 ml Sodium hydroxide solution 1 M in an amount sufficient to obtain a pH of 7-10.5 The ingredients were mixed in a Turmix, Turrax or a similar mixer. The resultant "coarse emulsion" was homogenized in an homogenizer of the type Moulin-Gaulin microfluidizer or the like. The emulsion obtained was sterilized in an autoclave at 120'C for 20 minutes.

Example 3 Ethyl esters of fatty acids obtained from animal or vegetable fat were mixed with phospholipids from eggs or soyabean oil and glycerol in the following proportions: Ethyl esters of fatty acids 100 g Phopholipids 12 g Glycerol 22.5 g These ingredients were thoroughly mixed in a Turmix or Turrax apparatus or like mixers. Sterile and pyrogen-free water was then added to the mixture to a total volume of 1000 ml. The emulsion obtained will be sterile, provided that the emulsion is prepared from sterile and pyrogenfree ingredients under aseptic conditions. When this is not the case, the emulsion can be heat sterilized. This methodology will provide an emulsion of desirable particle size.

WO 89/05638 PCT/SE88/00680 12 Example 4 Diazepam was dissolved in ethyl esters of fatty acids obtained from animal or vegetable fat, and an emulsion was prepared from the solution. The ingredients were used in the following proportions: Diazepam 0.5 g Ethyl ester 10 g Phospholipid from eggs 1.2 g Glycerol 2.25 g Sterile and pyrogen-free water to 100 ml Sodium hydroxide solution 1 M to pH 7-10.5 The emulsion was poured into bottles of desired volume and the emulsion then heat sterilized at 120'C.

The diazepam/ethyl-ester emulsion of this example was compared with a diazepam/soyabean emulsion with regard to creaming in vitro with plasma and serum derived from seriously ill patients under intensive care. The method by which creaming is determined is given in Swedish Patent Application No. 8505047-4 filed 25 October 1985. The results obtained are set forth in Tables 1 and 2 below. It will be seen from the results that the creaming activity decreased dramatically the creaming time had increased) when ethyl ester was used as the hydrophobic phase in diazepam-containing emulsions, instead of soy-oil.

Table 1.

Investigations concerning the creaminz of diazepam/ethylester emulsion and diazeoam/sov-oil emulsion.

The tests were carried out with serum deriving from patients under intensive care.

WO 89/05638 WO 89/05638PCT/SE88/00680 Patient Creaming times (hours) of diazepam emulsions containing: Sovoi. Ethyl ester 497 S-G ~499 H 486 H 501 H 505 S-G 498 H 499 H 500 H 502 S-G 506 S-G 488 K-G 415 S-G 503 S-G 507 S-G 414 S-G 496 S-C.

1/2 1/2 1/2 1 1 2 2 2 2 2 3 3 3 3 14 Table 2 7nvestizations concerning the creaming of diazepam/et-hvl ester emulsion and diazepam/sov-oil emulsion The tests were carried out with olasma deriving from patients under intensive care.

i i, I I- 14 Patient Creaming time (hours) of diazepam emulsion the hydrophobic part of which comprised: Soy-oil Ethyl ester 497 S-G 1/2 4 506 S-G 1/2 7 486 H 1/2 24 499 H 1/2 24 500 H 1/2 24 507 S-G 1 24 502 S-G 1 24 501 H 1 24 505 S-G 1 24 **488 K-S 2 24 494 S-G 2 24 a S 495 S-G 2 24 498 H 2 24 496 S-G 3 24 ea: 503 S-G 3 24 490 K-S 5 24 487 K- S 5 24 0. 491 S-G 6 24 Comparison of sleeping time (general anesthesia) in rat between diazepam in an ethyl ester emulsion made according to this example and regular diazepam in a soybean oil emulsion (DiazemulsR, Kabi, Stockholm, Sweden) has been performed. The results from this comparison (Study 110) are shown in Table 3.

14a Table 3. Sleeping time in rat after intravenous injection of diazepam according to this invention compared with that of conventional diazepam emulsion with soybean oil (Diazemuls The amount of diazepam injected was 35 mg per kg body weight.

Diazepam in ethyl ester Diazepam in soybean oil emulsion (Batch 369) emulsion (DiazemulsR, Kabi) Rat Sleeping time Rat Sleeping time No. Minutes No. Minutes 836 71 834 11 844 116 838 9 845 73 843 7 846 76 850 18 S847 95 851 848 93 852 14 855 81 854 11 Mean 86 Mean 12 SEM 6.1 SEM 1.4 The results show a very pronounced prolongation of the sleeping time (narcosis.) from 12 to 86 minutes by using the diazepam dissolved in the particles of an ethyl ester emulsion according to this invention. A prolongation of the sleeping time was also observed with other dosages of diazepam. This is not a synergistic effect, because emulsions of ethyl ester of fatty acid did not show any pharmacological properties in this respect. The ethyl esters obviously potentiate the effect of when administered intravenously.

1 4b Example An emulsion was prepared from the following ingredients: Pregnenolone Ethyl ester of fatty acids obtained from animal or vegetable fat Phospholipid from egg Glycerol T 0.

600 mg 20 g 1.2 g 2.5 g i Sterile and pyrogen-free water to a quantity of 100 ml Sodium hydroxide solution 1 M to pH 7-10.5 Homogenization was effected in the same manner as that described in Example 2. The emulsion was poured into bottles and heat sterilised at 1200C for 20 minutes.

The effect on sleeping time (general anesthesia) after intravenous injection of the pregnalonone emulsion made according to this example was investigated and compared with the effect of a pregnalonone emulsion made in the conventional way by using soybean oil. Each rat was injected with both emulsions. The interval between the injections were not less than 3 days. The results from one series of investigation (Study 144) are summarized in Table 4.

S

Table 4. Sleeping time in rat after intravenous injection of pregnalonone emulsion prepared according to this invention and example 5 compared with the effect of a soybean oil emulsion containing prenalonone. The dosage of pregnalonone was 5 mg per kg body weight.

Pregnalonone in ethyl Pregnalonone in ester emulsion soybean oil emulsion Rat Sleeping time Sleeping time No. Minutes Minutes S1138 30 21 1142 33 27 1143 30 18 1144 27 19 1145 36 24 1146 27 21 Mean 30.5 Mean 21.7 SEM 1.4 SEM 1.4 7/4 The results from this study show that the use of pregnalonone in an emulsion of ethyl esters of fatty acids will prolong the sleeping time or anesthesia with about in comparison with pregnalonone in an emulsion of soy bean oil.

Example 6 Iodized soyabean oil 30 ml Ethyl ester of fatty acid obtained from soyabean oil 10 ml Phenylalanine 0.2 g Phospholipid from eggs 2.0 g Glycerol 2.25 g Sterile and pyrogen-free water to an amount of 100 ml 15 Sodium hydroxide solution 1 M to pH 7.5-10 S. The mixture was homogenized in the same manner as that described in Example 2 and the emulsion was poured into bottles and then heat sterilized at 120 0 C for 20 minutes.

The particle size of the emulsion was determined in a conventional manner and found to lie between 0.15-0.20 micron.

p Example 7 ":'.Amphotericin B is an antifungal antibiotic. The substance is soluble in dimethyl acetamide and dimethylsulfoxide, but very difficult to dissolve in water and common organic solvents. An infusion suspension can be prepared with sodium deoxycholate. This suspension, however, is highly unstable and must therefore be used within 8 hours from the time of its preparation. It has now been found that a stable emulsion having the following composition can be 2 WO 89/05638 PCT/SE88/00680 prepared when ethyl ester from vegetable oil is used as a solution promotor.

Amphotericin B 75 mg Ethyl ester of fatty acids from soyabean oil 15 g Soyabean oil 22.5 g Phospholipid from eggs 3.37 g Glycerol 6.75 g Sterile and pyrogen-free water to an amount of 300 ml Sodium hydroxide solution 1 M to pH 7.5-10 The emulsion was prepared and sterilized in as that described in Example 2.

the same way Example 8 Perfluorodecalin (Flutec PP5 from ISC Chemicals Ltd.) 28 g Ethyl ester of fatty acids from soyabean oil 10 g PhospholiDid from eggs 1.2 g Glycerol 2.5 g Sterile and pyrogen-free water to an amount of 100 ml Sodium hydroxide solution 1 M to pH 7-10 The emulsion was prepared and sterilized in the same manner as that described in Example 2.

Claims (11)

1. A parenterally administrable emulsion comprising a hydrophobic phase as a vehicle for carrying pharmacologically active agent emulsified in an aqueous phase, one or more emulsifying agents in an amount sufficient to emulsify said hydrophobic phase in said aqueous phase, at least one lipophilic pharmacologically active agent being dissolved or dispersed in the hydrophobic phase in a pharmacologically effective amount, wherein said emulsifying agent comprises a phospholipid from eggs or soybeans, said emulsion has a particle size from 0.1 to 0.3 p.m, and said hydrophobic phase comprises one or more C2. 4 alkyl esters of pharmacologically acceptable C9- 2 2 fatty acids, and wherein the alkyl ester content of the emulsion is from 5 to 60% by weight.

2. An emulsion according to claim 1, characterized in that the alkyl esters are ethyl i esters. I

3. The emulsion according to claim 1 or claim 2 characterized in that the hydrophobic phase also includes glyceryl esters of fatty acids, the weight ratio of alkyl esters to glyceryl esters being from 10:1 to 1:10.

4. The emulsion according to any of claims 1 to 3, characterized in that the aqueous S* phase of the emulsion contains amino acids and/or glycerol, fructose, xylitol and/or sorbitol. S*

5. The emulsion according to any of claims 1 to 4, characterized in that the S pharmacologically active substance or substances are selected from the groups of active depressants, anaesthetics, analgesics, central stimulants, spasmolytics, muscle relaxing substances, substances which affect the cardiac and vascular system, such as vasodepressors, substances which affect the respiratory system, such as asthma agents, contrast substances for X-ray or NMRI investigations, antibiotics, cytostatics and chemotherapeutics.

6. The emulsion according to any of claims 1 to 5, characterized in that the emulsion has dissolved or dispersed in the alkyl esters at least one iodized fat, iodized fatty acid alkyl ester or perfluorocarbon compound in an amount of 1 to 60% by weight. S. S 18

7. The emulsion according to any of claims 1 to 6, characterized in that it contains alkyl esters of synthetic fatty acids or fatty acids produced in some other way having an even or an odd number of carbon atoms.

8. Method of preparation of a parenterally administrable pharmaceutical composition comprising preparation of an emulsion having an alkyl ester content of 5 to 60% by weight said emulsion consisting of a hydrophobic phase comprising one or more C2-4 alkyl esters of pharmacologically acceptable C9-22 fatty acids with a water phase wherein said emulsion comprises an emulsifying agent having a particle size from 0.1 to 0.3 pm. said emulsifying agent comprising a phospholipid from eggs or soybeans; in combination with a lipophilic pharmacologically active agent. DATED this 17th day of February, 1992. KABI P'IARMACIA AB WATERMARK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRAUA DBM:JJC AU002821489.WPC [DOC.02] L 1923 INTERNATIONAL SEARCH REP4, j International Avolication No PCT /SE88 /00680 1. CLASSIFICATION OF SUSJF' T MATTER (if several ciafiic3tion symooia sootly, indicate all) According to international Patentaaaosification (IPC) or to both National Classification and IPC 4 A 61 K 31/23, 9/10, 49/0 0 If. FIELDS SEARCHED Minimum Documentation Searched I Clasification System classification Svn~ools IPC 4 j A 61 K 31/20, 31/23, 37/22, 31/685, 9/10 us Cl 514:785, 546, 549, 943; 424:311, 312, 314, 365 260:410.9R Documentation Searched other than Minimum 0ocumnanitiion to the Extent tht such Documents are Inciudeo Ini the Fieds SearCflod 4 SE, NO, DK, FI classes as above Ill. DOCUMENTS CONSIDERED TO ME RELEVANT' Category Citation of Document," with Indication, where appropriate, of the relevant passens12' Rlevant to Claim No. 13 X FR, A, 2 553 661 (RHONE-POULENC SANTE) 1l-3, 8, 10, 11 26 April 1985 See especially page 9 and claims Y 4-7,

9 X DE, A, 3 409 793 (TERUMO KK) i1-3,6,8,10,11 September 1985 See especially page 5 and claims BE, 899184 FR, 2542613 JP, 59172416 GB, 2139889 SE, 8401393 X EP, 145 873 (TERUMO KK) 1-4, 10, 11 26 June 1985 See examples and claims BE, 901206 JP, 60130519 JP, 60222418 X Patent Abstract of' Japan, Vol.

10, No 107 (C-341) 1-3, 10,

11 JP, A, 60-237017 (NIHON KEIKINZOKU KK) November 1985, See abstract Special categories of cited documents; 10"T later document publiished after the International filing date "A document defling the general state of the art which Is not or priority date and not in conflict with the application but c nsdrdt eo atclrrelevance cited to underatand the prncipie or theory underiying the conaderd tobe f paticlarInvention iarlier document but published on or after the internationial document of particular relevance; the claimed Invention filing date cannot be considered novel or cannot be considered to document which may throw double on priority ciaim(a) or Involve an Inventive sto which to cited to establish, the publication date of another document of particular r~a.1vaffcs; the claimed Invention Citation or other special reason (as specified) cannot be considered to Involve an Inventive stop when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other meana menta. such combination being obvious to a person skliled document published prior to the interniational filing data but In the art. later than the priority date claimed "46" document member of the %ame patent family IV. CERTIFICATION Date of the Actual Completion of the International Search Date of 48 !IV a nnrnsonal Search Report

1989-02-21 International Searching Authority 31gnature of Authortzed Offier Swedish Patent Office Wiklas orslund Form PCT1ISA/2iO (second shoat) (January IS) x Form PCTIISA/21O (ex -7 Intarnational Aooication No. PCT/SESS /00680 Il11. DOCUMENTS CONSIDERED TO BE RELEVANT (CONTINUED FROM THE SECOND SHEET) -I *7:,qor CltaMo at Docugymen. with indkicacA wflwe W opwua 0± trwa rment passacles Relevant to Clairm No-I X US, A 3 198 70)4 (K N ROY) 3 A'.gust 1965 See whole document 11 US, A, 3 158 541 (L H SUTHERLAND ET AL) 2)4 November 1964 See whole document 1-11 Form PCT1ISA/21O (extra Shoot) (.Jamas' INS)