CN100404545C - Process for preparing crystalline ciclesonide with defined particle size - Google Patents
Process for preparing crystalline ciclesonide with defined particle size Download PDFInfo
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- CN100404545C CN100404545C CNB2004800074813A CN200480007481A CN100404545C CN 100404545 C CN100404545 C CN 100404545C CN B2004800074813 A CNB2004800074813 A CN B2004800074813A CN 200480007481 A CN200480007481 A CN 200480007481A CN 100404545 C CN100404545 C CN 100404545C
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- 239000002245 particle Substances 0.000 title claims abstract description 33
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 title abstract description 4
- 229960003728 ciclesonide Drugs 0.000 title abstract description 4
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
- 238000000034 method Methods 0.000 claims abstract description 73
- 150000001875 compounds Chemical class 0.000 claims description 72
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 58
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- 239000000203 mixture Substances 0.000 claims description 24
- 239000003960 organic solvent Substances 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- 238000001556 precipitation Methods 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 20
- -1 cyclohexylmethylene Chemical group 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 238000002425 crystallisation Methods 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
- 230000008025 crystallization Effects 0.000 claims description 13
- 239000001301 oxygen Substances 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 230000010933 acylation Effects 0.000 claims description 8
- 238000005917 acylation reaction Methods 0.000 claims description 8
- 238000009835 boiling Methods 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 239000011877 solvent mixture Substances 0.000 claims description 4
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 6
- 230000000699 topical effect Effects 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 2
- 239000000243 solution Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 10
- 238000013019 agitation Methods 0.000 description 8
- 230000002349 favourable effect Effects 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 238000009826 distribution Methods 0.000 description 7
- 239000000443 aerosol Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- 238000001640 fractional crystallisation Methods 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 239000002050 international nonproprietary name Substances 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 3
- 229960004436 budesonide Drugs 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000013543 active substance Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000006345 epimerization reaction Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000013210 evaluation model Methods 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 210000002850 nasal mucosa Anatomy 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 1
- XUGISPSHIFXEHZ-UHFFFAOYSA-N 3beta-acetoxy-cholest-5-ene Natural products C1C=C2CC(OC(C)=O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 XUGISPSHIFXEHZ-UHFFFAOYSA-N 0.000 description 1
- YEYCQJVCAMFWCO-UHFFFAOYSA-N 3beta-cholesteryl formate Natural products C1C=C2CC(OC=O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 YEYCQJVCAMFWCO-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000018569 Respiratory Tract disease Diseases 0.000 description 1
- 150000001241 acetals Chemical group 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- CETKWEWBSMKADK-GSXVSZIWSA-N epostane Chemical compound C([C@]1(C)[C@@](C)(O)CC[C@H]1[C@@H]1CC2)C[C@@H]1[C@]1(C)[C@]32O[C@]3(C)C(O)=C(C#N)C1 CETKWEWBSMKADK-GSXVSZIWSA-N 0.000 description 1
- 229950002674 epostane Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000000867 larynx Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000010297 mechanical methods and process Methods 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001141 propulsive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a novel process for preparing crystalline ciclesonide with an advantageous particle size and to the use for producing pharmaceutical preparations, in particular for topical use. The crystalline ciclesonide obtained by the novel process has advantageous aerodynamic properties, and can be further processed to inhalable or nasally administered pharmaceutical preparations without further mechanical micronization.
Description
Invention field
The present invention relates to prepare the novel method of the crystallization ring shrinkage porosite (ciclesonide) with favourable particle diameter and size distribution and relate in the purposes of producing aspect the particularly local pharmaceutical formulations that uses of pharmaceutical formulations.The crystallization ring shrinkage porosite for preparing with this novel method has favourable performance, but particularly aspect the pharmaceutical formulations that further production inhaling type or intranasal are taken.
The known technology background
US4605517 relates to the method that a kind of preparation has the steroide of control particle diameter, it comprises steroide is dissolved in the organic solvent, mix to make this steroide precipitation with the non-solvent of steroide by the solution that will obtain, and when mixing control mixing time and stirring extent.
People such as Sjoestroem [J.Pharm.Sci (1993), 82 (6), 584-9] have described and have a kind ofly prepared the method for water microsolubility active compound small particle by carry out sedimentary method in O/w emulsion., steroids cholesteryl acetate and β-Gu Zaichun are dissolved in the organic solvent for this reason, and in the presence of tensio-active agent, are prepared into emulsion with water.The evaporation of organic solvent produces the steroide precipitation that particle diameter is reduced to 25nm.
People such as Hem [J.Pharm.Sci (1967), 56 (2), 229-233] have described hydrocortisone and carried out crystalline mechanism in ultrasonic.
EP 142309 A2 have described a kind of method for preparing active compound, and this method is mixed by this active compound is dissolved in the organic solvent and with non-solvent.For this reason, epostane is dissolved in the dimethyl formamide (DMF), and adds entry.Its particle diameter of the precipitation that obtains in this way is in a very narrow size range.
People such as Ruch [Journal of Colloid and Interface Science (2000), 229 (1), 207-211] have described a kind of the precipitation and have prepared the method for particle diameter at the budesonide particulate of micrometer range in ultra sonic bath.For this reason, with water be added in the budesonide solution in ultrasonic up to obtain precipitation or, when budesonide is when being dissolved in the solvent mixture, unnecessary volatile solvent at room temperature to be volatilized.
WO 90/03782 relates to a kind of method for preparing finely-divided solid, by solid being dissolved in a kind of liquid carrier solvent to form a kind of injection liquid, and this injection liquid is added in the contrary solvent prepares, this contrary solvent is the liquefied gas or the dense steam of supercutical fluid, compression.
WO92/08730 has described the especially method of steroide of a kind of crystallization organic substance., this steroide is dissolved in the tertiary mixture of lipophilic solvent, hydrophilic solvent and surfactant for this reason, and carries out crystallization.In other words by having obtained predetermined with non-mechanical method and being uniform particle diameter.
WO 00/38811 has described the crystal fine grain that a kind of preparation has the regulation size distribution, particularly has the equipment of the particulate that is fit to the suction particle diameter.
The ring shrinkage porosite is a kind of INN title (international nonproprietary name) of compound, and chemical name is 16, the 17-[(cyclohexylmethylene) two (oxygen)]-11-hydroxyl-21-(2-methyl isophthalic acid-oxopropoxy) pregnant steroid-1,4-diene-3,20-diketone [11 β, 16 α (R)].DE-A 41 29 535 discloses ring shrinkage porosite and other the epimeric pregnant steroid-1 with anti-inflammatory action; 4-diene-3; 20-diketone 16; the preparation of 17-acetal 21-ester; it has butyl, sec.-propyl, sec-butyl, cyclohexyl or phenyl on ring acetal ring, and its C-21 hydroxyl is by ethanoyl or isobutyryl acidylate.Also described by preparation high pressure liquid chromatography (HPLC) method to begin corresponding R epimer is separated from the R/S mixture.International Patent Application WO 98/09982 A1 has described the method that a kind of method by fractional crystallization is encircled the epimer-enriched of shrinkage porosite R epimer., but the form of ring shrinkage porosite with the R/S mixture is dissolved under boiling temperature in the suitable water compatibility organic solvent for this reason, adds entry, and this mixture is cooled to room temperature.Yet, the ring shrinkage porosite of the R epimer-enriched that obtains in this way must be carried out particle diameter and the distribution of mechanical micronization then with the pharmaceutical formulations that obtains to be fit to suck.This need obtain the active compound as this method product in the chemosynthesis process of ring shrinkage porosite, wherein active compound has been to have to be suitable for directly carrying out the particle diameter of next step imbedibility preparation processing and the form of distribution.This may exempt extra mechanical micronization process and can avoid thus the possible shortcoming that mechanical micronization brings (for example danger of Wu Raning, too small particle formation, compare the suction that produces by the undefined structure of micronization product with crystalline texture and increase).
Invention is described
Be surprised to find, the ring shrinkage porosite in water miscible solvent dissolving and will encircle the shrinkage porosite solution crystallization ring shrinkage porosite that obtains-itself and the ring shrinkage porosite that the method for describing obtains compare-the have particle diameter of suitable suction that be added to the water subsequently in WO98/09982 A1-.Therefore may further save mechanical micronization in the preparation inhalable pharmaceutical formulations process.
Therefore the present invention relates to prepare the method for the formula I compound of crystallized form with regulation particle diameter,
Formula I
This method may further comprise the steps:
But a) solution of preparation I compound in suitable water compatibility organic solvent;
B) solution that obtains in adding a) of Xiang Shuizhong and
C) separate the formula I compound precipitation that forms.
The chemical name of formula I compound is 16, the 17-[(cyclohexylmethylene) two (oxygen)]-11-hydroxyl-21-(2-methyl isophthalic acid-oxopropoxy) pregnant steroid-1,4-diene-3, the 20-diketone [11 β, 16 α (R, S)].The R epimer of this compound (based on the absolute configuration on the C-22) has INN (international nonproprietary name) ring shrinkage porosite.Term formula I compound comprises pure R epimer, pure S epimer and with the mixture of the R/S epimer of any blending ratio and the pharmaceutically acceptable solvate of formula I compound according to the present invention.
The process of the inventive method is favourable from mainly being that the formula I compound of R epimer (based on the absolute configuration on the C-22) form begins.Mainly be that the pure form of epimerization is meant existence at least 90% in context according to the present invention, preferably at least 95%, particularly at least 97%, preferred at least 99% R epimer especially.This formula I compound that mainly is R epimer form can be by for example being similar to the synthetic method described in the WO02/38584 and carrying out subsequently that acylation obtains or obtain with the fractional crystallization of preparation HPLC or the R/S epimer mixture by the formula I compound described in International Patent Application WO 98/09982.
When carrying out method of the present invention, but with formula I compound dissolution in suitable water compatibility organic solvent.But the suitable water compatibility organic solvent of being mentioned according to the present invention is alcohol, for example methyl alcohol, ethanol, n-propyl alcohol and Virahol, acetone, tetrahydrofuran (THF) (THF) or dimethyl formamide (DMF) and with the mixture of any mixed.During this period solvent have 10 ℃ to the temperature between the boiling point of this solvent be favourable, preferably 15 ℃ of temperature of extremely hanging down 10 ℃ than this solvent boiling point, particularly 15 ℃ to 35 ℃, especially preferably from 20 ℃ to 25 ℃, and this solvent is very particularly preferably room temperature (being that the solvent temperature is corresponding with the temperature in the room that carries out this method).Can advantageously under agitation this solution be added to the water and maintain simultaneously the temperature of this solvent subsequently.Add fashionable special preferably carry out in the mode that drips.The temperature of water according to the present invention preferably at 10 ℃ to 50 ℃, preferred 15 ℃ to 40 ℃, very particularly preferably 20 ℃ to 30 ℃.In a preferred embodiment, water is room temperature (promptly corresponding with the temperature in the room that carries out this method).The amount of the employed solvent of dissolution type I compound depends on the character and the temperature of solvent.Use that to be enough to make the consoluet solvent of formula I compound at least be favourable, preferably multiple spot a little again.To select be favourable to the amount of employed water in the inventive method so that dissolved formula I compound can quantitatively precipitate after adding entry.
The precipitation that forms is preferably separated by the method that precipitation is shifted out solution according to the present invention, particularly by filtering-depositing, wash precipitation with water and carry out the exsiccant method subsequently and separate.
The formula I compound that the inventive method obtains has the particle diameter of regulation.The particle diameter of regulation is meant particle diameter and the Particle Distribution that is fit to suction according to the present invention.The form that is fit to suck is meant that having aerodynamic diameter is 1 to 10 μ m, preferably at 1 to 5 mu m range, particularly preferably in the particle diameter of 1 to 3 mu m range.Preferred herein preparation is that particle size determination shows X
50[unit: μ m] for being less than or equal to 10, and be preferred 7.5, and very preferably 3, preferred especially 2 preparation.The lay special stress on X according to the present invention
50Scope 1.8 to 2.0.X in the particle size determination
5050% the mean particle dia that is meant all particulate cumulative volumes is less than described value.The mensuration of size distribution can be undertaken by the method for for example making laser diffraction with known method on solid matter.According to the present invention size distribution preferably according to for example employed dried testing method is measured in Sympatec HELOS-laser-diffractometer or equivalent instrument (instrument parameter on the Sympatec HELOS-laser-diffractometer can by as the setting of getting off, for example: the test duration (5s), Shi Ji (1000ms), with reference to test time (5s), test specification/lens (R2 0.25/0.45..87.5 μ m), starting condition (0.000s behind the start button), dispersed modules (RHODOS+VIBRI), evaluation model (HRLD), the height of bed (2mm), output (50%), dispersion pressure (it is the evaluations of 3.30 crust to 3.70 Palestine and Israels and Fraunhofer diffracting diagram that 3.50 crust, the permission of actual measurement pressure change).
The crystallization that has provided preferred formula I compound according to the present invention can suck form, this compound has particle diameter at 1.5 μ m to 7.5 μ m, preferred 1.75 μ m to 6.5 μ m, preferred especially 1.85 μ m to 5.5 μ m, the particularly particulate of the maximum ratio of 2 to 5 mu m ranges.(when this scope is meant and sucks because its grain size and directly be not deposited in mouth or the larynx or because its fineness and the part that sucks of breathing out again).Exemplary embodiment of the present invention is that the particulate of wherein maximum 55% (volume) is less than or equal to 1.85 μ m, and the crystallization that at least 75% (volume) is less than or equal to the formula I compound of 4.5 μ m can suck form.Preferred compound is not the micronization form.The micronization form is meant that this compound has carried out mechanical micronization step (as mechanical mill) according to the present invention.
Formula I compound can prepare in a manner known way, for example described in the DE-A 41 29 535.Alternatively, formula I compound also can be from the corresponding 21-oxy-compound shown in the formula II
Prepare by carrying out acylation with suitable acylating reagent.This 21-oxy-compound is described in for example WO95/24416 and WO 02/38584 to some extent.Acylation in this case can with the known method of those skilled in the art for example the method described in the WO 98/09982 carry out.
Therefore the invention still further relates to a kind of preparation and have the method for formula I compound of the crystallized form of regulation particle diameter,
Formula I
This method may further comprise the steps:
A) come preparation I compound by coming that with suitable acylating reagent formula II compound is carried out acylation;
B) but but add the method for entry or the method by the suspension of heating-type I compound in the mixture of suitable water compatibility organic solvent and water in the solution by the formula I compound in being dissolved in suitable water compatibility organic solvent the formula I compound that obtains in a) carried out crystallization;
C) from water/solvent mixture, remove the precipitation of the R epimer-enriched of the formula I compound that obtains;
D) repeating step b if desired);
E) preparation is at the solution of compound in the mixable organic solvent of suitable water that step c) obtains;
F) Xiang Shuizhong adds e) in the solution that obtains and
G) separate the formula I compound precipitation that forms.
Be step a), the b that carries out the inventive method) and c), advantageously at elevated temperatures, particularly under the boiling point of use solvent, but the R/S epimer mixture of formula I is dissolved in the suitable water compatibility organic solvent.Advantageously under agitation particularly in this solution, add entry and after water adds, under agitation cool off preferred cool to room temperature under the situation of boiling temperature subsequently in the temperature that maintains this rising.Alternatively, but the R/S epimer mixture of formula I can be suspended in the mixture of water and suitable water compatibility organic solvent and by heating, the boiling point that particularly is heated to this solvent mixture dissolves.Subsequently this solution is under agitation cooled off, preferably be cooled to room temperature.Cooling is advantageously carried out under slower situation, preferably at 2 to 10 hours internal cooling.Can be advantageously by adding nucleus (for example crystal seed), preferably all use the crystal seed of the pure R epimer of formula I to influence subsequently fractional crystallization in all cases.But the suitable water compatibility representative examples of organic that can mention in the inventive method step b) is acetone or particularly alcohol for example Virahol, n-propyl alcohol, methyl alcohol and preferred ethanol, with and the mixture of any blending ratio.R/S epimer mixture for dissolving 0.18mol formula I use 190-700ml, but the suitable water compatibility organic solvent of preferred 300-400ml is favourable.But water compares preferably at 0.1-1[v/v with water compatibility volume of organic solvent] scope, particularly at 0.25-0.75[v/v] scope.
From solution, the R/S epimer mixture of the R epimer-enriched of formula I removed [step c)] by carrying out with mode well known by persons skilled in the art, particularly by filtering mode subsequently.
The process of the inventive method can be advantageously from the enrichment of R epimer, R epimerization body burden 〉=75% for example, formula I compound particularly 〉=85% begins.In addition, the acylation in the step a) is by carrying out with mode well known by persons skilled in the art, and is for example described in an embodiment by carrying out acylation with suitable acylating reagent such as isobutyric anhydride.
The formula I crystalline compounds with regulation particle diameter that obtains by the inventive method can also further be processed into pharmaceutical formulations (preferably not having further micronization step), and it also is suitable wherein combining with other pharmaceutically active compound.Formula I compound is with itself or preferably uses in pharmaceutical formulations with the form that combines with suitable drug excipient, for example with the form of tablet, coated tablet, capsule, suppository, paste, emulsion, suspension, gel or solution, wherein the content of active compound is favourable 0.1 to 95%.The preferred pharmaceutical formulations of mentioning is to come those of topical by lung with by mucous membrane especially nasal mucosa.
The vehicle that is suitable for required pharmaceutical formulations is that those skilled in the art are familiar with on its professional knowledge base.Except solvent, jelling agent, ointment base and other active compound carriers, can use for example antioxidant, dispersion agent, emulsifying agent, sanitas, solubilizing agent or infiltration accelerating agent.
The formula I compound that obtains by the inventive method preferably is used for treating respiratory tract disease with the form administration that sucks.For this reason, formula I compound comes administration with the direct administration of powder type or with the atomized soln that contains it or the form of suspension.This material preferably passes through inhalation with the form of aerosol for this reason, and the aerosol particulate of its solid, liquid or blending ingredients has 0.5 to 10 μ m, advantageously is the diameter of 2 to 6 μ m.
Aerosol can produce by for example pressure manipulation nozzle atomizer or ultrasonic nebulizer, but advantageously by the metered aerosol of propelling gas manipulation or producing from the capsular micronization active compound of imbedibility of the no propelling gas of use.
Depend on used sucker system, this pharmaceutical formulations also comprises essential vehicle for example propulsive gas such as HFA 134a or 227 except active compound), solvent (as ethanol), surfactant, emulsifying agent, stablizer, sanitas, perfuming agent, filler (lactose used) or other suitable active compound as powder inhalator.
The ring shrinkage porosite pharmaceutical formulations that is suitable for sucking or is suitable for nasal mucosa medicine administration with and produce and for example describing to some extent among US6120752, US 6264923, W001/028562, WO01/028563 or the DE 19541689.This pharmaceutical formulations can be produced by well known to a person skilled in the art method.Usually, with active substance (be formula I compound, if desired, can with other active compound in conjunction with) mix mutually with the carrier of forming by one or more vehicle.In this case, active compound is segmented in solid and/or liquid vehicle usually and and then is made required pharmaceutical formulations.
In order to suck purpose, a large amount of apparatuses can be for adopting, and this apparatus can produce the optimum grain-diameter aerosol and can use the inhalation method that is fit to the patient as far as possible to take.Except use annex (barrier sheet, spreader) and pear-shaped containers (as
) and the automatic transmission driving mechanism of the aerosol that is used to measure (
) outside, also can adopt a series of technical solutions, particularly for powder inhalator (as
Or the technology of in EP 0 505 321, EP 407028, EP 650410, EP 691865, EP 725725, WO 99/21601, US 6120752 or US 6264923, describing), take with its best that can realize active compound.
About the composition and the production of nose administration pharmaceutical formulations, reference example such as WO 01/28562 and WO01/28563.
The following examples are further described the present invention without limitation.The RT stands for room temperature, min representative minute, h representative hour, m.p. represent fusing point, and abs. represents anhydrous.
Embodiment
1. the crystallization 16 that has the regulation particle diameter, the 17-[(cyclohexylmethylene) two (oxygen)]-11-hydroxyl-21-(the 2-methyl-
The 1-oxopropoxy) pregnant steroid-1,4-diene-3, the preparation of 20-diketone [11 β, 16 α (R, S)]
With 16,17-[(cyclohexylmethylene) two (oxygen)]-11-hydroxyl-21-(2-methyl isophthalic acid-oxopropoxy) pregnant steroid-1,4-diene-3,20-diketone [11 β, 16 α (R, S)] are dissolved in the ethanol of appropriate amount under the listed temperature in table.Under listed water temperature, solution is joined in the water of described amount with the form that drips, under vigorous stirring, keep this temperature simultaneously.Suction filtration leaches precipitation, washes with water and drying.
X in the table
50By in Sympatec HELOS-laser-diffractometer or equivalent instrument [parameter: test duration (5s), Shi Ji (1000ms), with reference to test time (5s), test specification/lens (R2 0.25/0.45..87.5 μ m), starting condition (0.000s behind the start button), dispersed modules (RHODOS+VIBRI), evaluation model (HRLD), the height of bed (2mm), output (50%), the middle use of dispersion pressure (it is the evaluations of 3.30 crust to 3.70 Palestine and Israels and Fraunhofer diffracting diagram that 3.50 crust, the permission of actual measurement pressure change) is done testing method and is measured by laser diffraction.Form contrast with the crystallization method described in the WO 98/09982, do not observe the enrichment of epimer.
| Embodiment | Ethanol (ml/g) | The ethanol temperature (℃) | Water (ml/g) | Water temperature (℃) | Productive rate (%) | X 50 (μm) |
| 1 | 5 | RT | 25.5 | RT | 94 | 2.0 |
| 2 | 7.5 | RT | 25.5 | RT | 95 | 1.8 |
| 3 | 7.5 | RT | 12.5 | RT | 95-98 | 1.9 |
| 4 | 7.5 | RT | 7.5 | RT | 96 | 2.0 |
| 5 | 7.5 | RT | 12.5 | 10 | 94-96 | 1.6 |
| 6 | 7.5 | RT | 12.5 | 30 | 92-95 | 1.9 |
| 7 | 7 | RT | 10 | RT | 97 | 1.8 |
| 8 | 7 | RT | 12 | 40 | 97 | 1.8 |
| 9 | 6 | RT | 10 | 20 | 90-97 | 1.8 |
| 10 | 6 | RT | 6 | 20 | 97 | 2.0 |
| 11 | 2.2 | 50 | 6 | 20 | 96-98 | 1.8 |
| 12 | 2.2 | 50 | 10 | 20 | 96 | 2.8 |
| 13 | 3 | 40 | 7 | 20 | 96 | 2.1 |
| 14 | 4 | 30 | 8 | 20 | 96 | 1.8 |
| 15 | 4 | 30 | 8 | 30 | 96-97 | 1.9 |
| 16 | 10 | 20 | 10 | 20 | 97 | 1.9 |
2.
Undertaken 16, the 17-[(cyclohexylmethylene by the method for describing among the WO 98/09982) two (oxygen)]-11- Hydroxyl-21-(2-methyl isophthalic acid-oxopropoxy) pregnant steroid-1,4-diene-3, the difference of 20-diketone [11 β, 16 α (R, S)] to The isomer enrichment
2.1 with 16 of 316g (584mmol), the 17-[(cyclohexylmethylene) two (oxygen)]-11-hydroxyl-21-(2-methyl isophthalic acid-oxopropoxy) pregnant steroid-1,4-diene-3,20-diketone [11 β, 16 α (R, S)], be called A (R/S epimer ratio is about 90/10 for thick product, oily) after this, be dissolved in 1.1 liters the abs. ethanol and under the ebullient situation, add 700ml water.Under vigorous stirring, this mixture is dropped to RT, and suction filtration leaches precipitation, with abs. ethanol/water=2/1 washing of 500ml and under 50 ℃ in vacuum drying oven dry 5h.
Productive rate: the A of 237g (438mmol, 75%), R/S epimer ratio is about 95/5.
m.p.199-201℃
Product is dissolved in the abs. ethanol of 900ml, and under the ebullient situation, adds 650ml water, and separation obtains product as stated above.
Productive rate: the A of 209g (386.5mmol, 88%), R/S epimer ratio is about 97/3.
m.p.201-203℃
Product is dissolved in the abs. ethanol of 800ml, and under the ebullient situation, adds 450ml water, and separation obtains product as stated above.
Productive rate: the A of 178g (329mmol, 85%), R/S epimer ratio is about 98.5/1.5.
m.p.205-206℃
Product is dissolved in the abs. ethanol of 600ml, and under the ebullient situation, adds 350ml water, and separation obtains product as stated above.
Productive rate: the A of 161g (298mmol, 90.5%), R/S epimer ratio＞99.5/0.5.
m.p.206.5-207℃
2.2 the A (R/S epimer ratio is about 89/11) of 1.5g (2.77mmol) is dissolved in the abs. methyl alcohol of 3ml and under the ebullient situation, adds 1ml water.Under agitation this mixture is dropped to RT, and suction filtration leaches precipitation, carry out drying with a spot of methanol=3/1 washing and by as above condition.
Productive rate: the A of 1.21g (80.6%), R/S epimer ratio is about 93: 7.
2.3 the A (R/S epimer ratio is about 91.5/8.5) of 5g (9.25mmol) is dissolved in the Virahol that boils of 15ml, and adds 10ml water.Under agitation this mixture is dropped to RT, and suction filtration leaches precipitation, carry out drying with a spot of isopropanol=2/1 washing and by as above condition.
Productive rate: the A of 4g (80%), R/S epimer ratio is about 94/6.
2.4 the A (R/S epimer ratio is about 89/11) of 1.5g (2.77mmol) is dissolved in the boiling acetone of 4ml, and adds 1ml water.Under agitation make mixture drop to RT, and suction filtration leaches precipitation, carry out drying with a spot of acetone=2/1 washing and by as above condition.
Productive rate: the A of 1.12g (75%), R/S epimer ratio is about 95/5.
3.
By the fractional crystallization method of describing among the WO 98/09982 obtain 16, the 17-[(cyclohexylmethylene) Two (oxygen)]-11-hydroxyl-21-(2-methyl isophthalic acid-oxopropoxy) pregnant steroid-1,4-diene-3,20-diketone [11 β, 16 α (R, S)] X 50 Value
Following table comprise by the method for describing among the WO 98/09982 obtain 16, the 17-[(cyclohexylmethylene) two (oxygen)]-11-hydroxyl-21-(2-methyl isophthalic acid-oxopropoxy) pregnant steroid-1,4-diene-3, the X of 20-diketone [11 β, 16 α (R, S)]
50Value (seeing embodiment 2).X
50Obtain by suitable method mensuration.The volume ratio of employed ethanol and water when this column data of ethanol/water is crystallization.
| Embodiment | Ethanol/water | X 50(μm) |
| 1 | 1/0.65 | 26.57 |
| 2 | 1/0.55 | 33.79 |
| 3 | 1/0.6 | 35.25 |
| 4 | 1/0.7 | 21.82 |
| 5 | 1/0.4 | 37.02 |
| 6 | 1/0.8 | 20.83 |
The result: by the method for describing among the WO 98/09982 obtain 16, the 17-[(cyclohexylmethylene) two (oxygen)]-11-hydroxyl-21-(2-methyl isophthalic acid-oxopropoxy) pregnant steroid-1,4-diene-3,20-diketone [11 β, 16 α (R, S)] has obviously higher X
50Value.These values are not at the X of the particle diameter that be fit to suck
50Within the value scope.
4.
Prepare initiated I compound by acylation
A:
16, the 17-[(cyclohexylmethylene) two (oxygen)]-the pregnant steroid of 11-hydroxyl-21-(2-methyl isophthalic acid-oxopropoxy)- 1,4-diene-3, the 20-diketone [11 β, 16 α (R, S)]
With 16 of 10g, the 17-[(cyclohexylmethylene) two (oxygen)] 11,21-dimonohydric pregnant-1,4-diene-3,20-diketone [11 β, 16 α (R, S)] and 6g salt of wormwood be suspended in the 50ml acetone, and under agitation add the 4.4ml isobutyric anhydride, and this mixture is heated 2.5h under refluxing.After being cooled to RT, in this suspension, add 100ml water lentamente.With the product filtered off with suction, wash with water and drying.The enrichment of R epimer is undertaken by as above method.
The productive rate of crude product: 11.4g (be theoretical yield 99.3%) 16, the 17-[(cyclohexylmethylene) two (oxygen)]-11-hydroxyl-21-(2-methyl isophthalic acid-oxopropoxy) pregnant steroid-1,4-diene-3, the 20-diketone [11 β, 16 α (R, S)]
The mensuration of the epimer ratio of formula I compound
The epimer ratio is measured by HPLC.
The HPLC condition:
Column material: Hypersil C18,5 μ m, 125 * 4.6mm
Detector wavelength: 242nm
Sample concentration: 0.5-1.5mg/ml
Loaded volume: 20 μ l
Flow velocity: 1ml/min
Oven temperature: 20 ℃
Compd A: elutriant water (45%)/ethanol (55%)
Claims (19)
1. preparation is without further micronization step is available, and particle diameter is characterised in that X
50In the formula I compound of the crystallized form of 1.8 to 2.0 mu m ranges, 16,17-[(cyclohexylmethylene) two (oxygen)]-11-hydroxyl-21-(2-methyl isophthalic acid-oxopropoxy) pregnant steroid-1,4-diene-3, the method for 20-diketone [11 β, 16 α (R, S)],
Formula I
This method may further comprise the steps:
But a) solution of preparation I compound in suitable water compatibility organic solvent;
B) solution that obtains in adding a) of Xiang Shuizhong and
C) separate the formula I compound precipitation that forms.
2. according to the method for claim 1, but it is characterized in that suitable water compatibility organic solvent is an alcohol.
3. according to the method for claim 2, it is characterized in that described alcohol is selected from methyl alcohol, ethanol, n-propyl alcohol and Virahol or its mixture with any mixed.
4. according to the method for claim 3, wherein said alcohol is ethanol.
5. according to the method for claim 1, but it is characterized in that water compatibility organic solvent is selected from acetone, tetrahydrofuran (THF) or dimethyl formamide.
6. according to the method for claim 1, but the temperature that it is characterized in that suitable water compatibility organic solvent at 15 ℃ to scopes than low 10 ℃ of this solvent boiling point.
7. according to the method for claim 6, but the room temperature when it is characterized in that the temperature of suitable water compatibility organic solvent and this method are carried out is corresponding.
8. according to the method for claim 1, the temperature that it is characterized in that water is at 10 ℃ to 50 ℃.
9. according to the method for claim 7, the room temperature of its feature when the temperature of water and this method are carried out is corresponding.
10. according to the method for claim 1, it is characterized in that the ratio of R epimer in the formula I compound is at least 90%.
11. according to the method for claim 10, the ratio that it is characterized in that R epimer in the formula I compound is greater than 95%.
12., it is characterized in that formula I compound is the ring shrinkage porosite according to the method for claim 1.
13., it is characterized in that the precipitation that will obtain after the step c) carries out drying subsequently according to the method for claim 1.
14. preparation is without further micronization step is available, particle diameter is characterised in that X
50In the method according to the formula I compound of claim 1 of the crystallized form of 1.8 to 2.0 mu m ranges, this method may further comprise the steps:
A) come that with suitable acylating reagent formula II compound is carried out acylation and come preparation I compound;
Formula II
B) but but add the method for entry or the method by the suspension of heating-type I compound in the mixture of suitable water compatibility organic solvent and water in the solution by the formula I compound in being dissolved in suitable water compatibility organic solvent the formula I compound that obtains in a) carried out crystallization;
C) from water/solvent mixture, remove the precipitation of the R epimer-enriched of the formula I compound that obtains;
D) repeating step b if desired);
E) but preparation at the solution of compound in suitable water compatibility organic solvent that step c) obtains;
F) Xiang Shuizhong adds e) in the solution that obtains and
G) separate the formula I compound precipitation that forms.
15., wherein step b) and e according to the method for claim 14) in employed organic solvent be identical solvent.
16. have the X of being characterized as
50The crystallization ring shrinkage porosite of the particle diameter of 1.8 to 2.0 mu m ranges, this ring shrinkage porosite is not the micronization form.
17. comprise the pharmaceutical composition according to the compound of claim 16, wherein said compound is to exist with the form of pharmaceutically acceptable vehicle with solia particle.
18. according to the pharmaceutical composition of claim 17, it is the aqeous suspension of this compound.
19. according to the pharmaceutical composition of claim 17, it is a dry powder.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP03007007.2 | 2003-03-27 | ||
| DE10314097.2 | 2003-03-27 | ||
| EP03007007 | 2003-03-27 |
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| Publication Number | Publication Date |
|---|---|
| CN1761678A CN1761678A (en) | 2006-04-19 |
| CN100404545C true CN100404545C (en) | 2008-07-23 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004800074813A Expired - Lifetime CN100404545C (en) | 2003-03-27 | 2004-03-26 | Process for preparing crystalline ciclesonide with defined particle size |
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| CN (1) | CN100404545C (en) |
| ZA (1) | ZA200506943B (en) |
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| CN106692115A (en) * | 2015-11-13 | 2017-05-24 | 天津金耀集团有限公司 | Ciclesonide suspension nasal spray composition |
| CN106883283B (en) * | 2015-12-15 | 2021-02-02 | 天津金耀集团有限公司 | Ciclesonide monohydrate, crystal form and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4605517A (en) * | 1983-10-29 | 1986-08-12 | Sterling Drug Inc. | Method of preparing steroid compounds of controlled particle size |
| US5482934A (en) * | 1990-09-07 | 1996-01-09 | Especialidades Latinas Medicamentos Universales, S.A. (Elmu, S.A.) | Pregna-1,4-diene3,20-dione-16-17-acetal-21 esters, process for their preparation, composition, and methods for the treatment of inflammatory conditions |
| CN1335787A (en) * | 1998-12-24 | 2002-02-13 | 葛兰素集团有限公司 | Apparatus and process for preparing crystalline particles |
| WO2002038584A1 (en) * | 2000-11-10 | 2002-05-16 | Altana Pharma Ag | Process for the production of 16,17-[(cyclohexylmethylen)bis(oxy)]-11,21-dihydroxy-pregna-1,4-dien-3,20-dion or its 21-isobutyrat by transketalisation |
-
2004
- 2004-03-26 CN CNB2004800074813A patent/CN100404545C/en not_active Expired - Lifetime
-
2005
- 2005-08-30 ZA ZA200506943A patent/ZA200506943B/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4605517A (en) * | 1983-10-29 | 1986-08-12 | Sterling Drug Inc. | Method of preparing steroid compounds of controlled particle size |
| US5482934A (en) * | 1990-09-07 | 1996-01-09 | Especialidades Latinas Medicamentos Universales, S.A. (Elmu, S.A.) | Pregna-1,4-diene3,20-dione-16-17-acetal-21 esters, process for their preparation, composition, and methods for the treatment of inflammatory conditions |
| CN1335787A (en) * | 1998-12-24 | 2002-02-13 | 葛兰素集团有限公司 | Apparatus and process for preparing crystalline particles |
| WO2002038584A1 (en) * | 2000-11-10 | 2002-05-16 | Altana Pharma Ag | Process for the production of 16,17-[(cyclohexylmethylen)bis(oxy)]-11,21-dihydroxy-pregna-1,4-dien-3,20-dion or its 21-isobutyrat by transketalisation |
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| Publication number | Publication date |
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| CN1761678A (en) | 2006-04-19 |
| ZA200506943B (en) | 2006-07-26 |
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