JPS6183197A - Manufacture of novel solvation of beclomethasone 17,21-dipropionate and use - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for producing a no-inglobil ether solvate of beclomethasone 17.21-diglopionate. These novel solvates are substantially volumetrically stable in both ultramicronized and non-micronized forms.
bulk-5table).

Ultramicronized forms are particularly needed for use in the production of stable aerosol formulations. Prior art and problems Petalomethasone 17.2 Is it possible to use 1-dipropionate per se in the treatment of asthma? It has been known since before Puri (for example, Morro Zoraun).
Brown) et al., Pritchish Medical Journals, (Br1tish Medical
Journal ), 1. sgs-90(1
972). Since then, the production of stable aerosols has been of great importance. First, British patent number 1.
No. 429.184, and later in British Patent Application No. 2.076.422, the use of hagnized hydrocarbons was proposed. However, it was observed that the halonated hydrocarbon solvates prepared therein, including the solvate of beclomethasone 17.21-dipropionate, were not volume stable. Since then, various other solvates have been proposed, including European Patent Nos. 39 and 36.
No. 9 describes hydrocarbon solvates, West German Patent Application No. 3.0111.550 describes ethyl acetate solvates, and British Patent Application No. 2.107,715 describes monohydric solvates. Each Japanese product is listed.

British Patent No. 1.42'? , No. 184 states that suitable particle sizes for steroids for inhalation into the bronchial system are 2 to 2.
A range of 5 microns is taught.

In addition, beclomethasone in an aerosol formulation 17°2
1-Dipropionate crystals tend to undergo phenomena of crystal growth and/or crystal agglomeration, forming crystals with a particle size of 20 microns or more. Such crystals may cause blockage of metering valves in the aerosol and are too large to penetrate adequately into the bronchial system.

According to the present invention, a novel zoisoglobil ether of beclomethasone 17.21-dipropionate is characterized in that beclomethasone 17.21-dipropionate is dissolved in an organic solvent and precipitated by stirring when diisoglobil ether is added. A method of making a solvate is provided. Another feature of the invention is the novel solvate prepared by the above method.

We have now discovered that it is possible to prepare a solvate of becamethacin 17°21-dipropionate and zoinoglovir ether that is substantially volume stable with respect to the solvate present.

Furthermore, these novel solvates can be micronized by conventional methods, such as fluid energy mills;
And it has surprisingly been found that these micronized forms of the solvates are also substantially stable. Furthermore, the unexpected fact has been established that such finely divided solvates do not cause appreciable crystal growth or aggregation when used in aerosol formulations.

The process of the invention is miscible with noiso7'a pyl ether and di-isopropyl ether or soluble in zoisoglobil ether and beclomethasone 1
7.21-Dipropionate is conveniently carried out using a mixed solvent system consisting of organic solvents capable of dissolving it. Preferred organic solvents are a) fluorinated hydrocarbons such as chloroform and dichloromethane and tetrahydrofuran and nooxane. may be selected from the group consisting of ether.

Beclomethasone 17.21-dipropionate is dissolved in an organic solvent at a temperature ranging from room temperature to the reflux temperature of the organic solvent. Sufficient di-isopropyl ether is then added with constant stirring until complete crystallization occurs. Alternatively, only enough organic solvent is used to just dissolve the beclomethasone 17.21-dipropionate and then diisoglobil ether is added until the mixture becomes slightly cloudy. Slowly about 0'C°
The solvate crystallizes from the mixture upon cooling to .

The required crystalline solid can be obtained by conventional means, such as filtration, washing with zoisoglobil ether and subsequent drying. The dry solid is then micronized by known techniques, such as by comminution with a fluid energy mill or a ball mill. The particle size range is preferably 2-5 microns, which can be obtained directly from micronization processing or by classification.

The solvates thus obtained were analyzed by various methods. For example, the infrared spectrum of beclomethasone 17.21-dipropionate and beclomethasone 17.2
The infrared spectrum of 1-dipropionate cubyl ether solvate is 3200-3500 CM
This difference is due to the elimination of hydrogen bonding in the solvent-phased crystal due to the presence of solvating molecules and this is due to the
80G K has a broad absorption band of 35% in a solvated crystal.
This is to move it to the 00- absorption band. Similarly, there are other differences, such as the stretching frequency of the carbonyl group at about 1720 cIn.
Differences in frequencies and other bands throughout the spectrum are also evident.

1 under vacuum to confirm the exact amount of solvate present.
The loss in the drying test at 05°C can be advantageously used. Thus, the loss due to drying is usually about IO weight/
Analysis by gas chromatography showed that both the no-inglobil ether and the organic solvent used in the crystallization mixture were combined into the crystal structure of the solvate.

Therefore, beclomethasone 17.21-dipropionate is actually solvated with a pair of solvating molecules. These solvating molecules are beclomethasone 17.2
It is present in molar proportions ranging from 1 to 6 moles per mole of 1-dipropionate.

Yet another feature of the invention is a stable aerosol formulation containing the solvate prepared as described above.

The propellant to be used and the actual aerosol canister and valve are well known to those skilled in the art. The o1 propellant is trichlorofluoromethane (Freon).
) IIR) and Tsukurdifluoromethane (Freon 12R) will typically deliver a metered dose of 50 μV of active ingredient. The maximum daily dose is usually beclomethasone.
17.21-Dipropionate about 600 μ? O is
Therefore, the presence of a total amount of about 10 wt/w of di-isogumipyl ether and organic solvent used in the crystallization mixture is believed to have no appreciable toxic effect.

EXAMPLES Next, the present invention will be explained by examples, but these are merely for illustrative purposes and are not intended to limit the present invention in any way.

Example 1 Beclomethasone 17.21-dipropionate Method A for producing globil ether solvate: Peclomethasone 17.21-dipropionate (+0
0.0.9: 0.192 mol) in chloroform (1
t) Kill! Interpretation nine. The resulting solution was filtered and diisoglobil ether (4t) was added with constant stirring. Stirring was then continued for an additional hour, and the solid thus formed was then filtered, washed with a small amount of noringlopyl ether, and dried at 35'C. The yield of solvate was 104.99.

The product had the following analytical values.

Loss on drying: +0.8% (dried to constant weight under vacuum at +05°C) Gas chromatography: 6,'l (di-isogumipyl ether) 3.0t (chloroform) Karl Fischer = 0,4t ( Water) Melting point: 2
10-2°C Method B: Pekuamethacin 17.21-dipropionate ('5
0.011: 0.096%
-C50wd,') and the resulting solution r
passed. Sea index vir ether (2 t) saturated with water was then added with constant stirring and stirring continued for a further 1 hour. The precipitate was filtered, washed with sea index ether and dried at 35°C.

The yield of Bek-a-methacin 17.21-digcubionate non-propyl ether solvate was 47.7 g, and the analytical values of the product were as follows.

Loss on drying: 12.7% (105°C under vacuum
Gas chromatography: 6.9% (Seindecvir ether) 4.5
% (Chloroform) Karl Fischer: 0.57 Chi (Water) Melting point: 211-2°C Method Danixan (500d) was mixed with beclomethasone 17°21
-diglopionate (+00.09: 0.192 mol) and the mixture was warmed to dissolve the solid material. The resulting solution was then filtered and seaindecvir ether (5t) was added with constant stirring. After complete precipitation had occurred, the mixture was cooled in a water bath and filtered to form a solid, then washed with sea indecvir ether and dried at 35°C. The yield of dioxane/no-in propyl ether solvate was fl 110.5 #. After micronization, the product had the following analytical values:

Loss on drying: l+, 4% (dried to constant weight under vacuum at 105 tons) Gas chromatography: 3.096 (Seindexvir ether) 7.2
Whisper (dioxane) Karl Fischer: 0.91 Chi (Wed)
Melting point: 210-1'c Method D: Beclomethasone 17.21-nopropionate (+0
0.09:0.192 mol) was dissolved in tetrahydrofuran (500 tIt) with slight warming and the resulting solution was filtered. Sea index vir ether (5t) was then added with constant stirring and the mixture was brought to O
'Ct. The solid was then filtered, washed with a small amount of sea index ether and dried at 35°C. The yield of solvate was 109.11. Beclomethasone 17.21-diglopionate after ultrafine treatment
The tetrahydrofuran/di-inzolopyl ether complex had the following analytical values.

Loss on drying: 10.5% (105°C under vacuum
Gas chromatography: 6.5% (Seindecvir ether) 4.5% (Tetrahydrofuran) Karl Fischer: 0.97% (Water) Melting point: 210- 1'C Beclomethasone 17.21- A spray formulation of the no-inpropyl ether solvate of nogrobionate can be prepared as follows.

Claims (1)

[Claims] 1. Di-isopropyl ether solvation of beclomethasone 17,21-dipropionate, characterized in that beclomethasone 17,21-dipropionate is dissolved in an organic solvent and precipitated by addition of di-isopropyl ether. How things are manufactured. 2. The production method according to claim 1, wherein the organic solvent is selected from the group consisting of halogenated hydrocarbons and ethers. 3. The production method according to claim 2, wherein the halogenated hydrocarbon is chloroform or dichloromethane. 4. The production method according to claim 2, wherein the ether is tetrahydrofuran or dioxane. 5. The method of claim 1, wherein the solvate produced contains about 10% solvating substance. 6. Using a propellant gas such as trichlorofluoromethane or dichlorodifluoromethane and incorporating the di-isopropyl ether solvate of beclomethasone 17,21-dipropionate into an aerosol inhaler/canister. A method for producing stable aerosols. 7. A solvate of beclomethasone 17,21-dipropionate, preferably containing 3 to 10% by weight of di-isopropyl ether.