Method for producing a flurane complex

Abstract

A method for producing a flurane complex, comprising the steps of producing an aqueous solution of sulfobutylether--cyclodextrin (SBECD); controlling the temperature of said solution to a temperature of from 2 to 15 C.; adding the flurane to the aqueous solution; allowing the solution to react to produce the complex; and separating the complex.

Claims

1. A method for producing a flurane complex, characterized by the following steps: a. preparing an aqueous solution of sulfobutylether--cyclodextrin (SBECD), b. controlling the temperature of said solution to a temperature of from 2 to 15 C., c. adding the flurane to the aqueous solution, d. allowing the reaction to produce the complex, e. separating off the complex.

2. The method as claimed in claim 1, characterized in that the aqueous solution prepared in step a. comprises SBECD at a concentration of from 5 to 20% by weight.

3. The method as claimed in claim 1, characterized in that the flurane in step c. is added in a molar ratio to the SBECD of from 4:1 to 1:1.

4. The method as claimed in claim 1, characterized in that the complex is separated off by freeze-drying.

5. The method as claimed in claim 1, characterized in that the flurane is selected from the group consisting of sevoflurane, enflurane, isoflurane, desflurane and methoxyflurane.

6. The method as claimed in claim 5, characterized in that the flurane is sevoflurane.

7. A complex of SBECD and a flurane, obtainable by a method as claimed in claim 1, wherein the flurane content is greater than 8% by weight.

8. The complex as claimed in claim 7, characterized in that the flurane content is greater than 8.2% by weight.

9. The complex as claimed in claim 7, characterized in that the flurane is sevoflurane.

10. The complex as claimed in claim 7 characterized in that the molar ratio of SBECD to flurane is at least 1:0.6.

11. The complex as claimed in claim 7 for use as a medicament.

12. An anesthetic formulated for oral and/or intravenous administration, characterized in that said anesthetic comprises a complex as claimed in claim 7.

Description

(1) Working examples of the invention are described below. The figures show:

(2) FIG. 1: X-ray powder diffractograms of SBECD and a complex according to the invention;

(3) FIG. 2: Capillary electropherograms of SBECD and a complex according to the invention;

(4) 1. Materials Used

(5) distilled water

(6) sulfobutylether--cyclodextrin (SBECD)

(7) sevoflurane

(8) SBECD was purchased from Cyclo Lab Cyclodextrin Research & Development Laboratory Ltd., Hungary. Sevoflurane was purchased from Abbott GmbH, Wiesbaden.

(9) 2. Determination of the Sevoflurane Content of the Complexes Produced

(10) The sevoflurane content of the complexes was determined by gas chromatography. The gas chromatography conditions were as follows:

(11) Gas chromatograph: Shimadzu GC-17A

(12) Detector: Injector: Flame ionization detector (FID) Shimadzu AoC-5000 auto injector

(13) Software: Shimadzu Class-VP Version 7.4

(14) Gases:

(15) Carrier: Helium (99.999%)

(16) other gases: nitrogen (99.999%) synthetic air (99.999%) hydrogen (Whatman hydrogen generator)

(17) Column: Rtx624 (30 m0.32 mm1.8 mm) (Restek)

(18) Temperature Program:

(19) TABLE-US-00001 Rate Temperature Time ( C/min.) ( C.): (min): 38 4.0 40 220 1.5

(20) Injector temperature: 220 C.

(21) Detector temperature: 220 C.

(22) split ratio: 100:1

(23) Rate: 30 cm/s

(24) The injection program was as follows: after an incubation time of 10 min at 65 C., a vapour sample having a volume of 250 l at 70 C. was injected into the gas chromatograph.

(25) Sample Preparation

(26) Reference solutions: 1 ml of distilled water is placed in the vials with 250 l of DMF.

(27) Calibration solutions: 100 mg of sevoflurane is weighed into 2 ml glass flasks and made up to the mark with DMF as stock solution.

(28) Different amounts of this stock solution (20, 65, 110, 155 and 200 l) are made up in each case to 200 l with DMF and introduced into head space vials (19.5 ml) with 1 ml of distilled water.

(29) Sample solution: 50 mg of the sample complex is placed in a head space vial (19.5 ml) with 1 ml of distilled water and 200 l of DMF.

EXAMPLE 1

(30) This example describes the preparation of an SBECD complex of sevoflurane.

(31) In a round-bottomed flask, 22.8 g (10.54 mmol) of SBECD were dissolved in 190 ml of water at room temperature under continuous stirring. This gave a clear solution which was cooled to 8 C. 5.1 g (25 mmol) of sevoflurane were added, the round-bottomed flask was tightly sealed and the solution was stirred at 400 min.sup.1 at 8 C. for a period of 3 h. This gave a homogeneous liquid phase having a sevoflurane content of 0.75% by weight.

(32) The solution obtained was frozen at 50 C. and lyophilized for 24 h at a pressure in the range 6.0 to 8.7 Pa. This gave an amorphous solid which was ground and sieved through a sieve having a mesh size of 0.3 mm. The residual water content was low (see below for data) such that a further freeze-drying step was not necessary.

(33) The sevoflurane content of the solid complex (determined as described above) was 8.6% by weight.

EXAMPLE 2

(34) The influence of temperature on the preparation of the complex was investigated in this example. The preparation of example 1 was repeated with deviations in the temperature of the solution during the preparation (non-inventive comparative examples).

(35) At a preparation temperature of 22 C., the sevoflurane content of the solid complex was 1.7% by weight and, at 30 C., 0.7% by weight.

(36) It is apparent even at temperatures of 22 C., particularly also at 30 C., that only a very low yield can be achieved. The sevoflurane content of the complex is significantly lower than in the method according to the invention. The method disclosed in the prior art according to DE 10 2010 042 615 A1 (preparation at 50 C.) is therefore expected to be practically unfeasible.

EXAMPLE 3

(37) The structure of SBECD and the complex according to example 1 was examined by X-ray diffractometry. Conventional CuK radiation was used. The reflection peaks were recorded in a range of 2 angles from 5 to 40.

(38) In FIG. 1 it can be seen that SBECD (lower curve) and the complex (upper curve) equally have the reflection pattern of an amorphous substance.

(39) The amorphous structure was confirmed by observation under a light microscope at 100-fold magnification under polarized light. No interference pattern was visible which confirms the amorphous structure.

EXAMPLE 4

(40) In this example, it was confirmed by capillary electrophoresis that the structure of the complexing agent is not affected by the method according to the invention and remains intact. FIG. 2 shows (upper panel) the electropherogram of SBECD and below the corresponding electropherogram of the complex according to example 1. The comparison shows that the structure of the complexing agent is not adversely affected by the method according to the invention.

EXAMPLE 5

(41) The solid obtained according to example 1 was stored for 14 days (14 d) in an open container at 40 C. Properties listed in the table below were determined at the stated time intervals.

(42) TABLE-US-00002 0 d 2 d 7 d 14 d Sevoflurane content [wt %] 8.6 8.6 8.6 8.6 Redissolvability clear clear Residual water content [wt %] 3.5 4.7

(43) To determine the redissolvability, 100 mg of the complex were dispersed in 0.9 ml of distilled water. The determination of the residual water content was carried out according to the Karl-Fischer method. Both parameters were determined only at the start of the experiment and upon conclusion after 14 days.

(44) It is evident that the sevoflurane content does not change even upon prolonged storage under unfavorable conditions and the complex is therefore very stable. Even after 14 days under these storage conditions, it can be reconstituted with water and without further excipients to give a clear solution without any difficulty. The residual water content under these unfavorable storage conditions had only increased marginally.