COMPOSITION OF PREGNANOLOLE COMPRISING A STABLE OIL-IN-WATER EMULSION

Abstract: A composition for intravenous administration of 3-alfa-hydroxy-­ 5-beta-pregnan-20-one (pregnanolone), comprising a stable oil-in-water emulsion, capable of being sterilized by auto­ claving, of from 0.1 to 1.0 g of pregnanolone.

Description: FIELD OF THE INVENTION The present invention relates to a novel pharmaceutical composition for intravenous administration comprising 3alfa-hydroxy-5beta-pregnan-20-one, in the following referred to as pregnanolone as active ingredient. BACKGROUND OF THE INVENTION It has long been known that a number of steroids have pharmacological effects as anaesthetics. Reference is made e g to Selye, Anaesthetic effects of steroid hormones, Proc Soc Exp Biol Med Vol 46, 116-121 (1941). However, many such components which have been tested have proved to suffer from undesirable properties causing side effects which have prevented clinical use of the steroids studied. The solubility characteristics of such compounds have caused problems which have proved difficult to overcome. In particular, many of these compounds are highly lipophilic, which has contributed greatly to the problems in preparing stable, clinically useful formulations for intravenous use. The anaesthetic properties of pregnanolone were first described by Figdor et al, Central activity and structure in a series of water-soluble steroids, J Pharm Exp Therap Vol 119, 299-309 (1957). In this paper, the aim was to overcome the administration-detoxification problem of the known steroids with anaesthetic activity by conversion to water-soluble ester derivatives, which thus would be suitable for intravenous administration (Figdor et al loc cit p 300). The substances were tested in aqueous suspension containing methyl cellulose as suspending agent. However, the results were not successful. Gyermek, in his paper "Pregnanolone: A Highly Potent, Naturally Occurring Hypnotic-Anaesthetic Agent" Proc Soc Exp Biol Med Vol 125, 1058-1062 (1967) described animal studies using pregnanolone dissolved in propylene glycol. Since such preparations are not suitable for clinical use, no suggestions are given how to solve the problem of obtaining pregnanolone in a clinically acceptable and stable administration formula. Three steroids have been used clinically as anaesthetics, but none of these is currently being used. The compound 21-hydroxypregnan-3,20-dione, also known as hydroxydione and under the trade name Viadril, was introduced in 1955. Reference is made to Laubach et al, Steroid anaesthetic agent, Science Vol 122, 78 (1955). Because of several disadvantages it was withdrawn. The compound 3alfa-hydroxy-5alfa-pregnan-11,20-dione, was put on the market under the trade name Althesin. Reference is made to Atkinson et al, Action of some steroids on the central nervous system of the mouse, J Med Chem Vol 8, 426-432 (1965), and to British patent specifications 1317184 and 1379730. This substance was brought into solution by adding the less active 21-acetate and a co-solvent, a non-ionic surface active polyoxyethylated castor oil available under the trade name Cremophor-EL. Also this steroid product was, however, withdrawn because of serious side effects. The third steroid anaesthetic product, minaxolone, was subjected to clinical evaluation in 1979. It was withdrawn because of problems with its toxicology profile. In summary, the original screening studies in experimental animals, from which studies the animals were not allowed to survive were carried out using three types of pharmaceutical formulations: 1. ex tempore solutions in warm peanut or sesame oil which were injected as supersaturated solutions after being cooled to body temperature and sometimes containing a precipitate of crystalline material. 2. ex tempore aqueous suspensions prepared in roller mills with cellulose derivatives as thickening agents, 3. solutions in tissue irritating propylene glycol. The exploratory synthetic chemistry which followed these studies was directed towards derivatives such as acetates, semisuccinates having higher water solubility than the parent compounds and also having the ability to form sodium salts. These derivatives must be hydrolysed by the body before exerting the clinical effect, giving an unacceptable slow onset of action. As described above this direction of research did not result in clilnically acceptable formulations. There is accordingly a great need for a clinically useful effective steroid anaesthetic product which can be brought into an administration forumla which is stable and suitable for intravenous administration. The present invention provides such a composition comprising an emulsion of pregnanolone. Emulsions containing pharmaceutical active ingredients have earlier been disclosed. US 3 917 830 discloses a composition for use by injection as an anaesthetic comprising 3 ∂-hydroxy 5∂-pregnane - 11,20 dione in solution in an inert organic liquid medium. The composition may be in the form of a solution which also contains water, a non-aqueous solution or an emulsion or microemulsion. US 4 340 594 discloses a fat emulsion containing a steroid having an anti-inflammatory activity. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel, clinically useful and phamaceutically acceptable composition for intravenous administration comprising pregnanolone as active ingredient. The novel composition is capable of withstanding sterilization by autoclaving, which is an important advantage. The novel compositions of the invention comprise in a general sense, pregnanolone in an amount of from 0.1 to 1.0 g per 100 ml in a lipid oil-in-water emulsion, where the active substance is substantially dissolved in the oil phase. More particularly, the novel emulsion of the invention comprises: a) pregnanolone in an amount of from 0.1 to 1.0 per 100 ml of the final composition b) a lipoid in an amount of from 10 to 30 g per 100 ml of the final composition, said lipoid being selected from coconut oil, borago oil, safflor oil, cotton seed oil, soybean oil, and synthetic-type structured glyceride lipid which contains a mix of long chain and medium chain fatty acids in the molecule c) an emulsifying agent in an amount of from 1 to 5 g per 100 ml of the final composition, said emulsifying agent being selected from egg yolk phospholipids and soya phospholipids d) water for injection e) glycerol to isotonicity of the final composition. If desired, also the following components may be added: f) acetylated monoglycerides in an amount of from 0 to 20, preferably from 5 to 10, g per 100 ml of the final composition g) cholesterylhemisuccinate, in an amount of from 0.01 to 0.2 g per 100 ml of the final compostion. The amount of pregnanolone is preferably from 0.3 to 0.8 and principally from 0.4 to 0.5 g per 100 ml of the final composition. The amount of lipoid is preferably from 15 to 20 g per 100 ml of the final composition. The lipoid is pharmacologically inert. The amount of actetylated monoglycerides, if present, is preferably from 5 to 10 g per 100 ml of the final composition. The amount of glycerol is such as to give an isotonic final composition, which means an amount of from 1.0 to 2.5 g glycerol per 100 ml of the final composition. For preparing the novel oil-in-water emulsion of present invention, it is suitable to dissolve, in a first step, the active substance, pregnanolone, in the lipoid. The resulting solution is then emulsified by means of conventionally used high pressure homogenizers, in an aqueous medium comprising water for injection, emulsifying agent, and glycerol as specified above and, if desired, acetylated monoglycerides and cholesterylhemisuccinate. In the resulting emulsion, the particle size of the oil droplets will be less than 5 µ, with a large part less than 1 µ. The average size of the oil droplets will be less than 1 µ, preferably from 0.2 to 0.3 µ. The novel, intravenously injectable, composition of the invention will accordingly essentially comprise a solution of pregnanolone in the lipoid component as hydrophobic phase, which hydrophobic phase is emulsified in a hydrophilic phase. The composition of the invention is further illustrated by the following examples: Example 1 An oil-in-water emulsion of pregnanolone was prepared from the following components: pH was adjusted to 7.7 with 1 M sodium hydroxide. In a first step, pregnanolone was mixed with the soybean oil, resulting in substantial dissolution therein. An emulsion was then prepared from the resulting pregnanolone-soybean oil composition, together with the additional indicated components. The resulting emulsion was stable and had an average particle size of from 0.2 to 0.3 µ and could be sterilized by autoclaving without decomposition. Example 2 - 4 An oil-in-water emulsion of pregnanolone was prepared as described in Example 1 with the following components: Example 5 An oil-in-water emulsion of pregnanolone according to Example 2 was prepared with the difference that 0.05 g cholesterylhemisuccinate per 100 ml of the final composition was also included in the emulsion. Example 6 An oil-in-water emulsion of pregnanolone according to Example 1 was prepared with the following components: Example 7 An oil-in water emulsion of pregnanolone was prepared as described in Example 1 with the following components: Example 8 An oil-in-water emulsion of pregnanolone according to Example 7 was prepared with the difference that 0.05 g cholesterylhemisuccinate per 100 ml of the final composition was also included in the emulsion. Example 9 An oil-in-water emulsion of pregnanolone was prepared as described in Example 1 with the following components: Example 10 An oil-in-water emulsion of pregnanolone was prepared as described in Example 1 with the following components: Example 11 An oil-in-water emulsion of pregnanolone according to Example 10 was prepared with the difference that no acetylated monoglycerides were included in the emulsion. The emulsions according to examples 2 - 11 were stable and had an average particle size as obtained according to Example 1 and could withstand sterilization by autoclaving. Upon intravenous administration to test animals, they produced the desired anaesthetic effect without giving rise to any serious side effects.

Claims: Claims for the following Contracting States: DE, FR, GB, IT and SE A composition for intravenous administration of 3alfa-hydroxy-5beta-pregnan-20-one (pregnanolone), comprising, calculated per 100 ml of the final composition, a stable oil-in-water emulsion, capable of being sterilized by autoclaving, of from 0.1 to 1.0 g of pregnanolone, with the proviso that the amount of 0,5 g is excluded. A composition according to claim 1, comprising, calculated per 100 ml of the final composition: a) pregnanolone in an amount of from 0.1 to 1.0 g b) a lipoid in an amount of from 10 to 30 g, selected from the group consisting of coconut oil, borago oil, safflor oil, cotton seed oil, soybean oil, and synthetic-type structured glyceride lipid which contains a mix of long chain and medium chain fatty acids in the molecule c) an emulsifying agent in an amount of from 1 to 5 g, selected from egg yolk phospholipids and soya phospholipids d) water for injection e) glycerol to isotonicity of the final composition. A composition according to claim 2, further comprising acetylated monoglycerides in an amount of from 0 to 20 g. A composition according to claim 3, further comprising cholesterylhemisuccinate in an amount of from 0.01 to 0.2 g. A composition according to any of claims 1 - 4, comprising, calculated per 100 ml of the final composition: a) pregnanolone in an amount of from 0.4 to 0.5 g b) soybean oil in an amount of from 15 to 20 g c) water for injection d) glycerol to isotonicity of the final composition. A process for the preparation of a composition for intravenous administration of pregnanolone, characterized in that an oil-in-water emulsion is prepared from the following components, calculated per 100 ml of the final composition: a) pregnanolone in an amount of from 0.1 to 1.0 g, with the proviso that the amount of 0,5 g is excluded. b) a lipoid in an amount of from 10 to 30 g, selected from the group consisting of coconut oil, borago oil, safflor oil, cotton seed oil, soybean oil. and synthetic-type structured glyceride lipid which contains a mix of long chain and medium chain fatty acids in the molecule c) an emulsifying agent in an amount of from 1 to 5 g, selected from egg yolk phospholipids and soya phospholipids d) water for injection e) glycerol to isotonicity of the final composition, whereby component a) is substantially dissolved in component b) and the resulting preganolone-lipoid composition then is emulsified with components c), d) and e). Use of a composition according to any of claims 1 - 5 for the manufacture of a medicament for anaesthetizing a patient by intravenous administration. An oil-in-water emulsion of pregnanolone according to any of claims 1 - 5 for use in obtaining anaesthesia in a patient. Claims for the following Contracting States: BE, CH, LI, LU, NL. A composition for intravenous administration of 3alfa-hydroxy-5beta-pregnan-20-one (pregnanolone), comprising, calculated per 100 ml of the final composition, a stable oil-in-water emulsion, capable of being sterilized by autoclaving, of from 0.1 to 1.0 g of pregnanolone. A composition according to claim 1, comprising, calculated per 100 ml of the final composition: a) pregnanolone in an amount of from 0.1 to 1.0 g b) a lipoid in an amount of from 10 to 30 g, selected from the group consisting of coconut oil, borago oil, safflor oil, cotton seed oil, soybean oil, and synthetic-type structured glyceride lipid which contains a mix of long chain and medium chain fatty acids in the molecule c) an emulsifying agent in an amount of from 1 to 5 g, selected from egg yolk phospholipids and soya phospholipids d) water for injection e) glycerol to isotonicity of the final composition. A composition according to claim 2, further comprising acetylated monoglycerides in an amount of from 0 to 20 g. A composition according to claim 3, further comprising cholesterylhemisuccinate in an amount of from 0.01 to 0.2 g. A composition according to any of claims 1 - 4, comprising, calculated per 100 ml of the final composition: a) pregnanolone in an amount of from 0.4 to 0.5 g b) soybean oil in an amount of from 15 to 20 g c) water for injection d) glycerol to isotonicity of the final composition. A process for the preparation of a composition for intravenous administration of pregnanolone, characterized in that an oil-in-water emulsion is prepared from the following components, calculated per 100 ml of the final composition: a) pregnanolone in an amount of from 0.1 to 1.0 g b) a lipoid in an amount of from 10 to 30 g, selected from the group consisting of coconut oil, borago oil, safflor oil, cotton seed oil, soybean oil. and synthetic-type structured glyceride lipid which contains a mix of long chain and medium chain fatty acids in the molecule c) an emulsifying agent in an amount of from 1 to 5 g, selected from egg yolk phospholipids and soya phospholipids d) water for injection e) glycerol to isotonicity of the final composition, whereby component a) is substantially dissolved in component b) and the resulting preganolone-lipoid composition then is emulsified with components c), d) and e). Use of a composition according to any of claims 1 - 5 for the manufacture of a medicament for anaesthetizing a patient by intravenous administration. An oil-in-water emulsion of pregnanolone according to any of claims 1 - 5 for use in obtaining anaesthesia in a patient. Claims for the following Contracting States: AT, GR. A process for the preparation of a composition for intravenous administration of 3 alfa-hydroxy-5beta-pregnan-20-one (pregnanolone), characterized in that an oil-in-water emulsion, capable of being sterilized by autoclaving, is prepared from the following components, calculated per 100 ml of the final composition: a) pregnanolone in an amount of from 0.1 to 1.0 g b) a lipoid in an amount of from 10 to 30 g, selected from the group consisting of coconut oil, borago oil, safflor oil, cotton seed oil, soybean oil and synthetic-type strucutred glyceride lipid which contains a mix of long chain and medium chain fatty acids in the molecule c) an emulsifying agent in an amount of from 1 to 5 g, selected from egg yolk phospholipids and soya phospholipids d) water for injection e) glycerol to isotonicity of the final composition whereby component a) is substantially dissolved in component b) and the resulting pregnanolone-lipoid compostion then is emulsified with components c), d) and e). A process according to claim 1, characterized in that the emulsion further comprises acetylated monoglycerides in an amount of from 0 to 20 g. A process according to claim 2, characterized in that the emulsion further comprises cholesterylhemisuccinate in an amount of from 0.01 to 0.2 g. A process according to any of claims 1 - 3, characterized in that the emulsion comprises, calculated per 100 ml of the final composition: a) pregnanolone in an amount of from 0.4 to 0.5 g b) soybean oil in amount of from 15 to 20 g c) water for injection d) glycerol to isotonicity of the final composition. Use of a composition prepared according to any of claims 1 - 4 for the manufacture of a medicament for anaesthetizing a patient by intravenous administration. Claims for the following Contracting State: ES. A process for the preparation of a composition for intravenous administration of 3 alfa-hydroxy-5beta-pregnan-20-one (pregnanolone), characterized in that an oil-in-water emulsion, capable of being sterilized by autoclaving, is prepared from the following components, calculated per 100 ml of the final composition: a) pregnanolone in an amount of from 0.1 to 1.0 g, with the proviso that the amount of 0.5 g is excluded b) a lipoid in an amount of from 10 to 30 g, selected from the group consisting of coconut oil, borago oil, safflor oil, cotton seed oil, soybean oil and synthetic-type strucutred glyceride lipid which contains a mix of long chain and medium chain fatty acids in the molecule c) an emulsifying agent in an amount of from 1 to 5 g, selected from egg yolk phospholipids and soya phospholipids d) water for injection e) glycerol to isotonicity of the final composition whereby component a) is substantially dissolved in component b) and the resulting pregnanolone-lipoid composition then is emulsified with components c), d) and e). A process according to claim 1, characterized in that the emulsion further comprises acetylated monoglycerides in an amount of from 0 to 20 g. A process according to claim 2, characterized in that the emulsion further comprises cholesterylhemisuccinate in an amount of from 0.01 to 0.2 g. A process according to any of claims 1 - 3, characterized in that the emulsion comprises, calculated per 100 ml of the final composition: a) pregnanolone in an amount of from 0.4 to 0.5 g b) soybean oil in amount of from 15 to 20 g c) water for injection d) glycerol to isotonicity of the final composition. Use of a composition prepared according to any of claims 1 - 4 for the manufacture of a medicament for anaesthetizing a patient by intravenous administration.

Inventors: JEPPSSON, ROLAND INGOLF
Applicants: KABI PHARMACIA AB
Application year: 1987
Main classification: A61K9
IPC codes: A61K31, A61P23, A61K9