CN107961217B - Mometasone furoate aerosol composition - Google Patents
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Abstract
The invention relates to a mometasone furoate aerosol composition, which contains mometasone furoate, a propellant and a pharmaceutically acceptable carrier, wherein the mometasone furoate exists in a crystal form, and has characteristic peaks in diffraction angle 2 theta of 9.8 degrees +/-0.1 degrees, 12.0 degrees +/-0.1 degrees, 14.6 degrees +/-0.1 degrees, 16.4 degrees +/-0.1 degrees, 17.3 degrees +/-0.1 degrees, 17.9 degrees +/-0.1 degrees, 19.7 degrees +/-0.1 degrees and 24.8 degrees +/-0.1 degrees by X-ray powder diffraction.
Description
Technical Field
The invention relates to an aerosol containing glucocorticoid, in particular to a mometasone furoate aerosol composition and a preparation method thereof.
Background
Medicinal aerosol systems consist of a valve, a container, a pressure pack of contents (including drugs, additives, propellants, etc.) which are released in a controlled manner at a predetermined pressure when the valve is opened. Means for controlling release include quantitative and non-quantitative. Metered dose aerosols are commonly used for systemic or topical treatment after inhalation and include both solution and suspension aerosols.
Mometasone furoate [9, 21-dichloro-11 beta, 17-dihydroxy-16 alpha-methyl pregna-1, 4-diene-3, 20-dione 17- (2-furoate)]The medicine is a novel glucocorticoid medicine without fluorine developed by the American prodigiosin, has the effects of anti-inflammation, anti-allergy and the like, can be used for treating skin diseases, rhinitis, asthma and COPD, and has the advantages of high curative effect, few adverse reactions and the like. Mometasone furoate aerosol developed by DOHME company of MERCK SHARP 4 months 4 in 2014
HFA is approved by FDA on the market in the United states and is in the form of suspension aerosol.
The work of crystal form research on drugs has become more and more important at present, and different polymorphic forms of a drug substance may have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure and density, which may directly affectThe handling and/or production of the drug substance and formulation, and can affect the stability, solubility, and bioavailability of the formulation. The mometasone furoate exists in a polymorphic form, and the mometasone furoate suspension type nasal spray which is researched and developed by Moshadong company at present
The mometasone furoate monohydrate is used, and the mometasone furoate aerosol developed and marketed by Xianlingbao company
The HFA uses mometasone furoate anhydride. In addition, several documents report polymorphism of mometasone furoate, such as: the existence of mometasone furoate in three crystal FORMs, namely monohydrate, anhydrous crystal FORM FORM1 and anhydrous crystal FORM FORM2, is reported in the literature (Journal of pharmaceutical sciences, Volume:94, Issue:5, Pages:2493-2509, Journal,2005) and the corresponding XRD spectrum is disclosed. The document discovers that anhydrous crystal FORM1 is most stable under heating conditions, mometasone furoate monohydrate can be transformed into metastable anhydrous crystal FORM2 in the process of heating and dehydration, and anhydrous crystal FORM2 is transformed into stable anhydrous crystal FORM1 by continuing heating, but in a lower temperature and high humidity environment, the monohydrate crystal FORM is more stable than FORM1 crystal FORM, because FORM1 has higher solubility in water than monohydrate. The document (IP.com,10(3B),10-11, Journal,2010) discloses another new mometasone furoate crystal form, which is called as a crystal form III in the invention, and the X-ray powder diffraction of the crystal form III has characteristic peaks at diffraction angles 2 theta of 6.3 degrees, 7.4 degrees, 7.8 degrees, 8.2 degrees, 9.3 degrees, 9.6 degrees, 9.8 degrees and 12.1 degrees. However, according to the preparation method of mometasone furoate crystal FORM III disclosed in the document, the experimental process is repeated, the mometasone furoate crystal FORM III reported is not obtained, but the anhydrous mometasone furoate crystal FORM1 is obtained, which is specifically shown in comparative example 1.
Furthermore, patent CN1149222, CN1137899, US4472393, EP 0057401, US005886200, literature (Journal of Medicinal Chemistry, Volume:30, Issue:9, Pages:1581-8, Journal, 1987), literature (Green Chemistry, Volume:15, Issue:1, Pages: 210-.
In addition, the X-ray powder diffraction spectra of the mometasone furoate monohydrate and the mometasone furoate anhydrous crystal FORM are basically consistent with the spectra of the mometasone furoate monohydrate and the mometasone furoate anhydrous crystal FORM FORM1 reported in the literature (Journal of pharmaceutical sciences, Volume:94, Issue:5, Pages:2493-2509, Journal,2005), as shown in the attached drawings 1 and 2 of the specification.
Although mometasone furoate in its anhydrous crystalline FORM1 and mometasone furoate monohydrate have good stability, they have disadvantages such as: under the condition of illumination, related substances grow faster; mometasone furoate monohydrate is unstable when heated, is easy to lose water in the air flow crushing process, is easy to generate static electricity during crushing, has serious particle agglomeration, is not beneficial to the preparation of aerosol and the like. In addition, tests show that the lung deposition rate of the aerosol prepared from the mometasone furoate anhydrous crystal FORM FORM1 and mometasone furoate monohydrate is unstable, and the lung deposition rate is obviously reduced after the aerosol is stored for 24 months at 30 +/-2 ℃ and 60% RH +/-5% RH relative humidity.
Therefore, it is needed to overcome the above technical problems of the existing mometasone furoate aerosol, and provide a stable aerosol with higher lung deposition rate.
Disclosure of Invention
The invention provides a mometasone furoate aerosol composition and a preparation method thereof, and the aerosol composition has higher lung deposition rate.
The mometasone furoate suspension type aerosol composition contains mometasone furoate, a propellant and a pharmaceutically acceptable carrier, wherein the mometasone furoate exists in a crystal form, and has characteristic peaks at diffraction angles of 2 theta of 9.8 degrees +/-0.1 degrees, 12.0 degrees +/-0.1 degrees, 14.6 degrees +/-0.1 degrees, 16.4 degrees +/-0.1 degrees, 17.3 degrees +/-0.1 degrees, 17.9 degrees +/-0.1 degrees, 19.7 degrees +/-0.1 degrees and 24.8 degrees +/-0.1 degrees by X-ray powder diffraction.
The mometasone furoate suspension type aerosol composition is characterized in that the X-ray powder diffraction of mometasone furoate has characteristic peaks at diffraction angles 2 theta of 8.1 degrees +/-0.1 degrees, 15.0 degrees +/-0.1 degrees, 16.7 degrees +/-0.1 degrees.
The mometasone furoate suspension type aerosol composition is characterized in that the propellant is one or two of HFA134a (tetrafluoroethane) or HFA227 (heptafluoropropane).
The mometasone furoate suspension type aerosol composition is characterized in that the propellant is HFA227 (heptafluoropropane).
The mometasone furoate suspension type aerosol composition is characterized in that the pharmaceutically acceptable carrier comprises a cosolvent/cosolvent and a surfactant.
The mometasone furoate suspension type aerosol composition is characterized in that the cosolvent/cosolvent is absolute ethyl alcohol, and the surfactant is selected from tween, oleic acid, lecithin or poloxamer.
The mometasone furoate suspension type aerosol composition is characterized in that the surfactant is oleic acid.
In the research process of the mometasone furoate crystal form, a brand-new mometasone furoate crystal form is unexpectedly found and named as a crystal form M. Compared with the anhydrous crystal FORM FORM1 and monohydrate, the mometasone furoate crystal FORM M has good stability under the illumination condition. Meanwhile, the crystal form M is stable under the condition of being prepared into aerosol, and particles are not easy to aggregate, and the lung deposition rate is high.
The mometasone furoate crystal form M exists in a crystal form, and has characteristic peaks at diffraction angles 2 theta of 9.8 degrees +/-0.1 degrees, 12.0 degrees +/-0.1 degrees, 14.6 degrees +/-0.1 degrees, 16.4 degrees +/-0.1 degrees, 17.3 degrees +/-0.1 degrees, 17.9 degrees +/-0.1 degrees, 19.7 degrees +/-0.1 degrees and 24.8 degrees +/-0.1 degrees in X-ray powder diffraction.
The mometasone furoate crystal form M exists in a crystal form, and has characteristic peaks at diffraction angles 2 theta of 8.1 degrees +/-0.1 degrees, 9.8 degrees +/-0.1 degrees, 12.0 degrees +/-0.1 degrees, 14.6 degrees +/-0.1 degrees, 15.0 degrees +/-0.1 degrees, 16.4 degrees +/-0.1 degrees, 16.7 degrees +/-0.1 degrees, 17.3 degrees +/-0.1 degrees, 17.9 degrees +/-0.1 degrees, 19.7 degrees +/-0.1 degrees and 24.8 degrees +/-0.1 degrees by X-ray powder diffraction.
It is to be understood that the diffraction intensity of the characteristic peak may vary slightly from crystal preparation technique, sample mounting method and measurement instrument to crystal preparation technique and is also within the scope of the present invention. In addition, the diffraction angle 2 θ value may be affected by instrument variation and other factors, so that the above-mentioned diffraction angle 2 θ value having characteristic peaks may vary within ± 0.2 ° from the existing value.
The preparation method of the mometasone furoate crystal form M is characterized in that the mometasone furoate is obtained by adopting acetonitrile recrystallization and drying.
Mometasone furoate is readily soluble in chloroform, soluble in acetone, dichloromethane, etc., slightly soluble in methanol, ethanol, ethyl acetate and acetonitrile, and hardly soluble in water and n-hexane. In the research, the mometasone furoate anhydrous crystal FORM FORM1 is found to be obtained by using one or more organic solvents (acetone, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, dichloromethane, chloroform, dimethylformamide, dimethyl sulfoxide, n-hexane, ethyl acetate) and the like for recrystallization, and is particularly shown in the comparative example.
The invention example 2 shows that the results of the influence factors, the accelerated test and the room temperature sample retention long-term stability test on the mometasone furoate crystal FORM M show that the detection items of the mometasone furoate crystal FORM M do not have obvious changes, and the impurities of the anhydrous crystal FORM FORM1 and monohydrate are obviously increased under the strong light condition, which indicates that the crystal FORM M has better stability under the strong light condition. Through thermogravimetric differential thermal analysis research, the mometasone furoate crystal form M has no endothermic peak in the range of room temperature to 200 ℃.
The powder diffraction instrument used in the present invention is Rigaku D/max-2500 powder diffraction instrument, a product of Japan science Co. The thermogravimetric-differential thermal analyzer used in the present invention is a japanese physical standard type TG-DTA analyzer.
Description of the drawings:
FIG. 1 is an X-ray powder diffraction pattern of a commercially available mometasone furoate monohydrate crystalline form
FIG. 2 is an X-ray powder diffraction spectrum of a commercially available mometasone furoate anhydrous crystalline FORM FORM1
FIG. 3 is the X-ray powder diffraction spectrum of mometasone furoate crystal form M prepared in the invention example 1
FIG. 4 is a TG-DTA spectrum of mometasone furoate crystal form M prepared in the invention example 1
The specific implementation mode is as follows:
the invention will now be further described by way of the following examples, which are not intended to limit the scope of the invention in any way. It will be understood by those skilled in the art that equivalent substitutions for the technical features of the present invention, or corresponding modifications, can be made within the scope of the present invention.
The same lot numbers were used for the same reagents and reagents in the following examples. Mometasone furoate anhydrous crystalline FORM FORM1 and monohydrate were purchased from Tianjin medicine GmbH.
Inventive example 1 preparation of mometasone furoate form M
Dissolving 1g of commercially available mometasone furoate in 50ml of acetonitrile, heating until the solution is clear, evaporating the solvent, separating out crystals, filtering and drying to obtain the mometasone furoate crystal form M.
The crystals after drying were subjected to X-ray powder diffraction, and X-ray powder diffraction was found to have characteristic peaks at 2 θ of 8.1 °, 9.8 °, 12.0 °, 14.6 °, 15.0 °, 16.4 °, 16.7 °, 17.3 °, 17.9 °, 19.7 °, and 24.8 °, as shown in fig. 3 of the specification. The TG-DTA spectrogram of the mometasone furoate crystal form M is shown in the attached figure 4 in the specification.
Inventive example 2 mometasone furoate polymorph stability test
The content and the related substances are measured according to the analysis method of mometasone furoate recorded in the United states pharmacopoeia USP 36.
EXAMPLE 2-1 influential factor test
A proper amount of mometasone furoate sample is taken and placed in a weighing bottle to be spread into a thin layer with the thickness of less than or equal to 5mm, and the following experiment is carried out, and the result is shown in table l.
High temperature test
The sample is placed in a weighing bottle with an opening, placed at 60 ℃ for 10 days, sampled on the 5 th and 10 th days, and detected.
2. High humidity test
A proper amount of the sample was placed in a constant humidity desiccator at 25 ℃ under a relative humidity of 92.5% for 10 days, and samples were taken on the 5 th and 10 th days.
3. Test by intense light irradiation
Respectively taking mometasone furoate crystal FORM M, monohydrate and anhydrous crystal FORM FORM1 samples, placing the samples in a lighting box with a fluorescent lamp, placing the samples for 10 days under the condition that the illumination is 4500lx +/-500 lx, and sampling on the 5 th day and the 10 th day.
TABLE 1 mometasone furoate influencing factor test results
The experimental results show that under the strong light condition, the mometasone furoate crystal FORM M is more stable than the monohydrate and the anhydrous crystal FORM FORM 1.
Example 2-2 accelerated test
Taking 3 batches of mometasone furoate crystal form M samples, and placing for 6 months according to a commercially available package under the condition of 40 ℃ +/-2 ℃ and 75% +/-5% relative humidity. Samples were taken at 1 st, 2 nd, 3 rd and 6 th months for testing, and the results are shown in Table 2.
TABLE 2 acceleration test results of mometasone furoate form M
Examples 2-3 Long term stability test for Room temperature Retention
The mometasone furoate crystal form M is subjected to room temperature sample retention long-term stability test, 3 batches of mometasone furoate crystal form M samples are taken and placed for 24 months according to a commercially available package under the condition that the temperature is 30 +/-2 ℃ and the relative humidity is 60% +/-10%. The samples were taken at months 1, 2, 3, 6, 12, 18 and 24 respectively, and the results are shown in Table 3.
TABLE 3 Long term stability test for room temperature retention
The results of the influence factor, the acceleration test and the room temperature sample retention long-term stability test on the mometasone furoate crystal form M show that each detection item of mometasone furoate has no obvious change and has good stability, and the results of the X-ray powder diffraction test show that the crystal form has no change and can keep good stability.
EXAMPLE 3 preparation of mometasone furoate Aerosol and Lung deposition Rate Studies
The mometasone furoate crystal FORM M is used as an active ingredient in examples 3-1 to 3-3, the mometasone furoate anhydrous crystal FORM FORM1 is used as an active ingredient in examples 3-4 to 3-6, and the mometasone furoate monohydrate is used as an active ingredient in examples 3-7 to 3-9. The D90 of the mometasone furoate crystal form M is less than or equal to 4.6 mu M. D90 of mometasone furoate anhydrous crystal FORM FORM1 is less than or equal to 4.6 mu m. The D90 of the mometasone furoate monohydrate is less than or equal to 4.6 mu m,
examples 3-1 to 3-9 specific formulations are given in Table 3.1, and the same inhalation device was used for all examples.
The deposition rate of the effective part of mometasone furoate is measured by adopting a new generation of medicinal impactor (NGI), the deposition rate of the effective part (namely the proportion of the medicament smaller than 5 microns in the recycled medicament) is calculated by using calculation software, and the detection result is shown in a table 3.2.
TABLE 3.1 examples 3-1 to 3-9 formulations
TABLE 3.2 pulmonary deposition rates of mometasone furoate examples 3-1 to 3-9
Comparative example preparation of mometasone furoate in the FORM of crystalline anhydrous FORM1
Comparative example 1
Reference (ip.com,10(3B),10-11, Journal,2010), described in the examples section, prepares mometasone furoate crystals, and subjects the obtained crystals to X-ray powder diffraction measurement, wherein the X-ray powder diffraction thereof has characteristic peaks at diffraction angles 2 θ of 9.1 °, 13.6 °, 15.3 °, 15.8 °, 16.6 ° and 25.4 °, and is identified as mometasone furoate anhydrous crystal FORM 1.
Comparative example 2
Reference patent CN1149222C example 1 gives crude mometasone furoate with a purity of 95%, and mometasone furoate with a purity of 97% obtained by purification, and the obtained crystals are subjected to X-ray powder diffraction measurement, and the X-ray powder diffraction of the crystals has characteristic peaks at diffraction angles 2 θ of 9.1 °, 13.6 °, 15.3 °, 15.8 °, 16.6 ° and 25.4 °. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Comparative example 3
Referring to patent CN1137899C, in example 4, mometasone furoate crystals were obtained by recrystallization from methanol-water, and the obtained crystals were subjected to X-ray powder diffraction measurement, and the X-ray powder diffraction thereof had characteristic peaks at diffraction angles 2 θ of 9.1 °, 13.6 °, 15.3 °, 15.8 °, 16.6 °, and 25.4 °. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Comparative example 4
Comparative example 4-1
Reference is made to patent US4472393 example 12, method I, wherein mometasone furoate crystals are obtained by recrystallization from methanol-water and the obtained crystals are subjected to X-ray powder diffraction measurement, wherein the X-ray powder diffraction has characteristic peaks at diffraction angles 2 theta of 9.1 degrees, 13.6 degrees, 15.3 degrees, 15.8 degrees, 16.6 degrees and 25.4 degrees. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Comparative example 4-2
Reference is made to patent US4472393 example 12, method II, mometasone furoate crystals are prepared and the crystals obtained are subjected to X-ray powder diffraction measurements with characteristic peaks at diffraction angles 2 θ of 9.1 °, 13.6 °, 15.3 °, 15.8 °, 16.6 ° and 25.4 °. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Comparative example 5
Comparative example 5-1 referring to patent EP 0057401 example 14, mometasone furoate crystals were obtained by recrystallization from methanol-water, and the obtained crystals were subjected to X-ray powder diffraction measurement, which showed characteristic peaks at diffraction angles 2 θ of 9.1 °, 13.6 °, 15.3 °, 15.8 °, 16.6 °, and 25.4 °. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Comparative example 5-2 referring to patent EP 0057401 example 20, mometasone furoate crystals were obtained by recrystallization from methanol-water, and the obtained crystals were subjected to X-ray powder diffraction measurement, which showed characteristic peaks at diffraction angles 2 θ of 9.1 °, 13.6 °, 15.3 °, 15.8 °, 16.6 °, and 25.4 °. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Comparative example 6
According to the method of the reference (Journal of Medicinal Chemistry, Volume:30, Issue:9, Pages:1581-8, Journal, 1987), mometasone furoate crystals were obtained by recrystallization from methanol-water, and the obtained crystals were subjected to X-ray powder diffraction measurement, and the X-ray powder diffraction thereof had characteristic peaks at diffraction angles 2. theta. 9.1 °, 13.6 °, 15.3 °, 15.8 °, 16.6 °, and 25.4 °. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Comparative example 7
Referring to patent US5886200, example 3, crude mometasone furoate with a purity of 93% was obtained and purified according to the method of example 4 to obtain mometasone furoate crystals with a purity of 96%, and the obtained mometasone furoate crude product and mometasone furoate crystals were subjected to X-ray powder diffraction measurement, and X-ray powder diffraction thereof all had characteristic peaks at diffraction angles 2 θ of 9.1 °, 13.6 °, 15.3 °, 15.8 °, 16.6 ° and 25.4 °. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Comparative example 8
In the reference (Green Chemistry, Volume:15, Issue:1, Pages:210-225, Journal), page 222, 4.3 experimental part, mometasone furoate crystals were obtained and subjected to X-ray powder diffraction measurement, wherein X-ray powder diffraction thereof all had characteristic peaks at diffraction angles 2 theta of 9.1 DEG, 13.6 DEG, 15.3 DEG, 15.8 DEG, 16.6 DEG and 25.4 deg. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Comparative example 9
According to the method of the reference (Tetrahedron, Volume:55, Issue:11, Pages:3355-3364,1999, Journal), mometasone furoate crystals were obtained by recrystallization from methanol, and the obtained crystals were subjected to X-ray powder diffraction measurement, wherein the X-ray powder diffraction thereof showed characteristic peaks at diffraction angles 2 θ of 9.1 °, 13.6 °, 15.3 °, 15.8 °, 16.6 °, and 25.4 °. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Comparative example 10
In the reference (shanghai medicine, volume 24, No. 10, P241), mometasone furoate crystals were prepared and the obtained crystals were subjected to X-ray powder diffraction measurement, and the X-ray powder diffraction thereof had characteristic peaks at diffraction angles 2 θ of 9.1 °, 13.6 °, 15.3 °, 15.8 °, 16.6 °, and 25.4 °. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Comparative example 11
Dissolving 1g of commercially available mometasone furoate in 120ml of ethanol, heating until the solution is clear, evaporating the solvent until crystals are precipitated, filtering, drying, and carrying out X-ray powder diffraction measurement on the obtained crystals, wherein the X-ray powder diffraction of the crystals has characteristic peaks at diffraction angles of 2 theta, 9.1 degrees, 13.6 degrees, 15.3 degrees, 15.8 degrees, 16.6 degrees and 25.4 degrees. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Comparative example 12
Dissolving 1g of commercially available mometasone furoate in 160ml of isopropanol, heating until the solution is clear, evaporating the solvent until crystals are precipitated, filtering, drying, and measuring the obtained crystals by X-ray powder diffraction, wherein the X-ray powder diffraction of the crystals has characteristic peaks at diffraction angles of 2 theta, 9.1 degrees, 13.6 degrees, 15.3 degrees, 15.8 degrees, 16.6 degrees and 25.4 degrees. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Comparative example 13
Dissolving 1g of commercially available mometasone furoate in 5ml of tetrahydrofuran, adding 5ml of n-hexane, cooling until crystals precipitate, filtering, drying, and carrying out X-ray powder diffraction measurement on the obtained crystals, wherein the X-ray powder diffraction has characteristic peaks at diffraction angles of 2 theta (9.1 degrees), 13.6 degrees, 15.3 degrees, 15.8 degrees, 16.6 degrees and 25.4 degrees. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Comparative example 14
Dissolving 1g of commercially available mometasone furoate in 9ml of dioxane, adding 5ml of n-hexane, cooling until crystals are precipitated, filtering, drying, and carrying out X-ray powder diffraction measurement on the obtained crystals, wherein the X-ray powder diffraction has characteristic peaks at diffraction angles of 2 theta of 9.1 degrees, 13.6 degrees, 15.3 degrees, 15.8 degrees, 16.6 degrees and 25.4 degrees. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Comparative example 15
Dissolving 1g of commercially available mometasone furoate in 5ml of dimethylformamide, heating until the solution is clear, adding 5ml of ethanol, then cooling until crystals are precipitated, filtering, drying, and carrying out X-ray powder diffraction measurement on the obtained crystals, wherein the X-ray powder diffraction of the crystals has characteristic peaks at diffraction angles of 2 theta of 9.1 degrees, 13.6 degrees, 15.3 degrees, 15.8 degrees, 16.6 degrees and 25.4 degrees. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Comparative example 16
Dissolving 1g of commercially available mometasone furoate in 12ml of dimethyl sulfoxide, heating until the solution is clear, adding 5ml of methanol, then cooling until crystals are precipitated, then filtering and drying, and carrying out X-ray powder diffraction measurement on the obtained crystals, wherein the X-ray powder diffraction of the crystals has characteristic peaks at diffraction angles of 2 theta of 9.1 degrees, 13.6 degrees, 15.3 degrees, 15.8 degrees, 16.6 degrees and 25.4 degrees. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Comparative example 17
Dissolving 1g of commercially available mometasone furoate in 14ml of dichloromethane, adding 5ml of n-hexane, cooling until crystals precipitate, filtering, drying, and carrying out X-ray powder diffraction measurement on the obtained crystals, wherein the X-ray powder diffraction has characteristic peaks at diffraction angles of 2 theta (9.1 degrees), 13.6 degrees, 15.3 degrees, 15.8 degrees, 16.6 degrees and 25.4 degrees. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Comparative example 18
Dissolving 1g of commercially available mometasone furoate in 10ml of chloroform, adding 5ml of n-hexane, cooling until crystals precipitate, filtering, drying, and carrying out X-ray powder diffraction measurement on the obtained crystals, wherein the X-ray powder diffraction has characteristic peaks at diffraction angles of 2 theta, 9.1 degrees, 13.6 degrees, 15.3 degrees, 15.8 degrees, 16.6 degrees and 25.4 degrees. Identified as FORM1 in its anhydrous crystalline FORM.
Comparative example 19
Dissolving 1g of commercially available mometasone furoate in 16ml of acetone, adding 5ml of n-hexane, cooling until crystals are precipitated, filtering, drying, and carrying out X-ray powder diffraction measurement on the obtained crystals, wherein the X-ray powder diffraction has characteristic peaks at diffraction angles of 2 theta, 9.1 degrees, 13.6 degrees, 15.3 degrees, 15.8 degrees, 16.6 degrees and 25.4 degrees. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Comparative example 20
Dissolving 1g of commercially available mometasone furoate in 15ml of ethyl acetate, adding 5ml of n-hexane, cooling until crystals precipitate, filtering, drying, and carrying out X-ray powder diffraction measurement on the obtained crystals, wherein the X-ray powder diffraction has characteristic peaks at diffraction angles of 2 theta (9.1 degrees), 13.6 degrees, 15.3 degrees, 15.8 degrees, 16.6 degrees and 25.4 degrees. Identified as mometasone furoate anhydrous crystalline FORM fom 1.
Claims (7)
1. The mometasone furoate suspension type aerosol composition contains mometasone furoate, a propellant and a pharmaceutically acceptable carrier, wherein the mometasone furoate exists in a crystal form, and has characteristic peaks at diffraction angles of 2 theta of 9.8 degrees +/-0.1 degrees, 12.0 degrees +/-0.1 degrees, 14.6 degrees +/-0.1 degrees, 16.4 degrees +/-0.1 degrees, 17.3 degrees +/-0.1 degrees, 17.9 degrees +/-0.1 degrees, 19.7 degrees +/-0.1 degrees and 24.8 degrees +/-0.1 degrees by X-ray powder diffraction.
2. The mometasone furoate suspension aerosol composition according to claim 1, wherein the X-ray powder diffraction of mometasone furoate has characteristic peaks at diffraction angles 2 θ of 8.1 ° ± 0.1 °, 15.0 ° ± 0.1 °, 16.7 ° ± 0.1 °.
3. The mometasone furoate suspension aerosol composition as claimed in any one of claims 1 or 2, wherein the propellant is selected from one or both of HFA134a or HFA 227.
4. The mometasone furoate suspension aerosol composition as claimed in claim 3, wherein the propellant is HFA 227.
5. The mometasone furoate suspension aerosol composition as claimed in any one of claims 1-2, 4, wherein the pharmaceutically acceptable carrier comprises a cosolvent and a surfactant.
6. The mometasone furoate suspension aerosol composition as claimed in claim 5, wherein the cosolvent is absolute ethanol, and the surfactant is selected from tween, oleic acid, lecithin or poloxamer.
7. The mometasone furoate suspension aerosol composition of claim 6, wherein the surfactant is oleic acid.
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| CN1233960A (en) * | 1996-08-29 | 1999-11-03 | 先灵公司 | Chlorofluorocarbon-free mometasone furoate aerosol formulations |
| CN101652123A (en) * | 2007-02-09 | 2010-02-17 | 先灵公司 | Stable pharmaceutical drug aerosols |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1233960A (en) * | 1996-08-29 | 1999-11-03 | 先灵公司 | Chlorofluorocarbon-free mometasone furoate aerosol formulations |
| CN101652123A (en) * | 2007-02-09 | 2010-02-17 | 先灵公司 | Stable pharmaceutical drug aerosols |
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