DE2162554A1 - Anesthetic preparation - Google Patents

Description

The invention relates to an improved anesthetic preparation, which is particularly suitable for intravenous administration.

It has long been known that a number of steroids have central nervous system depressant and pharmacodynamic effects as anesthetics or hypnotics. These compounds have been extensively studied in order to find anesthetics to replace such compounds as thiopentone sodium (free international abbreviation for ethylisoamylthiobarbital sodium), which are commonly used but are known to be dangerous and disadvantageous to a certain extent. The literature shows that a very large number of steroids have been studied in this regard. Part of this work is, for example, in "Methods in Hormone Research" (edited by Ralph I. Dorfman, Vol. Ill, Part A, Academic Press London and New York 1964, pages 415-475) by H. Witzel, Z. Vitamin Hormon -Permentforschung 1959, 10, pages 46-74; H. Selye, Endocrinology, 1942, 30 , pp. 437-453 and SK Figdor et al., J. Pharmacol. Exptl. Therap., 1957, 119 * pp. 299-309.

A thorough study of the relevant literature reveals that anesthetic steroids generally have poor activity and / or long induction times.

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With such connections a number of undesirable Side effects such as paresthesia and damage to the veins were noted. Various of the steroid compounds that dii * are anesthetically effective are poorly soluble. Therefore, research has often tried to find solubilizing groups, for example by forming partial esters of di- or polybasic acids to introduce into such steroids. These However, work to date has not resulted in any satisfactory anesthetically effective steroids. Anesthetically effective Steroids are generally relatively simple pregnane derivatives which often have a hydroxyl group in the 3-position, where so far the 3ß-hydroxides when carrying out the investigations 3 ° t-hydroxy compounds were preferred.

In patent specification no (patent application / ⁷ ^ 30 ¹ I ⁰ I, $ )

anesthetic preparations were described which contain 3a-hydroxy-5a-.pregnan-ll, 20-dione as the main anesthetically active compound. As described in the above patent, this substance shows remarkable properties as an anesthetic. The preparations described in the cited patent are therefore suitable for inducing anesthesia and have a short induction time, with the effect occurring immediately with a suitable dosage. The solutions are therefore excellent anesthetics that can be used in human and veterinary medicine to induce anesthesia which must then be maintained, for example by inhalation anesthetics such as ether, trifluorobromochloroethane, nitrous oxide and triehloroethylene. However, the solutions can maintain anesthesia and analgesia to a sufficient degree to permit various surgical procedures without the aid of an inhalation anesthetic. The desired level of anesthesia can be maintained through repeated or even continuous administration if necessary. The patient's condition after the anesthesia is removed is

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drawn, he feels good, in contrast to the unpleasant ones After-effects of the usual anesthetics. Furthermore, the aforementioned anesthetically effective solutions generally cause none of the undesirable side effects previously associated with anesthetic steroids.

The preparations in the above patent contain ^ a-hydroxy-5a-pregnan-ll, 20-dione.

It has now been found that anesthetically effective preparations in the form of sterile aqueous suspensions for injections It is possible to produce the anesthetically effective steroid 5ct-Hydroxy-5ct-pregnan-11,20-dione mentioned as the active component contain.

Thus, aqueous suspensions can be used for intravenous administration are suitable and have the desired anesthetic properties described in the above patent, getting produced. Although the anesthetically effective steroid is in solid form in the preparation according to the invention is present, it appears that after intravenous injection, the steroid rapidly dissolves in solution in the blood. "|

The preparations according to the invention are made according to known methods Methods prepared, i.e. the preparation generally contains a parenterally acceptable surfactant to to favor the dispersion of the active steroid and agglomeration to prevent the particles. The surface-active agent must of course be physiological for that to be treated Individual (human or animal) compatible, i.e. it should not cause any physiologically inadmissible side effects in the dosage used.

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In general, nonionic surfactants are for suitable for this purpose. The preparations according to the invention preferably contain one as surface-active compounds or more nonionic surfactants, their

HLB value is preferably at least 9, generally less than 15.

If several surfactants are used, is the HLB value of the individual agents preferably not more than 30.

Particularly suitable surfactants are those which Have polyoxyethylene groups, for example those of following classes:

PοIyoxyäthyIierte derivatives of Pettsäureglyeeridölen with 12 to 20 carbon atoms in the fatty acid portion, for example rhicinus oil, preferably with at least J55 * for example 35 to 45 or 60 or more oxyethylene groups per mole of oil. Polyoxyethylene ethers having from 10 to JO oxyethylene groups of long chain alcohols, for example with 12 to l8 carbon atoms such as dodecanol. "

Polyoxyethylene-polyoxypropylene ether preferably with 5 to 16o each, for example with 15 to 150 and 15 to 50, oxyethylene and oxypropylene units. Polyoxyethylene ethers with 6 to 12 oxyethylene groups of alkylphenols with preferably 6 to 10 carbon atoms in the alkyl group.

Polyoxyethylated fatty acid esters -nit for example 12 to Carbon atoms in the fatty acid part and preferably 15 to

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Oxyethylene groups of sugar alcohol anhydrides, for example Sorbitan or mannitan.

Polyethylene glycol ester, preferably with 6 to 40 ethylene oxide Units of long-chain fatty acids with, for example, 12 to 18 carbon atoms, such as polyethylene glycol monooleate, preferably with 8 ethylene oxide units.

Long-chain alkanoyl mono- and dialkanolamides with 10 to 16 Carbon atoms in the alkanoyl part and 1 to 5 carbon atoms men in the alkanol part, for example Lauroylmonor and diethanolamides.

Other suitable surfactants are phospholipids such as lecithins, for example egg or soybean lecithin.

Examples of nonionic surface-active agents of the above classes, which are particularly suitable for use in the preparations according to the invention are suitable;

"Cremophor EL", polyoxyethylated rhicinus oil with about 4-0, | Ethylene oxide units per triglyceride unit j

"Tween 8o", polyoxyethylene sorbitan monooleate with about 20 ethylene oxide units ι

"Tween 6o", polyoxyethylene sorbitan monostearate with about 20 Ethylene oxide units j

"Tween 40", Polyoxyäthylensorbltanmonopalmitat with about 20 Ethylene oxide units j

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"Pluronic f68", a block copolymer of ethylene oxide and propylene oxide with about 150 ethylene oxide units and about 40 propylene oxide units; and

35 "f polyoxyethylene dodecyl ether with about 23 ethylene oxide units.

The preparations according to the invention furthermore contain, if desired, a parenterally permissible suspending agent in order to keep the steroid in suspension. Means for suspending, which can be used are, for example parenterally acceptable hydrophilic colloids such as dextran, preferably dextran having an average molecular weight of ¹ 15-000 to 70,000.

Various other types of suspending agents known for their utility in injectable pharmaceutical preparations are known, can be used in the preparation according to the invention are used, for example polyvinylpyrrolidone, polyvinyl alcohol, sorbitol, mannitol, a polyoxyethylene glycol, Carboxymethyl cellulose, colloidal silicon oxide and colloidal silicates.

If desired, the preparation according to the invention can be Antifoam agents, for example a parenterally acceptable silicone antifoam agent such as dimethylpolysiloxane.

Furthermore, the preparation can contain one or more parenterally permissible water-soluble substances that the preparation make approximately isotonic with blood, for example dextrose or glycerin.

The anesthetically effective active component in the inventive Preparation preferably has a very small partial

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_{size to 3,} with average particle sizes of less than 5} im being preferred. The steroid advantageously has a particle size of less than 2 μm . The suspensions preferably contain 0.1 to 2.0 wt -.% Active steroid, say on the total weight of the preparation.

The anesthetically effective steroid is expediently produced by rapid precipitation from solution in a suitable solvent obtained in the form of small particles. For example, the steroid can be in a solvent such as dimethylformamide, Dimethylacetamide or tetrahydrofuran dissolved and the resulting solution to water, which is preferably a surface-active Means, for example of the type mentioned above, contains, under Stirring, for example with a high speed stirrer, can be added. The precipitation becomes preferable at lower Temperature run, for example at 5 C, to the formation to favor of small particles. Other methods of making small particle size crystals from solutions are known to the person skilled in the art.

In general, the preparation according to the invention contains at least 0.5, usually 0.5 to 5% by weight, of the surface-active agent. When an agent is used for suspending g, k-Anri this 0.1 to IQ wt -.% Make up the preparation.

If an antifoam agent is used, this should be done in fairly small amounts, for example in the order of magnitude of 50 to 150 p.p.m. (Weight units) be present.

pie e.rf-in accordance with the preparation is preferably in for the. Dosage suitable units, for example in containers WIFs ampoules or vials, each of these containers 10 Contains up to 30 mg of the anesthetically effective steroid. While-

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which the administered amount is known to depend on the physical condition of the patient and the required degree and length of Depending on the anesthesia, doses within the above-mentioned limits are appropriate, from which the anesthesiologist take the amount required for each patient can.

The preparation according to the invention can be in the form of a combination preparation wherein the first container contains the steroid and the second container contains the liquid suspending medium. The contents of the two containers can be checked by the anesthetist, " for example immediately before use.

The preparation according to the invention can be in the form of a powder, e.g. a wettable powder which, for example immediately prior to administration, is easily immersed in sterile water for allows the injection to disperse. Such wettable powders can be made by using the same ingredients, how they are used for the production of suspensions. The various ingredients have been selected by conventional methods for the preparation of a dispersible product. The wettable powders preferably contain a freeze-dried mixture of the active steroid and surfactant. Make such wettable powders an appropriate form of the first component of the combination preparation, that has been described above.

The preparations according to the invention can of course marketed as anesthetics for parenteral administration together with printed instructions for use.

The following examples illustrate the invention.

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example 1 Aqueous suspension

5 ml of a 20% solution of j5a-hydroxy-5a-pregnan ~ ll, 20-dione in dimethyl formamide at 60 ° C. become 95 ml of a 2.5% by weight solution of "Cremophor EL" at 5 ° C added while stirring at high speed. The precipitate is washed by centrifugal decantation and a 1% by weight suspension is prepared in an aqueous medium containing 1% by weight "Cremophor EL", 5 % dextrose, 6 % dextran (molecular weight 40,000) and 100 ppm silicone antifoam.

Example 2 Aqueous suspension

A precipitate of ^ a-hydroxy- ^ a-pregnan-ll ^ O-dione, which like was prepared in Example 1, was used for the preparation of a 1 wt, - $ igen aqueous suspension., the 1 wt .- ^ "Cremophor EL ", 0.9 wt .- ^ polyvinylpyrrolidone and 100 p.p.m. silicone antifoam contains, manufactured.

Example 3

0.2 g of j5a-hydroxy-5a-pr "egnan-ll, 20 ~ dione are finely ground in a jet mill. 0.02 g of" Pluronic F68. "Are mixed with distilled water for 15 minutes in a small agate mill to form a thick slurry . processed and freeze-dried, the freeze-dried Peststoff can easily again wt .- ^ 1 to a suspension in a solution containing 0.2 wt -% "Pluronic P68", 5 wt .- ^ dextrose containing 100 ppm Siliccnantischaummittel be dispersed..

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Example 4

To 2.5 wt -.% "Tween 8o ^'r at 5 ° C was added 5 ml of a 20 wt .- # ^x strength solution of JKX-hydroxy ^ a-pregnan-ll ^ O-dione in dimethylformamide at 6o ° C The precipitated steroid was freeze-dried and could in a solution, .the 1 wt. % "Cremophor EL",
1 wt -.% Dextran (molecular weight 20,000) and 100 ppm silicone antifoam agent were added to an 1 ^ strength suspension are dispersed .-.

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Claims (21)

Claims 1. Anesthetic preparation suitable for parenteral administration, characterized in that it is the active component j5a-Hydroxy-5a-pregnan ~ ll, 20-dione in solid porir. contains. 2. Preparation according to claim 1, characterized in that it in the form of a suspension of the active component in one aqueous medium. 3. Preparation according to claim 2, characterized in that it contains at least 0.5 wt .- ^ one for parenteral administration suitable surfactant .contains. 4. Preparation according to claim 3 * characterized in that it contains 0.5 to 5 wt .- ^ of the surfactant. 5. Preparation according to claim 3 or 4, characterized in that the surface-active agent has an HLB value of at least 9. 6. Preparation according to one of claims 3 to 5 *, characterized in that that the surfactant has an HLB value of not more than 15. 7. Preparation according to one of claims 3 to 6, characterized in that that the surfactant is a polyoxyethylated Derivative of a fatty acid glyceride oil having 12 to 20 carbon atoms and at least 35 oxyethylene groups per. Mol Fettölj a polyoxyethylene ether of an alcohol with 12 to 18 carbon atoms and 10 to 30 oxyethylene groups Polyoxyethylene-polyoxypropylene ethers with 5 to 16o oxyethylene groups and 15 to 50 oxypropylene groups; a polyoxyethy- 209827/1035 lated fatty acid ester of sorbitan or mannitan with 12 up to 18 carbon atoms in the fatty acid residue and 15 to 30 oxyethylene groups; a polyethylene glycol ester of a fatty acid with 12 to 18 carbon atoms and 6 to 40 oxyethylene groups or is a phospholipid. 8. Preparation according to one of the preceding claims, characterized characterized as containing a parenterally acceptable suspending agent. 9 · Preparation according to claim 8, characterized in that the suspending agent is a hydrophilic colloid, polyvinylpyrrolidone, polyvinyl alcohol, sorbitol, mannitol Contains polyoxyethylene glycol, carboxymethyl cellulose, colloidal • silicon oxide or a colloidal silicate. 10. Preparation according to claim 8, characterized in that the means for suspending a dextran with a through • average molecular weight is from 15,000 to 70,000. 11 Formulation according to any of claims 8 to 10, characterized in that a ⁿ ss they contain 0.1 to 10 wt -% contains the means for suspending.. 12. Preparation according to one of the preceding claims, characterized in that it contains an antifoam agent. 13 · Preparation according to claim 12, characterized in that it contains dirnethylpolysiloxane as an antifoam agent. l4. Preparation according to claim 12 or 13, characterized in that that they are 50 to 150 p.p.m. of the antifoam. ~ 13 - 15. Preparation according to one of the preceding claims, characterized characterized as being isotonic with blood. 16. Preparation according to one of the preceding claims, characterized characterized in that the active component has a particle size of less than 5 pm. 17. Preparation according to one of the preceding claims, characterized characterized as being 0.1 to 2.0 wt. Ji based on the preparation of the active component. 18. Preparation according to one of the preceding claims, characterized characterized in that it is in the form of units containing 10 to 300 mg 3a-hydroxy-5a-pregnan ~ ll, 20-dione. 19. Preparation according to one of the preceding claims, characterized characterized in that it is in the form of a wettable powder containing a parenterally acceptable surfactant and dispersed in sterile water. can be, is present. 20. Preparation ηεοη claim 19, characterized in that them in the form of a freeze-dried mixture of the active. | Component and the surfactant is present. 21. Combination preparation suitable for use as an anesthetic, characterized in that it is in a first container as an active component. 3a-hydroxy-5a-pregnan-ll, 20-dione and in a second container, a sterile injectable aqueous suspension medium for the active component contains. '