DE2162593A1 - Medicinal compositions containing 3 alpha-hydroxy-5-alpha-pregnane-11,20-dione - Google Patents

Description

Dr. F. Zumstein Sr. - Dr. E. Assmann Dr. R. Koenii; sborc | er - Dipl. Phys. R. Holzbauer

LV. F. Hnir.-ioin j'sn ..

Patent attorneys

8 Munich 2, Bräuhausstraße 4 / III

14 / af
"Anesthetics 10"

GLAXO LABORATORIES LTD., A British Company of

Greenford, Middlesex, England

Medicinal compositions containing 2a-hydroxy-5a-pregnane-11,20-dione

The present invention relates to pharmaceutical compositions with anesthetic effectiveness.

It has long been known that many steroids are one effective central nervous system depression and act pharmacodynamically as anesthetics or sleep aids. Such compounds have been studied in a variety of ways in order to find anesthetics with which one substances how to replace thiopentone sodium, which are normally used, but to some extent in their use

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dung are accompanied by difficulties and disadvantages. From the It can be seen from the literature that a great many steroid compounds have been studied in this regard. Summaries and Discussions of the work carried out are for example in ■ "., · -. "Methods in Hormone Research" (edited by Ralph I. Dorfman, Volume III, Part A, Academic Press, London and New York 1964, pages 415-475) i H. Witzel, "Z. Vitamin Hormon-Fermentr forscht '1959, JO, pages 46-74; H. Selye, "Endocrinology" 1942, 30, pages 437-453 »S-K. Figdor et al., "J. Pharmacol. Exptl. Therap. "1957, JJL9, pp. 299-309 and Atkinson et al.," J. Med. * Chem. "1965, 8, pages 426-432.

A review of the literature indicates that it is anesthetic effective steroids generally have poor potency and / or long induction times. With such connections A large number of undesirable side effects such as paresthesia and venous damage were found.

Many steroid compounds having anesthetic activity have low solubility at the same time, and so it has been So far a lot of research has been done on the introduction of solubilizing agents Groups in such steroids e.g. through the formation of partial esters with di- or polybasic acids directed. However, such a work has so far not been the case Discovery of a satisfactory anesthetic steroid compound guided. Anesthetic steroids are generally relatively simple pregnane derivatives, often in the 3-position are hydroxylated, with the result that in the latter case, 3ß-hydroxy compounds are generally preferred over 3 <x -hydroxy compounds, were examined.

In the German patent specification (German patent application P 20 30 4Ö2.3 by the same applicant), 'anesthetic'

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Compositions described which contain as essential anesthetic component 3 <x-hydroxy-5a-pregnane-11,20-dione. As in the above-mentioned patent, this substance has very valuable properties in human and veterinary medicine as an anesthetic and thus induces the anesthesia and has short induction periods, the anesthetic Effect is actually instantaneous at appropriate doses. The solutions are thus excellent anesthetics for the induction of anesthesia, e.g. by inhalation of an anesthetic like ether, halothane, nitrous oxide and trichlorethylene shall be. However, the solutions are also able to treat anesthesia and analgesia in a sufficient amount Maintain mass, allowing various surgical operations to be inhaled without the aid of an anesthetic can be performed and with the required level of anesthesia by repeated administration if necessary (or by continuous administration) can be maintained. The return from anesthesia (if this was induced only by solutions of the above-mentioned earlier patent) is excellent, whereby the patient feels a sense of well-being as opposed to that of malaise according to the effects generally associated with conventional Anesthetics are associated shows. In addition, the aforementioned anesthetic solutions generally do not cause undesirable Side effects that used to be apparent with steroid anesthetics occurred. The compositions of the above patent are aqueous solutions containing 3a-hydroxy-5a-pregnane-11,20-dione contain.

According to the present invention, it was found that 3a-hydroxy-5a-pregnane-11,20-dione has good solubility in a wide variety of organic liquids. This discovery made it possible Compositions based on or derived from solutions of said steroid in organic liquids

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to formulate. It was also found that the solubility of the said steroid (3cc-hydroxy-5a-pregnan-11,20-dione, referred to below under the name "steroid i" becomes) in organic liquids and especially in oils and liquids of an oily nature very significantly by the Presence of steroids of the general formula

II

HO '

CH ₂ OR C = O

is increased [where R is an alkanoyl group with a straight or branched chain (with e.g. 2-4 carbon atoms, which if desired substituted e.g. by a carboxyl group may be) or an unsubstituted or substituted aroyl or aralkanoyl group].

In the following, for the sake of simplicity, reference is made to a steroid of the general formula II under the designation “steroid II” in the description. Steroids II, which show a remarkable solubility-increasing effect with respect to steroid I in organic solvents and in particular in oils and liquids of an oily nature, include in particular compounds of the above general formula II in which the group R is acetyl, propionyl, iso- 3-butyryl -, hemisuccinyl or benzoyl group. The 21-acetoxy compound (R = acetyl) is

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_ 5 -

solubility promoters according to the invention are particularly suitable.

According to the present invention, a composition is provided, those for medical use by injection in the form of an anesthetic, the 3oc-hydroxy-5cc ~ pregnan-11,20-dione contains in solution in an inert organic liquid injection medium, is suitable.

The term "inert organic liquid injection medium" as used herein means an organic liquid containing a Solvent for the steroid substances used according to the invention is, which is suitable for parenteral injection in medicine, the opposite of the mentioned steroid substances is inert and which acts essentially as a liquid injection vehicle for the steroid, being the predominant Component represents. The organic solution according to the invention can additionally contain water, however Of course, in these cases the organic liquid will make up the vast majority (i.e. more than $ 50) of the total Injection vehicle will make up.

It goes without saying that the inert organic liquid injection medium becomes preferably be non-volatile and thus have a boiling point higher than 80 ° C for practical purposes.

The composition according to the invention falls under four categories, which broadly as aqueous organic solutions and non-aqueous organic solutions along with emulsions and microemulsions can be described. In the latter two cases, the composition contains the above-mentioned organic Solution along with additional water.

Aqueous organic solutions

The steroid I can be used in certain parenterally suitable aqueous

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Solutions of an inert organic liquid medium are dissolved e.g. in aqueous solutions with lower di- and polyvalent values Alcohols e.g. with two or three hydroxyl groups and 1-6 carbon atoms, such as propylene glycol and glycerine (which are in the form their formals may be present), water-soluble esters such as esters of an α-hydroxycarboxylic acid and an alcohol with 1-6 carbon atoms such as ethyl lactate and water-soluble amides e.g. amides of aromatic carboxylic acids with a ring nitrogen atom or N- (ß-hydroxyethyl) lactamide. Enlarged in such solutions the additional presence of steroid II significantly P the soluble amount of steroid I.

The concentration of steroid I in the aqueous organic solutions is preferably within the range of 0.1-4 wt -.%, And, when the steroid is present II, of 0.5-10 wt -.% Steroid I, wherein the preferred weight ratios from Steroid II to Steroid I are within the range of 1:20 to 1: 1 in terms of weight.

The aqueous organic solutions can be prepared by dissolving the steroid (s) in an aqueous solution of the inert organic liquid medium. For a quicker resolution, the steroid (s) can preferably be stored in Ψ

a volatile organic solvent, preferably with a boiling point of less than about 80 ° C, which with Water is miscible, can be dissolved, and the inert organic liquid medium selected can be a volatile lower aliphatic Ketone e.g. with 1-6 carbon atoms such as acetone or methyl ethyl ketone or volatile halogenated hydrocarbons such as chloroform or methylene chloride. The organic medium is then added. The volatile solvent can then removed by evaporation, e.g. by passing a stream of an inert gas through the solution, e.g. nitrogen, and then add water.

* or an α-hydroxycarboxylic acid, such as nicotinic acid amide

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Solvents such as lower aliphatic ketones and volatile halogenated hydrocarbons such as chloroform and methylene chloride are of course unsuitable for parenteral injection and are therefore to be distinguished from liquids that can be used as an inert organic injection medium for the purposes of the invention.

Non-aqueous organic solutions

Inert organic liquid media that have been found to be particularly suitable carriers for preparing solutions of the steroid I include lipophilic solvents such as oils (this term is used to describe liquids that have the physical characteristics of oils, regardless of their chemical constitution) for example higher aliphatic alcohols having, for example, 10-15 carbon atoms and alkanoyl (C _1-10 ) esters thereof; Esters, in particular mono-, di- and triglyceride esters, and alkyl (eg ^^ ~ esters of higher fatty acids with, for example, 12-18 carbon atoms and hydrocarbon oils such as liquid paraffin or squalene (squalane). Particular examples of oils which can be considered according to the invention include in particular vegetable oils, for example coconut oil, castor oil, corn oil, peanut oil, soybean oil and cottonseed oil, esters such as ethyl or n-octyl oleate, isopropyl or tridecyl myristate and isopropyl palmitate / rt-dodecane and n-hexadecane.

Solutions in oils can be prepared with 0.1 to 5 wt. % Steroid I and, if Steroid II is present, from 0.3 to 25 wt.% Steroid I. The preferred weight ratios of Steroid II to Steroid I are for example within the range from 1:20 to 1: 1.

It should be noted, however, that according to this aspect, the present invention also solutions in the absence of water,

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aqueous emulsions and microemulsions can be produced. However, in such emulsions it is the effective steroid in solutions in the organic phase. For the purpose of the invention, such emulsions and microemulsions are as Consider organic solutions of the steroid that are emulsified with water.

The oil emulsions according to the invention are not general for intravenous injections applicable but can be injected intramuscularly.

The non-aqueous solutions can be prepared by dissolving the active steroid (s) in the selected inert organic liquid medium. However, in order to speed the resolution, it is preferred to put the steroid in one first volatile solvent which is miscible with the selected medium, e.g. a low one (e.g. with 1-6 carbon atoms) aliphatic ketone such as acetone or methyl ethyl ketone or a halogenated hydrocarbon such as chloroform or methylene chloride. Acetone is preferred. The initial one Solution can then be added to the inert organic liquid medium and the volatile solvent, e.g. Evaporation, such as by bubbling a stream of an inert gas such as nitrogen through the solution.

Emulsions

Emulsions according to the invention can be in a generally conventional Alternatively, they can be prepared using a parenterally suitable surface-active component. The surface-active Component must of course be one that is physiologically appropriate for the species to be treated (humans or animals) is tolerated, i.e. it should not have any physiologically undesirable side effects even at the dosages used cause.

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Generally, the surfactant component will have an HLB of at least 9, but preferably below 15. The surfactant component can be a mixture of two or more individual surfactants as described below. The surface-active component preferably has an HLB value of no greater than 30.

Particularly suitable surface-active agents are those which carry a polyoxyethylene group, such as: polyoxyethylated derivatives of fatty (C ₁₂ -C ₂₀ ) glyceride oils, e.g. castor oil, preferably with at least 35 (e.g. 35 to 45 or 60 or more) oxyethylene groups per mole . fatty oil. Polyoxyethylene ethers (with 10 to 30 oxyethylene groups) of long-chain alcohols (with, for example, 12-18 carbon atoms).

Polyoxyethylene-polyoxypropylene-ether preferably with 5 to (e.g. 15-150) and from 15 to 50 oxyethylene and oxypropylene groups each. Polyoxyethylene ether (with 6 to 12 oxyethylene groups) of alkylphenols, the alkyl groups of which preferably contain 6-10 carbon atoms.

Polyoxyethylated (preferably with 15 to 30 oxyethylene groups) Fatty acid (e.g. C-io-ir) esters of sugar alcohol anhydrides e.g. sorbitan or mannitan.

Polyethylene glycol ester (preferably with 6 to 40 ethylene oxide units) of long-chain fatty acids (with e.g. 12-18 carbon atoms) e.g. polyethylene glycol mono-oleate (preferably with, for example, 8 ethylene oxide units).

Long-chain (for example C _10-1 / -) alkanoyl mono- and dialkanolamides (the alkanol parts of which contain, for example, 1-5 carbon atoms), for example lauroyl mono- and bethanolamides, are particularly suitable.

209828 / T105

216-593

Other suitable surfactants include phospholipids such as lecithins, e.g., egg or soybean lecithins, the have proven to be particularly suitable.

Examples of non-ionic surfactants dev aforementioned type which the present invention are preferably in accordance with a sehliessen:

Cremophor EL, a polyoxyethylated castor oil with about 40 Ethylene oxide units per triglyceride unit;

Tween 8o, polyoxyethylene sorbitan mono-oleate with about 20 ethylene oxide units;

Tween 6o, polyoxyethylene sorbitan monostearate with about 20 ethylene oxide units en;

Tween 40, polyoxyethylene sorbitan monopalmitate with about 20 ethylene oxide units.

Pluronic P68, a block copolymer of ethylene oxide and propylene oxide with about 150 oxyethylene and about 40 oxypropylene units.

Pluronic L81, a block copolymer of ethylene oxide and propylene oxide with about 6 oxyethylene and about 40 oxypropylene units; and

Pluronic P77 »a block copolymer of ethylene oxide and propylene oxide with about 155 oxyethylene and about 35 oxypropylene units.

In addition to the emulsifying agent, an emulsion-stabilizing agent can be used Agent be present, such as a parenterally suitable surfactant of comparably low HLB value e.g.% on an HLB value within the range 3-8, e.g. glyceryl monostearate, mannitan or sorbitan mono-oleate (Arlacel A or 80); or * a higher alcohol (e.g. with 12-18 carbon atoms) as is usually used for this purpose

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e.g. cetyl alcohol is used.

The inert organic liquid medium which is used for the preparation of the emulsions according to the invention can in general a water-immiscible member of the class of those above in connection with the non-aqueous organic solutions described type.

Emulsions made from steroid I and steroid II in oil-in-water systems in which the inert organic liquid medium is a coconut oil, castor oil, corn oil, peanut oil, Soybean oil or cottonseed oil, or liquids like one liquid paraffin, squalene and higher esters (e.g. with 12-18 Carbon atoms) fatty acids such as ethyl oleate and isopropyl myristate or palmitate are particularly preferred.

The emulsions can contain, for example, 5 to 50% by weight of oil, preferably 10-20%. The amount of the surface-active component present can be within the range from 0.1 to 5 * 0% by weight , preferably from 0.2 to 3.0% by weight.

In the emulsions according to the invention, the concentration of steroid I is preferably within the range of 0.1-2.5 $ and, when Steroid II is present, Steroid I is preferably within the range of $ 0.3-12. The relative weight ratios of steroid II to steroid I are preferred within the range from 1:20 to 1: 1.

The droplet size of the emulsion is preferably less than (5 X ^ m) *, in particular less than 1 ^ u. to avoid embolism during intravenous injection and to ensure the physical stability of the emulsion.

The emulsions can generally be made according to the conventional one

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Kind of administered. It is usually beneficial to have a solution of the steroid in the inert organic liquid medium according to that described above for the non-aqueous organic solutions Method to form. This oily liquid can then with the surfactant and water e.g. Homogenization or sonication can be emulsified.

Microemulsions

The term "microemulsions" is used herein to mean optical. clear emulsions to define the water along with an oil contained as an inert organic liquid medium, the liquid being contained by a surface-active agent in the form of a continuous aqueous dispersion medium and wherein the system is actually optically clear when in transmitted light is viewed. Such microemulsions are different from emulsions or suspensions that are cloudy or are opaque, if not additional components! how thickeners are added, which in turn are added to the microemulsions Give opacity.

Optically clear microemulsions such as those according to the invention are used, include all colloidal solutions in which particles or droplets of the dispersion phase one

Have a diameter of less than 000 Å and therefore not a considerable one Cause more opacity in visible light. The size of the particles is generally in the range of approximately 50-800 A, as opposed to normal or macro emulsions, in which the average droplet size is seldom less than 500 Å. The necessary conditions for Formation of microemulsions are such that the resulting system is thermodynamically stable, in contrast to macroemulsions, which are necessarily thermodynamically unstable, although even the equilibrium conditions for the phase separation can be significantly displaced (L.I. Osipow, "J. Soc.

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Cosmetic Chem. "1913, Jj> pages 277-288; LM Prince, ¹¹ J. Colloid and Interface Science", 1967, j? 3, pages 165-173).

The microemulsions, which are generally optically clear solutions' are, are not only more pleasing in their appearance than emulsions or suspensions, but also have a manufacturing aspect Advantages. They are far easier to sterilize, and the preparations are generally more than one through the Shocks caused by transport and more stable to temperature changes during storage. You can get through it quickly simple mixing of the components without energetic homogenization getting produced.

Surprisingly, considerable amounts can be used, for example in the order of magnitude of ^J \ 2% w / v. or more of steroid I, in particular when steroid II is present, can be incorporated into the microemulsions according to the invention.

When using Steroid I without Steroid II it is difficult to get more than 0.1-0.6 wt .- ^ of the steroid, but when a steroid II is introduced, the proportion of steroid I can be increased substantially, e.g., in that area from $ 0.3 - $ 12. Preferably the ratio is steroid II to steroid I within the range of 1:20 to 1: 1.

The amount of steroid that is in the microemulsions of the invention can be introduced will depend in each case on the components present, in particular on the surface-active ones Means.

As has already been recognized by those skilled in the art, it is necessary to that, with regard to the very small radius of curvature, the carrier has a surface disordering agent) should contain. Such surface-destroying

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remedies are usually ambivalent (araphiphilic) Substances of lower chain length than the actual surfactant, and one. can imagine that these exert a "lubricating" effect by being between the long ambivalent ones (amphiphilic) molecules of the actual surface-active Push in by means.

It should be noted that many are nonionic surfactants Agents that are commercially available contain components with a relatively short chain such as alcohols, which enables are to react as a surface-destroying agent without the addition of any other material that has this effect.

Such. ambivalent agents that destroy the surface include physiologically suitable long-chain alcohols, preferably with at least 12 (e.g. 12-i8) carbon atoms and polyethylene glycols with a molecular weight higher than 4000 a.

The weight ratio of added surface destroying Agent to the entire actual surface-active agent, which is advantageously applied to transparent stable Obtaining solutions is very dependent on the temperature range at which clarity is required. The amount depends that is, on the nature of the inert organic liquid medium and other surfactants used. Pure the Mixtures preferred according to the invention have been found that the percentage of total surfactant to allow clarity at body temperature, advantageously 5-6O; £, preferably 10-15 $. It can be noted that the minimum amount of actual surfactant that is required to make a clear solution produce, often lower, if a the surface

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destructive agent is present.

The inert one used in the emulsions according to the invention Organic liquid medium can generally be a water-immiscible member of the class described above in connection with the non-aqueous organic solutions.

The inert organic liquid medium can be, for example, an oil which is a liquid at body temperature. In general, however, the liquid component is preferably liquid at 35 ° C, more preferably at room temperature and below so as to facilitate the handling of injectable preparations.

The liquid medium can be a lipophilic material such as an aliphatic hydrocarbon, including branched-chain and cycloaliphatic hydrocarbons or mixtures thereof, for example ri-dodecane or n-hexadecane. Purified paraffin oil and saualen are particularly suitable examples of this class. Other lipophilic materials include synthetic or natural long chain esters or mixtures thereof such as isopropyl myristate, tridecyl myristate, n-octyl oleate, or vegetable oils such as coconut oil, castor oil, peanut oil, soybean oil or cottonseed oil.

The ones according to the invention used for the preparation of the microemulsions Surfactants can generally be the same as those above for use in manufacture of the emulsions according to the invention have been described.

When the lipophilic material is an ester or a straight or branched chain aliphatic hydrocarbon such as paraffin oil or squalene, the surfactant preferably has an HLB (hydrophile-lipophile balance) value of at least 9> preferably less than 15, preferably between 9 and 11. It should be reiterated that if a

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Mixture of surfactants is used, it is the resulting HLB value of the mixture (i.e. the "surfactant Components "), which should fall within the above range.

The preferred surfactants are as follows five classes:

1. Fatty acid ( e.g. C. ~ .q) esters of sugar alcohol anhydrides

e.g. from sorbitan or mannitan. Percentages of fatty acids in such substances include oleate, stearate, laurate residues, etc.

Are sorbitan mono-oleate and mannitan mono-oleate particularly suitable and mannitan mono-oleate is in a "specially purified" degree, which is the case with injectable preparations widely used. Commercially available products in this class include: Arlacel A (mannitan mono-oleate), Arlacel 80 (sorbitan mono-oleate) and Arlacel 20 (sorbitan mono-laurate).

2. Kthylenoxydkondensate the products of class (1) (with for example 15-50 oxyethylene groups). Polyoxyethylene sorbitan mono-oleate and monolaurate are particularly suitable. Commercially available products in this class include: Tween 80 (polyoxyethylene (20) sorbitan mono-oleate), Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 81 (polyoxyethylene (5) sorbitan mono-oleate) and Tween 85 (polyoxyethylene (20) sorbitan trioleate). The figures in brackets at the nomenclature of the above products are given refer to the approximate number of oxyethylene units. the In fact, products are always mixtures, and this number means just the average chain length.

3. Polyoxyethylene derivatives of alkyl phenols. The alkyl parts such phenols preferably contain 6 to 10 carbon atoms, for example as in octyl or nonyl groups. Products this

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Types with polyoxyethylene chains of various lengths (e.g. 6-12 oxyethylene groups) are commercially available.

4. polyoxyethylene derivatives (eg with 10-30 oxyethylene) of fat (eg C ₁₂ _i8 ^ alcohols such as lauryl, stearyl, etc. Again, materials available from varying chain lengths.

5. Ethylene oxide condensates from glyceride oils, e.g. from castor oil like Cremophor EL, a polyoxyethylated castor oil with about 4-0 oxyethylene units per triglyceride unit. The glyceride oil can e.g. have 12-20 carbon atoms and the condensate at least 35 oxyethylene groups per mole of fatty oil. These the latter class is particularly preferred.

The microemulsions can be quickly removed by dissolving the steroid in the inert organic liquid medium, e.g. according to that described above for the non-aqueous organic solutions Method can be prepared in which a suitable surfactant is dissolved in the medium and injected with Water is mixed. Due to the thermodynamic stability of the microemulsions, there is very little energy for the dispersion necessary.

Generally the ratio of surfactant to inert organic liquid medium in the microemulsion is preferably at least 2: 1, the concentration of the organic liquid medium preferably being at least 5 $ and preferably no more than 30 wt .- ^.

Pharmaceutical administrations

The various forms of the compositions according to the invention are preferably administered in the form of dosage units, i.e. in containers such as ampoules or

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Vials, each such container 10 to 300 mg des Contains steroid I above anesthetic agent. While the Dose to be administered to the respective patient, as it is known in anesthesia, from the physical one The dosage units depend on the patient's constitution and the required depth and duration of anesthesia with an active ingredient content within the above range the anesthetist with a usual Deliver the unitary amount of anesthetic that is specifically required for a given patient Dose can be easily taken.

The compositions can also be one or more parenterally Include compatible water-soluble substances that serve to make the compositions nearly isotonic with

To make blood, substances suitable for this purpose are dextrose, glycerin and sodium chloride.

The following examples illustrate the invention without restricting it. The percentages are percentages by weight.

example 1

A mixture of 0.45 g of j5ct-hydroxy-5a-pregnan-11,20-dione and 0.15 g of SI-acetoxy-jfa-hydroxy-Sa-pregnan-H, 20-dione was in 3 ml of acetone dissolved. To this 5 ml of coconut oil were added. The acetone was removed by sparging with nitrogen. the clear solution of the steroid in oil became 45 ml of a 1 ^ -igen Tween 80 solution added while vigorously using a turbine mixer was kept moving. After 5 minutes of agitation determined the particle size of the emulsion by repeatedly passing it through a laboratory homogenizer reduced. The emulsion no longer contained any particles which were larger than 5 μm in diameter and which

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the majority of them were smaller than 1/1 / in terms of their diameter. The resulting emulsion contained a total of 1.2 % steroids and 10% coconut oil.

Example 2

Example 1 was repeated except that peanut oil (20 #) was used in place of coconut oil and the emulsifier Cremophor EL ($ 1) instead of Tween 80 was.

Example 3

Example 1 was repeated except that castor oil (10 #) was used instead of coconut oil and the emulsifier was a mixture of soy leclthin (i £) and Pluronic F68 (2%) instead of Tween 80.

Example 4

Example 1 was repeated except that castor oil (5 #) and cetyl alcohol (1 #) were used to dissolve the steroids and the emulsifier was Cremophor EL (1J6) instead of Tween 80 .

Example 5

Example 1 was repeated with the exception that isopropyl myristate (1Oi) was used instead of coconut oil and Cremophor EL ($ 1) used as an emulsifier in place of Tween 80 became.

Example 6

A mixture containing 0.9 g of 3a-hydroxy-5a-pregnane-11,20-dione and Contained 0 * 3 g of 21-acetoxy-3a-hydroxy-5cc-pregnan-11,20-dione, was dissolved in 5 ml of acetone. To this 50 ml of propylene

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glycol added. The acetone was heated in a Nitrogen stream removed. The solution of steroids in propylene glycol was diluted to 100 ml with sterile water.

Attacked 7

Example 6 was repeated with the exception that propylene glycol was replaced by 50 ml of glycerol formal.

Example 8

0.9 g of 3 "-hydroxy-5oC-pregnan-11,20-dione and 0.5 S 21-acetoxy-3a-hydroxy-5o'-pregnan-11,20-dione were dissolved in 5 ml acetone at 20 ⁰ C solved. The resulting solution was added to a mixture of 5 g coconut oil and 10 g Cremophor EL. The acetone was ^{removed at 50 °} C. by a stream of nitrogen. The solution was heated for 15 minutes to 70 ⁰ C in a nitrogen stream and subsequently diluted with sterile distilled water containing 0.25 g sodium chloride enthJeLt to a final volume of 100 ml. The solution was gently stirred or shaken until homogeneous.

Example 9

0.45 g of 5or-hydroxy-5cr-pregnane-11,20-dione and 0.15 g of 21-acetoxy-5oc-hydroxy-5a-pregnane-11,20-dione were added to a mixture of 2.5 g of coconut oil and 5 g Cremophor EL dissolved to J50 minutes was heated in a nitrogen stream at 70 ⁰ C. While stirring gently, the helsse solution was diluted to a final volume of 50 ml with sterile distilled water containing 0.125 g of sodium chloride.

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Example 10

Example 8 was repeated with the exception that a mixture of 5 g coconut oil and 15 g Tween 80 was used.

Example 11

A mixture containing 0.9 g of 3a-hydroxy-5ct-pregnan-11,20-dione and 0.3 g of 21-ethoxy-3a-hydroxy-5a-pregnane-11,2ö-dione contained, was dissolved in 5 ml of acetone. To this was added 20 ml of soybean oil added containing 1 g of Arlacel A and 0.5 g of Pluronic LSI. After removing the acetone by a stream of nitrogen, the resulting clear solution was 80 ml of an aqueous solution, containing 1 g of Pluronic F68 and 2.5 g of glycerin was added and the mixture emulsified in a hand-held homogenizer.

Example 12

A mixture containing 9 g of 3a-hydroxy-5oc-pregnane-11,20-dione and 3 g of 21-acetoxy-3a-hydroxy-5a-pregnane-11,20-dione was dissolved in 40 ml of acetone. 200 ml of coconut oil containing 2 g of cetyl alcohol were added to this. The acetone was removed and the solution mixed with 800 ml of water containing 3K Pluronic F68, 12 g soy lecithin and 25 g glycerin. The mixture was subsequently processed in a high-pressure homogenizer VörricJ
greed.

Device for 30 minutes at 281 kg / cm ² (4000 lb / sq.in) emul-

Example 13

0> 9 S 3σ-hydroxy-5a-pregnane-11,20-dione and 0.3 g of 21-acetoxy-3ahydroxy-5a-pregnane-11,20-dione were dissolved in 5 ml of acetone and the solution with 20 g of coconut oil containing 0.1 g of cetyl alcohol, mixed. The acetone was removed and the solution with 80 ml of distilled water, the 2.5 g of glycerine, 1.2 g of soy leci-

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thin containing 0.3 g Pluronic F68 and 0.2 g Pluronic F77. The mixture was emulsified in a hand-held homogenizer and then autoclaved for 20 minutes

sterilized at 1.1 kg / cm (15 lb / sq.in).

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Claims (34)

Claims 1. Pharmaceutical composition suitable for use in injections, characterized in that it is used as an anesthetic 3a-Hydroxy-5tx-pregnane-11,20-dione in solution in an inert organic liquid medium. 2. Composition according to claim 1, characterized in that that it is in the form of a solution which also contains water. 3. Composition according to claim 1 or 2, characterized in that that the inert organic liquid medium is a polyhydric alcohol, a water-soluble ester or a water-soluble one Contains amide. 4. Composition according to any one of the preceding claims, characterized in that the inert organic liquid medium Propylene glycol, glycerine, ethyl lactate, N- (ß-hydroxyethyl) lactamide, Contains glycerol formal or cicotinic acid amide. 5. Composition according to one of claims 2 to 4> characterized in that 3a-hydroxy-5oc-pregnane-11,20-dione in one
Amount from 0.1 to 4 percent by weight is present. 6. Composition according to claim 1, characterized in that it is in the form of a non-aqueous solution. 7. Composition according to claim 6, characterized in that the inert organic liquid medium is an oil. . 209828 / 11OB 8. Composition according to claim 7, characterized in that that the inert organic liquid medium is an aliphatic alcohol having 10 to 15 carbon atoms or an ester thereof with an aliphatic carboxylic acid with 1 to 6 carbon atoms, is an ester of a fatty acid having 12 to 18 carbon atoms, a hydrocarbon oil or a vegetable oil. 9. Composition according to claim 8, characterized in that the inert organic liquid medium tridecyl or isopropyl myristate, Isopropyl palmitate, ethyl or n-octyl oleate, liquid hydrocarbon, n-dodecane, n-hexadecane, squalene, coconut oil, castor oil, corn oil, peanut oil, soybean oil or cottonseed oil is. 10. Composition according to one of claims 6 to 9, characterized in that 3a-hydroxy-5oc-pregnane-11, 20-dione is present in an amount of 0.1 to 3 % by weight . 11. Composition according to claim 1, characterized in that it is in the form of an emulsion or microemulsion, the a continuous phase which is a water-immiscible inert organic liquid solution according to any one of the claims to 9 and additionally contains water. 12. The composition according to claim 1, characterized in that it _o rm an emulsion in P in which the disperse phase a is a water-immiscible, inert organic liquid medium according to claims 7 to 9 and the continuous phase is water. 13. Composition according to claim 12, characterized in that that it contains a parenterally suitable surface-active component with an HLB value of 9 to 15. 14. Composition according to claim 13, characterized in that that the surface-active component is a polyoxyäthylxertes derivative of a fatty glyceride oil (with 12 to 20 carbons 209828/11 Ob Atoms) with 35 Ms 45 oxyethylene groups per mole of fatty Oil, a polyoxyethylated ether of an alcohol with 12 Ms 18 carbon atoms and with 10 to 30 oxyethylene groups, a polyoxyethylene-polyoxypropylene-ether with 15 Ms 150 oxyethylene groups and 15 Ms 50 oxypropylene groups, one polyoxyethylated Fatty acid (with 12 to 18 carbon atoms) esters of sorbitan or mannitan with 15 to 30 oxyethylene groups, a Polyethylene glycol ester of a fatty acid (with 12 to 18 carbon atoms) with 6 to 40 oxyethylene groups or a phospholipid includes. 15. Composition according to any one of claims 12 to 14, characterized characterized in that, in addition, a parenterally suitable surface-active component with an HLB value of 3 to 8 as emulsion stabilizing agent is present. 16. Composition according to one of claims 12 to 15, characterized characterized in that an inert organic liquid medium is present in an amount of from 5 to 50% by weight. 17 · Composition according to any one of claims 12 to 16, characterized characterized in that the surfactant component is present in an amount of 0.1 to 5 wt .- ^. 18. Composition according to one of claims 12 to 17, characterized in that the droplet size of the emulsion is less than 5 JuL . 19. Composition according to one of claims 12 to 18, characterized characterized in that 3a-hydroxy-5a-pregnane-11,20-dione in is present in an amount from 0.1 to 2.5% by weight. 20. Composition according to claim 1, characterized in that it is in the form of a microemulsion in which the disperse phase is an inert organic which is immiscible with water liquid medium according to any one of claims 7 to 9 and the continuous phase comprises water. 209828/11 Ob 21. Composition according to claim. 20, characterized in that a surface-active component according to claim 13 or 14 is available, 22. Composition according to claim 20 or 21, characterized in that that an aliphatic alcohol with at least 12 coals of fat omen or a polyethylene glycol with a molecular weight of at least 4,000 is present as a surface destructive agent. 23 · Composition according to any one of claims 20 to 22, characterized characterized in that the content of the surface-active agent and the dip surface-destroying agent is 5 to 60% by weight. 24 · Composition according to one of claims 20 to 23, characterized in that the inert organic liquid medium is present in an amount of 5 to 30% by weight. 25. Composition according to any one of claims 20 to 24j characterized in that 3a-hydroxy-5a-pregnane-11,20-dione in is present in an amount from 0.1 to 0.6 wt. 26. Composition according to one of claims 1 to 4, 6 to 9, 11 to 18 or 20 to .24, characterized in that in addition a second steroid of the 5a-pregnan series with a 3cc-hydroxy group, an oxy group in the 11- and 20-positions and a group of the formula OR in the 21-position, in which R is a substituted or unsubstituted alkanoyl group with a straight or branched chain or a substituted or unsubstituted aroyl or aralkanoyl group is present is. 27. Composition according to claim 26, characterized in that that R is an acetyl group. 28. Composition according to claim 26 or 27, characterized 209828/1 105 indicates that the weight ratio of the second steroid increases the 3 <x-hydroxy-5a-pregnane-11,20-dione of 1:20 Ms 1: 1. 29 · Composition according to any one of claims 26 to 28, characterized characterized in that the 3a-hydroxy-5oc-pregnane-11,20-dione is present in an amount of from 0.5 to 10% by weight. 30. Composition according to one of claims 26 to 28, characterized in that the 3oc-hydroxy-5a-pregnane-11,20-dione is present in an amount of from 0.3 to 25 percent by weight. 31. Composition according to one of claims 26 to 28, characterized in that the 3a-hydroxy-5cc-pregnane-11, 20-dione is present in an amount of from 0.3 to 12 percent by weight. 32. Composition according to one of claims 26 to 28, characterized in that the 3 <x ~ hydroxy-5a-pregnane-11, 20-dione is present in an amount from 0.3 to 12% by weight. 33. Composition according to one of the preceding claims, characterized in that it is in 3? Orm of a unit dosage is present, each bosierungseinheit 10 to 300 mg of the 3oc-hydroxy-5ct-pregnane-11,20-dione contains. 34. Composition according to any one of the preceding claims, characterized in that it is isotonic with blood. 209828/1105