CN107961217A - A kind of momestasone furoate aerosol combination - Google Patents
A kind of momestasone furoate aerosol combination Download PDFInfo
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Abstract
The present invention relates to a kind of momestasone furoate aerosol combination, said composition contains momestasone furoate, propellant and pharmaceutically acceptable carrier, the momestasone furoate exists with crystal form, its X-ray powder diffraction has characteristic peak at 2 θ=9.8 ° ± 0.1 ° of the angle of diffraction, 12.0 ° ± 0.1 °, 14.6 ° ± 0.1 °, 16.4 ° ± 0.1 °, 17.3 ° ± 0.1 °, 17.9 ° ± 0.1 °, 19.7 ° ± 0.1 °, 24.8 ° ± 0.1 °.
Description
Technical field
The present invention relates to a kind of aerosol containing glucocorticoid, more particularly to momestasone furoate aerosol combination and
Its preparation method.
Background technology
The pressure that medicinal aerosol system is made of valve, container, content (including medicine, additives, propellant etc.)
Packaging, when the valve is open, content is discharged with predetermined pressure, in controlled manner.The mode of control release include it is quantitative and
Non-quantitation.Quantitative aerosol plays whole body or local therapeutic effects after being chiefly used in suction, its formulation includes solution aerosol and mixes
Outstanding type aerosol.
Momestasone furoate [9,21- bis- chloro- 11 β, the pregnant steroid-Isosorbide-5-Nitrae of -16 Alpha-Methyl of 17- dihydroxy-diene -3,20- diketone 17-
(2- furoates)], it is a kind of U.S.'s not fluorine-containing new glucocorticoid medicine that first spirit is developed, there is anti-inflammatory, antiallergy etc.
Effect, available for treatment skin disease, rhinitis, asthma and COPD, has the advantages that curative effect is high, adverse reaction is few.In April, 2014
The momestasone furoate aerosol of MERCK SHARP DOHME companies research and developmentHFA obtains listing batch in U.S. FDA
Standard, the product are suspension aerosol.
The crystal form research work of medicine has become more and more important at present, and the different polymorphics of a bulk pharmaceutical chemicals can have
Different chemically and physically characteristics, including fusing point, chemical reactivity, apparent solubility, rate of dissolution, optically and mechanically property,
Vapour pressure and density, these characteristics can directly affect the processing and/or production of bulk pharmaceutical chemicals and preparation, and can influence preparation
Stability, solubility and bioavilability.Momestasone furoate is there are polymorphic, at present by the furancarboxylic acid of MSD Corp.'s research and development listing
Mometasone suspension type nasal sprayMometasone furoate monohydrate is used, is researched and developed and listed by Schering Plough company
Momestasone furoate aerosolHFA uses momestasone furoate anhydride.In addition, more documents also report
The polymorphism of momestasone furoate, such as：Document (journal of pharmaceutical sciences, Volume:
94,Issue:5,Pages:2493-2509, Journal, 2005) reporting momestasone furoate, there are monohydrate, anhydrous crystal forms
Tri- kinds of crystal forms of FORM1 and anhydrous crystal forms FORM2, and disclose corresponding XRD spectra.The document is investigated by thermostabilization and finds nothing
Crystal type FORM1 is most stable in a heated condition, and mometasone furoate monohydrate can be transformed into during aquation is gone in heating
Metastable anhydrous crystal forms FORM2, continues to heat, and anhydrous crystal forms FORM2 is transformed into stable anhydrous crystal forms FORM1, but
In lower temperature and high humidity environment, monohydrate crystal form is than FORM1 stable crystal form, because FORM1 solubility in water
It is higher than monohydrate.Document (IP.com, 10 (3B), 10-11, Journal, 2010) discloses another momestasone furoate
Novel crystal forms, the present invention is referred to as crystal form III, the X-ray powder diffraction of crystal form III 2 θ=6.3 ° of the angle of diffraction, 7.4 °,
There is characteristic peak at 7.8 °, 8.2 °, 9.3 °, 9.6 °, 9.8 °, 12.1 °.But the sour Mometasone crystal form III according to disclosed in the document
Preparation method, repeat its experimentation, do not obtain its report momestasone furoate crystal form III, but obtained momestasone furoate without
Crystal type FORM1, is specifically shown in comparative examples 1.
In addition, patent CN1149222, CN1137899, US4472393, EP 0057401, US005886200, document
(Journal of Medicinal Chemistry,Volume:30,Issue:9,Pages:1581-8,Journal,
1987), document (Green Chemistry, Volume:15,Issue:1,Pages:210-225, Journal, 2013), text
Offer (tetrahedron, Volume:55,Issue:11,Pages:3355-3364, Journal, 1999) etc. report furancarboxylic acid not
The preparation method of meter Song, by repeating to test, find to be obtained according to these methods is momestasone furoate anhydrous crystal forms
FORM1, specifically as shown in comparative examples 1~10.
In addition, the x-ray powder through investigating commercially available mometasone furoate monohydrate and momestasone furoate anhydride crystal form spreads out
Penetrate spectrogram respectively with document (journal of pharmaceutical sciences, Volume:94,Issue:5,Pages:
2493-2509, Journal, 2005) report mometasone furoate monohydrate, the spectrogram of momestasone furoate anhydrous crystal forms FORM1
It is basically identical, specifically as shown in Figure of description 1 and 2.
Although momestasone furoate anhydrous crystal forms FORM1 and mometasone furoate monohydrate all have preferably stability,
It is respectively to have shortcoming, such as：Under illumination condition, related material increases very fast for the two；Mometasone furoate monohydrate heat is unstable
It is fixed, the easy dehydration in Crushing with Jet Mill, and it is easy to produce static electricity during crushing, particle aggregation is serious, is unfavorable for matching somebody with somebody for aerosol
Put.In addition, experiment finds the aerosol prepared using momestasone furoate anhydrous crystal forms FORM1 and mometasone furoate monohydrate
Agent, pulmonary deposition ratio is unstable, at 30 DEG C ± 2 DEG C, is stored 24 months under 60%RH ± 5%RH relative humidity, pulmonary deposition ratio
It is decreased obviously.
Therefore, above-mentioned technical problem existing for existing momestasone furoate aerosol is overcome, there is provided a kind of more stable, lung
Portion's deposition higher, be it is clinical there is an urgent need for.
The content of the invention
The present invention provides a kind of momestasone furoate aerosol combination its preparation method, the aerosol combination have compared with
High pulmonary deposition ratio.
A kind of momestasone furoate suspension aerosol composition, containing momestasone furoate, propellant and can pharmaceutically connect
The carrier received, the momestasone furoate exist with crystal form, its X-ray powder diffraction 2 θ=9.8 ° of the angle of diffraction ±
0.1°、12.0°±0.1°、14.6°±0.1°、16.4°±0.1°、17.3°±0.1°、17.9°±0.1°、19.7°±0.1°、
There is characteristic peak at 24.8 ° ± 0.1 °.
A kind of momestasone furoate suspension aerosol composition, it is characterized in that the X of the momestasone furoate is penetrated
Line powder diffraction has characteristic peak at 2 θ=8.1 ° ± 0.1 ° of the angle of diffraction, 15.0 ° ± 0.1 °, 16.7 ° ± 0.1 °, place.
A kind of momestasone furoate suspension aerosol composition, it is characterized in that the propellant is selected from
One or both of HFA134a (tetrafluoroethane) or HFA227 (heptafluoro-propane).
A kind of momestasone furoate suspension aerosol composition, it is characterized in that the propellant is HFA227
(heptafluoro-propane).
A kind of momestasone furoate suspension aerosol composition, it is characterized in that the pharmaceutically acceptable load
Body includes cosolvent/cosolvent and surfactant.
A kind of momestasone furoate suspension aerosol composition the, it is characterized in that cosolvent/cosolvent is
Absolute ethyl alcohol, the surfactant are selected from tween, oleic acid, lecithin or poloxamer.
A kind of momestasone furoate suspension aerosol composition, it is characterized in that the surfactant is oil
Acid.
Momestasone furoate crystal form research process are being carried out, are being surprisingly found that a kind of brand-new momestasone furoate is brilliant
Type, is named as crystal form M.Compared with anhydrous crystal forms FORM1 and monohydrate, the momestasone furoate crystal form M under illumination condition
With fine stability.At the same time in the case where being prepared into aerosol, crystal form M is also very stable, and is not easy to assemble between particle, and has
There is higher pulmonary deposition ratio.
The momestasone furoate crystal form M exists with crystal form, its X-ray powder diffraction 2 θ=9.8 ° of the angle of diffraction ±
0.1°、12.0°±0.1°、14.6°±0.1°、16.4°±0.1°、17.3°±0.1°、17.9°±0.1°、19.7°±0.1°、
There is characteristic peak at 24.8 ° ± 0.1 °.
The momestasone furoate crystal form M exists with crystal form, its X-ray powder diffraction 2 θ=8.1 ° of the angle of diffraction ±
0.1°、9.8°±0.1°、12.0°±0.1°、14.6°±0.1°、15.0°±0.1°、16.4°±0.1°、16.7°±0.1°、
There is characteristic peak at 17.3 ° ± 0.1 °, 17.9 ° ± 0.1 °, 19.7 ° ± 0.1 °, 24.8 ° ± 0.1 °.
It should be understood to the diffracted intensity of characteristic peak with crystal preparing technology, sample mounting procedure and measuring instrument not
, also should be within the scope of the invention with that can have micro change.In addition, the difference and other factors of instrument may influence diffraction
2 θ values of angle, so the above-mentioned 2 θ values of the angle of diffraction for having characteristic peak can change in existing value ± 0.2 °.
A kind of preparation method of the momestasone furoate crystal form M, it is characterized in that momestasone furoate uses recrystallized from acetonitrile,
It is dried to obtain.
Momestasone furoate is soluble in chloroform, dissolves in acetone, dichloromethane etc., be slightly soluble in methanol, ethanol, ethyl acetate and
Acetonitrile, is practically insoluble in water and n-hexane.Find under study for action, using one or more organic solvents (acetone, methanol, ethanol,
Isopropanol, tetrahydrofuran, dioxane, dichloromethane, chloroform, dimethylformamide, dimethyl sulfoxide (DMSO), n-hexane, acetic acid second
Ester) etc. recrystallization, that find is all momestasone furoate anhydrous crystal forms FORM1, specifically as shown in comparative examples.
Stayed from inventive embodiments 2 as can be seen that carrying out influence factor, accelerated test and room temperature to momestasone furoate crystal form M
Sample long-term stable experiment investigate the result shows that, there are not significant changes in each detection projects of momestasone furoate crystal form M, and anhydrous
Under intense light conditions, impurity significantly increases for crystal form FORM1, monohydrate, illustrates in contrast, crystal form M has under intense light conditions
There is more preferable stability.Momestasone furoate crystal form M of the present invention is studied through TG-DT A spectrum, in the range of room temperature~200 DEG C, nothing
Endothermic peak.
Powder diffraction instrument used is that Rigaku D/max-2500 powder diffractometers produce for Rigaku company in the present invention
Product.TG-DTA analysis instrument used is Rigaku standard type TG-DTA analyzers in the present invention.
Brief description of the drawings：
Fig. 1 is the X-ray powder diffraction spectrogram of commercially available mometasone furoate monohydrate crystal form
Fig. 2 is the X-ray powder diffraction spectrogram of commercially available momestasone furoate anhydrous crystal forms FORM1
Fig. 3 is the X-ray powder diffraction spectrogram of momestasone furoate crystal form M made from inventive embodiments 1
Fig. 4 is the TG-DTA spectrograms of momestasone furoate crystal form M made from inventive embodiments 1
Embodiment：
Below will by embodiment, the invention will be further described, these description be not present invention is made into
The restriction of one step.It should be understood by those skilled in the art that the equivalent substitution made to the technical characteristic of the present invention, or change accordingly
Into still falling within protection scope of the present invention.
Identical reagent and reagent use same lot number in following embodiments.Momestasone furoate anhydrous crystal forms FORM1 with
And monohydrate is purchased from Tianjin Tian Yao limited companies.
The preparation of 1 momestasone furoate crystal form M of inventive embodiments
Take the commercially available momestasone furoates of 1g to be dissolved in 50ml acetonitriles, be heated to dissolved clarification, then evaporate solvent, there is crystal analysis
Go out, then filter, is dry, obtaining momestasone furoate crystal form M.
To axonometry X-ray powder diffraction after drying, measure its X-ray powder diffraction 2 θ=8.1 °, 9.8 °,
There is characteristic peak at 12.0 °, 14.6 °, 15.0 °, 16.4 °, 16.7 °, 17.3 °, 17.9 °, 19.7 °, 24.8 °, it is specific such as specification
Shown in attached drawing 3.The TG-DTA spectrograms for the momestasone furoate crystal form M being prepared, specifically as shown in Figure of description 4.
2 momestasone furoate polymorphic stability test of inventive embodiments
Content and measure in relation to material are examined according to the analysis method of the American Pharmacopeia USP36 momestasone furoates included
Survey.
Embodiment 2-1 influence factors are tested
Take momestasone furoate sample appropriate, put in measuring cup, spread out into≤the thin layer of 5mm thickness, tested as follows, the result is shown in
Table l.
L, hot test
Test sample opening is put in measuring cup, is placed 10 days at a temperature of 60 DEG C, was sampled, is detected in the 5th day and the 10th day.
2nd, high wet test
Take sample to put in right amount in constant humidity drier, placed 10 days under the conditions of relative humidity 92.5% at 25 DEG C, in
Sample within 5th day and the 10th day.
3rd, strong illumination is tested
Momestasone furoate crystal form M, monohydrate, anhydrous crystal forms FORM1 test sample openings is taken to be placed on equipped with fluorescent lamp respectively
Lighting box in, in illumination be 4500lx ± 500lx under conditions of places 10 days, in the 5th day and the 10th day sampling.
1 momestasone furoate influence factor result of the test of table
It is above-mentioned test result indicates that, under intense light conditions, momestasone furoate crystal form M is than monohydrate and anhydrous crystal forms
FORM1 stablizes.
Embodiment 2-2 accelerated tests
3 batches, momestasone furoate crystal form M samples are taken, by commercially available back in 40 DEG C of ± 2 DEG C of relative humidity 75% ± 5% of temperature
Under the conditions of place 6 months.It is detected respectively at the 1st, 2,3, sampling in June, the results are shown in Table 2.
2 momestasone furoate crystal form M accelerated test results of table
Embodiment 2-3 room temperatures keep sample long-term stable experiment
Momestasone furoate crystal form M room temperatures keep sample long-term stable experiment, 3 batches, momestasone furoate crystal form M samples are taken, by commercially available
It is packaged under conditions of 30 DEG C of ± 2 DEG C of relative humidity 60% ± 10% of temperature and places 24 months.Respectively at the 1st, 2,3,6,12,
18th, sampling in 24 months is detected, and the results are shown in Table 3.
3 room temperature of table keeps sample long-term stable experiment
The long-term stable experiment that keeps sample to momestasone furoate crystal form M progress influence factor, accelerated test and room temperature investigates knot
Fruit shows that significant changes does not occur in each detection project of momestasone furoate, with good stability, has additionally carried out X and has penetrated
Line powder diffraction is tested, the results showed that crystal form does not change, which can keep good stability.
The preparation of 3 momestasone furoate aerosol of inventive embodiments and pulmonary deposition ratio are investigated
The active ingredient that embodiment 3-1~3-3 is used is momestasone furoate crystal form M, the work of embodiment 3-4~3-6 uses
Property component is momestasone furoate anhydrous crystal forms FORM1, and the active ingredient that embodiment 3-7~3-9 is used is one water of momestasone furoate
Compound.D90≤4.6 μm of momestasone furoate crystal form M.D90≤4.6 μm of momestasone furoate anhydrous crystal forms FORM1.Furancarboxylic acid not rice
D90≤4.6 μm of loose monohydrate,
The specific prescriptions of embodiment 3-1~3-9 are shown in Table 3.1, and all embodiments use identical suction apparatus.
Using the active component deposition of medicinal ram (NGI) the measure momestasone furoate of a new generation, and use software for calculation
Active component deposition (medicine i.e. less than 5 microns accounts for the ratio of the medicine of recycling) is calculated, testing result is shown in Table 3.2.
3.1 embodiment 3-1~3-9 prescriptions of table
3.2 embodiment 3-1~3-9 momestasone furoate pulmonary deposition ratio tables of table
The preparation of comparative examples momestasone furoate anhydrous crystal forms FORM1
Comparative examples 1
Bibliography (IP.com, 10 (3B), 10-11, Journal, 2010), the description of embodiment part, is prepared for chaff
Sour Mometasone crystallization, and obtained crystal is subjected to X-ray powder diffraction measure, its X-ray powder diffraction 2 θ of the angle of diffraction=
There is characteristic peak at 9.1 °, 13.6 °, 15.3 °, 15.8 °, 16.6 °, 25.4 °, confirm as momestasone furoate anhydrous crystal forms FORM1.
Comparative examples 2
Referenced patent CN1149222C embodiments 1 have obtained momestasone furoate crude product, and purity 95%, is obtained by purifying
Momestasone furoate, purity 97%, and obtained crystal is subjected to X-ray powder diffraction measure, its X-ray powder diffraction is spreading out
2 θ=9.1 ° of firing angle, 13.6 °, 15.3 °, 15.8 °, 16.6 °, have characteristic peak at 25.4 °.Confirm as momestasone furoate anhydrous crystal forms
FORM1。
Comparative examples 3
Referenced patent CN1137899C embodiments 4, momestasone furoate crystal has been recrystallized to give with methanol-water, and is incited somebody to action
The crystal that arrives carries out X-ray powder diffraction measure, its X-ray powder diffraction 2 θ=9.1 ° of the angle of diffraction, 13.6 °, 15.3 °,
There is characteristic peak at 15.8 °, 16.6 °, 25.4 °.Confirm as momestasone furoate anhydrous crystal forms FORM1.
Comparative examples 4
Comparative examples 4-1
12 method I of referenced patent US4472393 embodiments:Momestasone furoate crystal has been recrystallized to give with methanol-water, and
By obtained crystal carry out X-ray powder diffraction measure, its X-ray powder diffraction 2 θ=9.1 ° of the angle of diffraction, 13.6 °,
There is characteristic peak at 15.3 °, 15.8 °, 16.6 °, 25.4 °.Confirm as momestasone furoate anhydrous crystal forms FORM1.
Comparative examples 4-2
12 method II of referenced patent US4472393 embodiments:Momestasone furoate crystal, and the crystalline substance that will be obtained has been prepared
Body carry out X-ray powder diffraction measure, its X-ray powder diffraction 2 θ=9.1 ° of the angle of diffraction, 13.6 °, 15.3 °, 15.8 °,
There is characteristic peak at 16.6 °, 25.4 °.Confirm as momestasone furoate anhydrous crystal forms FORM1.
Comparative examples 5
0057401 embodiments 14 of comparative examples 5-1 referenced patents EP, furancarboxylic acid not rice has been recrystallized to give with methanol-water
Loose crystal, and by obtained crystal carry out X-ray powder diffraction measure, its X-ray powder diffraction 2 θ=9.1 ° of the angle of diffraction,
There is characteristic peak at 13.6 °, 15.3 °, 15.8 °, 16.6 °, 25.4 °.Confirm as momestasone furoate anhydrous crystal forms FORM1.
0057401 embodiments 20 of comparative examples 5-2 referenced patents EP, furancarboxylic acid not rice has been recrystallized to give with methanol-water
Loose crystal, and by obtained crystal carry out X-ray powder diffraction measure, its X-ray powder diffraction 2 θ=9.1 ° of the angle of diffraction,
There is characteristic peak at 13.6 °, 15.3 °, 15.8 °, 16.6 °, 25.4 °.Confirm as momestasone furoate anhydrous crystal forms FORM1.
Comparative examples 6
Bibliography (Journal of Medicinal Chemistry, Volume:30,Issue:9,Pages:1581-
8, Journal, 1987) method, momestasone furoate crystal is recrystallized to give with methanol-water, and obtained crystal is subjected to X
Ray powder diffraction measure, its X-ray powder diffraction 2 θ=9.1 ° of the angle of diffraction, 13.6 °, 15.3 °, 15.8 °, 16.6 °,
There is characteristic peak at 25.4 °.Confirm as momestasone furoate anhydrous crystal forms FORM1.
Comparative examples 7
Referenced patent US5886200 embodiments 3, have obtained momestasone furoate crude product, purity 93%, and according to embodiment
4 method purifies to obtain momestasone furoate crystal, and purity 96% is brilliant by obtained momestasone furoate crude product and momestasone furoate
Body carry out X-ray powder diffraction measure, its X-ray powder diffraction 2 θ=9.1 ° of the angle of diffraction, 13.6 °, 15.3 °, 15.8 °,
There is characteristic peak at 16.6 °, 25.4 °.Confirm as momestasone furoate anhydrous crystal forms FORM1.
Comparative examples 8
Bibliography (Green Chemistry, Volume:15,Issue:1,Pages:210-225, Journal), the
Page 222,4.3 experimental sections, have obtained momestasone furoate crystal, and obtained crystal is carried out X-ray powder diffraction measure, its
X-ray powder diffraction has characteristic peak at 2 θ=9.1 ° of the angle of diffraction, 13.6 °, 15.3 °, 15.8 °, 16.6 °, 25.4 °.Confirm
For momestasone furoate anhydrous crystal forms FORM1.
Comparative examples 9
Bibliography (Tetrahedron, Volume:55,Issue:11,Pages:3355-3364,1999,Journal)
Method, momestasone furoate crystal has been obtained with recrystallizing methanol, and obtained crystal is carried out X-ray powder diffraction measure, its X
Ray powder diffraction has characteristic peak at 2 θ=9.1 ° of the angle of diffraction, 13.6 °, 15.3 °, 15.8 °, 16.6 °, 25.4 °.Confirm as chaff
Sour Mometasone anhydrous crystal forms FORM1.
Comparative examples 10
Bibliography (Shanghai medicine the 10th phase of volume 24 in 2003, P241) method is prepared for momestasone furoate crystal, and
By obtained crystal carry out X-ray powder diffraction measure, its X-ray powder diffraction 2 θ=9.1 ° of the angle of diffraction, 13.6 °,
There is characteristic peak at 15.3 °, 15.8 °, 16.6 °, 25.4 °.Confirm as momestasone furoate anhydrous crystal forms FORM1.
Comparative examples 11
Take the commercially available momestasone furoates of 1g to be dissolved in 120ml ethanol, be heated to dissolved clarification, then evaporate solvent to there is crystal analysis
Go out, then filter, is dry, and obtained crystal is subjected to X-ray powder diffraction measure, its X-ray powder diffraction is in the angle of diffraction 2
θ=9.1 °, 13.6 °, 15.3 °, 15.8 °, 16.6 °, have characteristic peak at 25.4 °.Confirm as momestasone furoate anhydrous crystal forms
FORM1。
Comparative examples 12
Take the commercially available momestasone furoates of 1g to be dissolved in 160ml isopropanols, be heated to dissolved clarification, then evaporate solvent to there is crystal
Separate out, then filter, is dry, and obtained crystal is subjected to X-ray powder diffraction measure, its X-ray powder diffraction is in diffraction
2 θ=9.1 ° of angle, 13.6 °, 15.3 °, 15.8 °, 16.6 °, have characteristic peak at 25.4 °.Confirm as momestasone furoate anhydrous crystal forms
FORM1。
Comparative examples 13
Take the commercially available momestasone furoates of 1g to be dissolved in 5ml tetrahydrofurans, add the n-hexane of 5ml, be then cooled to crystal
Separate out, be then cooled to crystal precipitation, then filter, is dry, and obtained crystal is subjected to X-ray powder diffraction measure,
Its X-ray powder diffraction has characteristic peak at 2 θ=9.1 ° of the angle of diffraction, 13.6 °, 15.3 °, 15.8 °, 16.6 °, 25.4 °.Confirm
For momestasone furoate anhydrous crystal forms FORM1.
Comparative examples 14
Take the commercially available momestasone furoates of 1g to be dissolved in 9ml dioxane, add the n-hexane of 5ml, be then cooled to crystal
Separate out, then filter, is dry, and obtained crystal is subjected to X-ray powder diffraction measure, its X-ray powder diffraction is in diffraction
2 θ=9.1 ° of angle, 13.6 °, 15.3 °, 15.8 °, 16.6 °, have characteristic peak at 25.4 °.Confirm as momestasone furoate anhydrous crystal forms
FORM1。
Comparative examples 15
Take the commercially available momestasone furoates of 1g to be dissolved in 5ml dimethylformamides, be heated to dissolved clarification, add the ethanol of 5ml, then
Crystal precipitation has been cooled to, has then filtered, is dry, and obtained crystal is subjected to X-ray powder diffraction measure, its X-ray powder
Last diffraction has characteristic peak at 2 θ=9.1 ° of the angle of diffraction, 13.6 °, 15.3 °, 15.8 °, 16.6 °, 25.4 °.Confirm as furancarboxylic acid not rice
Loose anhydrous crystal forms FORM1.
Comparative examples 16
Take the commercially available momestasone furoates of 1g to be dissolved in 12ml dimethyl sulfoxide (DMSO)s, be heated to dissolved clarification, add the methanol of 5ml, then
Crystal precipitation has been cooled to, has then filtered, is dry, and obtained crystal is subjected to X-ray powder diffraction measure, its X-ray powder
Last diffraction has characteristic peak at 2 θ=9.1 ° of the angle of diffraction, 13.6 °, 15.3 °, 15.8 °, 16.6 °, 25.4 °.Confirm as furancarboxylic acid not rice
Loose anhydrous crystal forms FORM1.
Comparative examples 17
Take the commercially available momestasone furoates of 1g to be dissolved in 14ml dichloromethane, add the n-hexane of 5ml, be then cooled to crystal
Separate out, be then cooled to crystal precipitation, then filter, is dry, and obtained crystal is subjected to X-ray powder diffraction measure,
Its X-ray powder diffraction has characteristic peak at 2 θ=9.1 ° of the angle of diffraction, 13.6 °, 15.3 °, 15.8 °, 16.6 °, 25.4 °.Confirm
For momestasone furoate anhydrous crystal forms FORM1.
Comparative examples 18
Take the commercially available momestasone furoates of 1g to be dissolved in 10ml chloroforms, add the n-hexane of 5ml, be then cooled to crystal analysis
Go out, then filter, is dry, and obtained crystal is subjected to X-ray powder diffraction measure, its X-ray powder diffraction is in the angle of diffraction 2
θ=9.1 °, 13.6 °, 15.3 °, 15.8 °, 16.6 °, have characteristic peak at 25.4 °.Confirm as anhydrous crystal forms FORM1.
Comparative examples 19
Take the commercially available momestasone furoates of 1g to be dissolved in 16ml acetone, add the n-hexane of 5ml, be then cooled to crystal analysis
Go out, then filter, is dry, and obtained crystal is subjected to X-ray powder diffraction measure, its X-ray powder diffraction is in the angle of diffraction 2
θ=9.1 °, 13.6 °, 15.3 °, 15.8 °, 16.6 °, have characteristic peak at 25.4 °.Confirm as momestasone furoate anhydrous crystal forms
FORM1。
Comparative examples 20
Take the commercially available momestasone furoates of 1g to be dissolved in 15ml ethyl acetate, add the n-hexane of 5ml, be then cooled to crystal
Separate out, be then cooled to crystal precipitation, then filter, is dry, and obtained crystal is subjected to X-ray powder diffraction measure,
Its X-ray powder diffraction has characteristic peak at 2 θ=9.1 ° of the angle of diffraction, 13.6 °, 15.3 °, 15.8 °, 16.6 °, 25.4 °.Confirm
For momestasone furoate anhydrous crystal forms FORM1.
Claims (7)
1. a kind of momestasone furoate suspension aerosol composition, contain momestasone furoate, propellant and pharmaceutically acceptable
Carrier, the momestasone furoate exists with crystal form, its X-ray powder diffraction 2 θ=9.8 ° ± 0.1 ° of the angle of diffraction,
12.0°±0.1°、14.6°±0.1°、16.4°±0.1°、17.3°±0.1°、17.9°±0.1°、19.7°±0.1°、24.8°
There is characteristic peak at ± 0.1 °.
A kind of 2. momestasone furoate suspension aerosol composition as claimed in claim 1, it is characterized in that the furancarboxylic acid is not
The X-ray powder diffraction of meter Song has characteristic peak at 2 θ=8.1 ° ± 0.1 ° of the angle of diffraction, 15.0 ° ± 0.1 °, 16.7 ° ± 0.1 °, place.
A kind of 3. momestasone furoate suspension aerosol composition as described in claim 1-2, it is characterized in that the projectile
Agent is selected from one or both of HFA134a or HFA227.
A kind of 4. momestasone furoate suspension aerosol composition as claimed in claim 3, it is characterized in that the propellant
For HFA227.
5. claim 1-2,4 it is any as described in a kind of momestasone furoate suspension aerosol composition, it is characterized in that described
Pharmaceutically acceptable carrier include cosolvent/cosolvent and surfactant.
6. a kind of momestasone furoate suspension aerosol composition as claimed in claim 5, it is characterized in that the cosolvent/
Cosolvent is absolute ethyl alcohol, and the surfactant is selected from tween, oleic acid, lecithin or poloxamer.
A kind of 7. momestasone furoate suspension aerosol composition as claimed in claim 6, it is characterized in that the surface is lived
Property agent is oleic acid.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1233960A (en) * | 1996-08-29 | 1999-11-03 | 先灵公司 | Chlorofluorocarbon-free mometasone furoate aerosol formulations |
| US20070196459A1 (en) * | 2004-06-07 | 2007-08-23 | Jie Zhang | Compositions and methods for treating dermatitis or psoriasis |
| CN101652123A (en) * | 2007-02-09 | 2010-02-17 | 先灵公司 | Stable pharmaceutical drug aerosols |
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2016
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1233960A (en) * | 1996-08-29 | 1999-11-03 | 先灵公司 | Chlorofluorocarbon-free mometasone furoate aerosol formulations |
| US20070196459A1 (en) * | 2004-06-07 | 2007-08-23 | Jie Zhang | Compositions and methods for treating dermatitis or psoriasis |
| CN101652123A (en) * | 2007-02-09 | 2010-02-17 | 先灵公司 | Stable pharmaceutical drug aerosols |
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