CN106880637A - A kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation composition - Google Patents
A kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation composition Download PDFInfo
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- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
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Abstract
A kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation composition, containing (A) ciclesonide or its monohydrate, (B) formoterol fumarate or its hydrate, (C) Tiotropium Bromide or its monohydrate and pharmaceutically acceptable carrier, described carrier is the mixture of carrier A, carrier B and support C.
Description
Technical field
It is special the present invention relates to a kind of glucocorticoid, broxaterol and anticholinergic agents compound dry powder inhalation
It is not related to ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation and preparation method thereof.
Background technology
Foradil Aerolizer formoterol fumarate belongs to one kind of respiratory tract administration preparation.In the last few years, Foradil Aerolizer formoterol fumarate was due to its targeting, height
Effect, quick-acting, toxic and side effect it is small, it is pollution-free the advantages of, quickly grow.Glucocorticoid, broxaterol and anticholinergic drug
Thing is that treatment asthma and chronic pulmonary hinder most common medicine at present.Ciclesonide is a kind of new glucocorticoid, by Germany
Altana companies research and develop, and Ciclesonide aerosol in 2004, for treating asthma, exists successively afterwards in Australia's approval listing
The countries and regions such as U.S., Europe, day list.The said firm is investigated ciclesonide suspension nasal spray, and ciclesonide is suspended within 2008
Nasal sprayListed in the U.S. first, listed in countries and regions such as Europe, days successively afterwards.Fumaric acid Fu Mote
Sieve is the third generation broxaterol class suppressing panting calming medicine that Japanese Yamanouchi company develops, and in March, 1988 is in Japan
City.Tiotropium Bromide is the anticholinergic agents of specific selectivity, it is adaptable to the maintaining treatment of chronic obstructive pulmonary disease (COPD), bag
Chronic bronchitis and pulmonary emphysema are included, with the dyspneic maintaining treatment of property and the prevention of acute attack.Tiotropium Bromide is mesh
Preceding only one is long-acting, high selectivity M3 ARBs, and daily suction once can reach good treatment to COPD patient
Effect, preferably, long-term rule can be effectively improved pulmonary ventilation function, excessively inflation using Tiotropium Bromide and breathing is tired for compliance
Difficulty, improves exercise tolerance, and can reduce the acute exacerbation of COPD.Additionally, Tiotropium Bromide and other types of bronchodilator
Combination can increase bronchodilator effect without increasing adverse reaction, pretend as the line that COPD diagnosis and treatment guide is recommended maintains medicine
Thing.
The crystal formation research work of current medicine has become more and more important, particularly with solid pharmaceutical preparation, Chinese patent
ZL200580026414.0 disclose the difficulty or ease of the crystalline polymorphs often medicine preparation of certain drug, stability, solubility,
Storage stability, preparation difficulty or ease and an internal pharmacological important factor of judgment.
Document JOURNAL OF PHARMACEUTICAL SCIENCES, VOL.97, NO.9,2008, P3765,
EP929566, WO2008062450, WO2008035066, WO2007092574, US2010120737, EP2022796 etc. are reported
There is anhydrous ciclesonide amorphous substance, 4 kinds of anhydrous ciclesonide crystalline polymorphs (I, II, III, IV) and ring in ciclesonide
Rope how Division A League Matches of Germany Football solvate.The XRD spectra of ciclesonide crystal formation I is as shown in WO2008062450 accompanying drawings 1.Ciclesonide crystal formation
The XRD spectra of II is as shown in WO2007092574 accompanying drawings 1 and WO2008062450 accompanying drawings 2.The XRD spectrums of ciclesonide crystal formation III
Figure is as shown in WO2008062450 accompanying drawings 3.The XRD spectra of ciclesonide crystal formation IV is as shown in WO2007092574 accompanying drawings 2.At present
Research and report not on ciclesonide monohydrate.
We conduct in-depth research when ciclesonide bulk drug is developed to its crystal formation situation, and with reference to text
The method offered is prepared for anhydrous ciclesonide amorphous substance, ciclesonide crystalline polymorphs I and II, does not obtain ciclesonide knot
Brilliant polymorphic III and IV.For example, by repeating WO2007092574 comparative examples 1 and embodiment 2 and 3, what discovery was obtained
All it is ciclesonide crystal formation II, does not obtain ciclesonide crystal formation IV.By repeating WO2008062450 embodiments 8, find to obtain
Be ciclesonide crystal formation I, do not obtain ciclesonide crystal formation III.By continuous 10 days high temperature, high humidity, illumination influence factor
Experiment finds, in above-mentioned ciclesonide polymorphic, the only stable crystal form of ciclesonide crystal formation II, XRD spectra does not occur
Change (referring to Figure of description 1)；Ciclesonide crystal formation I (can refer to specification to ciclesonide crystal formation II transformations at high temperature
Accompanying drawing 4)；The XRD spectra of ciclesonide amorphous substance occurs that obvious diffraction maximum (refers to specification attached under illumination and high humidity
Fig. 5).In addition, we filter to isolate commercially available ciclesonide nasal sprayIn ciclesonide raw material, carry out X
Ray powder diffraction is determined, it is found that it is also crystal formation II.
When Foradil Aerolizer formoterol fumarate is prepared as active component with ciclesonide crystal formation II, find there are many difficulties, for example：Ring
Suo Naide crystal formations II is also easy to produce electrostatic when crushing, particle aggregation is serious, is unfavorable for the configuration of Foradil Aerolizer formoterol fumarate.In addition, configuration
Ciclesonide dry powder inhalant pulmonary deposition ratio is also undesirable.
When Foradil Aerolizer formoterol fumarate is prepared as active component with ciclesonide crystal formation II, find there are many difficulties, for example：Ring
Suo Naide crystal formations II is also easy to produce electrostatic when crushing, particle aggregation is serious, is unfavorable for the configuration of Foradil Aerolizer formoterol fumarate.In addition, configuration
Ciclesonide dry powder inhalant pulmonary deposition ratio is also undesirable.
The content of the invention
The invention provides a kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation composition, said composition
With pulmonary deposition ratio higher.
The present invention relates to a kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation, contain (A) ciclesonide
Monohydrate or ciclesonide, (B) formoterol fumarate or its hydrate, (C) Tiotropium Bromide or its hydrate and pharmacy
Upper acceptable carrier, described carrier is the mixture of carrier A, carrier B and support C；Calculated with weight ratio meter, the carrier A
Proportion is 2-8% in carrier mixture, and the d (0.9) of carrier A is less than 10 μm；Carrier B institute in carrier mixture
Accounting example is 40-60%, and the d (0.9) of carrier B is 80-100 μm；Support C proportion in carrier mixture is 40-
60%, the d (0.9) of support C is 180-200 μm.
Described a kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation, it is characterized in that containing ciclesonide
Monohydrate.
A kind of described ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation, it is characterized in that described strop how
Moral monohydrate with crystal form exist, its X-ray powder diffraction θ=5.1 of the angle of diffraction 2,9.0,11.2,12.8,15.0,
16.2nd, there is characteristic peak at 16.9,20.7.
Described a kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation, it is characterized in that containing fumaric acid good fortune
Mo Teluo dihydrates.
Described a kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation, it is characterized in that containing Tiotropium Bromide
Monohydrate.
Described a kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation, it is characterized in that the carrier is selected from
One or more in carbohydrate carrier, mannitol, amino acid.
Described a kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation, it is characterized in that described carrier choosing
One or more from maltose, trehalose, cellobiose, lactose, sucrose, fructose, glucose, mannitol, glycine.
Described a kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation, it is characterized in that described carrier is
Lactose.
Described a kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation, it is characterized in that described lactose choosing
One or more from alpha-lactose monohydrate, β-Lactis Anhydrous, amorphous spray-dried lactose, crystallizing and drying lactose.
Described a kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation, it is characterized in that described lactose is
Alpha-lactose monohydrate.
Surprisingly, in ciclesonide crystal formation research process is carried out, it was found that a kind of brand-new water of ciclesonide one
Compound, is investigated by stability test at present, and the brand-new ciclesonide monohydrate is compared with existing anhydrous ciclesonide
Crushing is easily facilitated, beneficial to the preparation of Foradil Aerolizer formoterol fumarate, and the obtained Foradil Aerolizer formoterol fumarate under identical prescription and preparation condition
With pulmonary deposition ratio higher, as shown in inventive embodiments 6.Therefore this brand-new ciclesonide monohydrate bulk drug can
With the new selection as ciclesonide formulation products, especially Foradil Aerolizer formoterol fumarate.
Ciclesonide monohydrate chemical structural formula is as follows：
Described ciclesonide monohydrate, it is characterized in that described compound exists with crystal form, its x-ray powder
Diffraction has characteristic peak at θ=5.1 ° of the angle of diffraction 2,9.0 °, 11.2 °, 12.8 °, 15.0 °, 16.2 °, 16.9 °, 20.7 °.
Described ciclesonide monohydrate, it is characterized in that described compound exists with crystal form, its x-ray powder
Diffraction θ=5.1 ° of the angle of diffraction 2,9.0 °, 11.2 °, 12.8 °, 15.0 °, 16.2 °, 16.9 °, 20.7 °, 21.8 °, 24.3 °,
29.1 °, have characteristic peak at 32.7 °.
Should be understood to the diffracted intensity of characteristic peak with crystal preparing technology, sample mounting procedure and measuring instrument not
With can micro change, also should be within the scope of the invention.Additionally, the difference and other factors of instrument may influence to spread out
The θ values of firing angle 2, so the above-mentioned θ values of the angle of diffraction 2 for having characteristic peak can change in existing value ± 0.1 °.
The preparation method of described ciclesonide monohydrate, it is characterized in that prepared using supercritical fluid technique, step
It is rapid as follows：
(1) ciclesonide solution is configured：5g ciclesonides are completely dissolved in the mixed of 200ml acetone and 20ml water at 50 DEG C
In conjunction solution；
(2) the ciclesonide solution by step (1) middle configuration is connected with solution pump, and operating pressure is controlled to 10MPa；
(3) feed carbon dioxide：By the CO in steel cylinder2Supercritical fluid anti-solvent equipment system is input into by booster pump, is entered
Enter crystallization kettle, flow control controls 50 DEG C of start-up temperature in 10ml/min, and pressure is 10MPa；
By above-mentioned steps (1) middle configuration ciclesonide solution by solution pump through supercritical fluid anti-solvent equipment body
Nozzle is rapidly sprayed into crystallization kettle in system, and flow is controlled to 1.5ml/min, and nozzle temperature is 50 DEG C, and its jet length is 5cm；
Entrainer ethanol is sprayed into crystallization kettle by entrained solution pump simultaneously, flow is controlled to 1.5ml/min；Operating time is
140min；It is continually fed into CO2Remaining solvent in crystallization kettle is cleaned；
(5) ciclesonide hydrate crystallization is separated out；The ciclesonide one for collecting the precipitation from solution at crystallization kettle bottom is hydrated
Thing.
A kind of preparation method of described ciclesonide monohydrate, it is characterized in that in the saturated solution M of ciclesonide,
Add crystal seed, cooling crystallization, the solution M by 1 parts by volume ethanol, the water of 0.1~0.15 parts by volume, 0.1~0.15 volume
Part acetonitrile composition, the X-ray powder diffraction of the crystal seed θ=5.1 ° of the angle of diffraction 2,9.0 °, 11.2 °, 12.8 °, 15.0 °,
16.2 °, 16.9 °, 20.7 °, 21.8 °, 24.3 °, 29.1 °, have characteristic peak at 32.7 °.
Ciclesonide monohydrate of the present invention is studied through TG-DT A spectrum, it is determined that containing a crystallization water.DTA spectrograms exist
In the range of room temperature~200 DEG C, there is an endothermic peak at 132 DEG C, corresponding TG spectrums are scalariform weightlessness line, and weightlessness is 3.1%, is calculated
One amount of the crystallization water is 3.2%, it was demonstrated that there is a crystallization water.
Find under study for action, using one or more organic solvent (methyl alcohol, ethanol, isopropanol, normal propyl alcohol, the tert-butyl alcohol, third
Ketone, acetonitrile, tetrahydrofuran etc.) recrystallized with the mixed solvent of water, even if under room temperature in vacuo drying condition as mild as a dove
Hardly result in ciclesonide monohydrate.Ciclesonide hydrate crystallization has surprisingly been obtained by supercritical fluid technique, will
The crystallization can be used as the crystal seed of the next step after crushing.It is surprised to find by research, in the system of above-mentioned ciclesonide monohydrate
In Preparation Method, the volume ratio of ethanol/water/acetonitrile is critically important in mixed solvent M needed for recrystallization, for example：When ethanol/water/acetonitrile
Volume ratio not in above range, even if add ciclesonide monohydrate crystal seed, the product for obtaining also be anhydrous strop
Nai De, such as comparative examples 1.On the other hand, the addition of the crystal seed of ciclesonide monohydrate is also critically important, is being added without crystalline substance
Kind, but in the case of other preparation condition identicals, what is obtained is also anhydrous ciclesonide, such as comparative examples 2.
From inventive embodiments 6 as can be seen that the brand-new ciclesonide monohydrate and existing anhydrous ciclesonide are brilliant
Type II is compared, and obtained Foradil Aerolizer formoterol fumarate has pulmonary deposition ratio higher under identical prescription and preparation condition.
Result table is investigated carrying out influence factor, accelerated test and 24 months room temperatures long-term stable experiment that keeps sample in addition
Bright, there are not significant changes in this each detection project of ciclesonide monohydrate (proterties, content, relevant material), with good
Stability, additionally carried out X-ray powder diffraction test, as a result show that crystal formation does not change, the crystal formation can keep
Good stability.
Powder diffraction instrument used is that Rigaku D/max-2500 powder diffractometers are 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 be ciclesonide crystal formation II obtained in comparative examples 14 X-ray powder diffraction spectrogram and 10 days influence because
Plain experimental result
Fig. 2 is the X-ray powder diffraction spectrogram of ciclesonide monohydrate obtained in inventive embodiments 1
Fig. 3 is the connection of supercritical fluid anti-solvent equipment and schematic flow sheet in inventive embodiments 1.
Wherein, 1 is ciclesonide solution, and 2 is solution pump, and 3 is nozzle, and 4 is crystallization kettle, and 5 is gas-liquid separation kettle, and 6 is gas
Body floss hole, 7 is raffinate collector, and 8 is booster pump, and 9 is CO2, 10 is entrainment agent solution pump, and P1 is equipment system pressure, P2
It is crystallization kettle operating pressure
Fig. 4 is the X-ray powder diffraction spectrogram of ciclesonide crystal formation I obtained in comparative examples 15 and 10 days influence factors
Experimental result
Fig. 5 be the unbodied X-ray powder diffraction spectrogram of ciclesonide obtained in comparative examples 12 and 10 days influence because
Plain experimental result
Specific 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 made to technical characteristic of the invention, or change accordingly
Enter, still fall within protection scope of the present invention.
Identical reagent and reagent use same lot number in following examples.
The supercritical methanol technology of inventive embodiments 1 prepares ciclesonide monohydrate
(1) ciclesonide solution 1 is configured：5g ciclesonides are completely dissolved in the mixed of 200ml acetone and 20ml water at 50 DEG C
In conjunction solution；
(2) the ciclesonide solution 1 by step (1) middle configuration is connected with solution pump 2, and operating pressure is controlled to 10MPa；
(3) feed carbon dioxide：By the CO in steel cylinder2Supercritical fluid anti-solvent equipment system is input into by booster pump 8,
Into crystallization kettle 4, flow control controls 50 DEG C of start-up temperature in 10ml/min, and pressure is 10MPa；
By above-mentioned steps (1) middle configuration ciclesonide solution 1 by solution pump 2 through supercritical fluid anti-solvent equipment
Nozzle 3 is rapidly sprayed into crystallization kettle 4 in system, and flow is controlled to 1.5ml/min, and nozzle temperature is 50 DEG C, and its jet length is
5cm；Entrainer ethanol is sprayed into crystallization kettle 4 by entrained solution pump 10 simultaneously, flow is controlled to 1.5ml/min；During operation
Between be 140min；It is continually fed into CO2Remaining solvent in crystallization kettle 4 is cleaned；
(5) ciclesonide hydrate crystallization is separated out；The water of ciclesonide one separated out from solution is collected at crystallization kettle bottom 4
Compound.
(6) residue is processed through gas-liquid separation kettle 5, and gas is discharged via gas discharge outlet 6, and raffinate flows into raffinate collector
7。
Dried crystal is analyzed using TG-DTA, weightless about 3.1%, confirm as ciclesonide monohydrate.Will
To crystal carry out X-ray powder diffraction measure, measure characteristic peak positions for 2 θ=5.1 °, 9.0 °, 11.2 °, 12.8 °,
15.0 °, 16.2 °, 16.9 °, 20.7 °, 21.8 °, 24.3 °, 29.1 °, 32.7 °, as shown in Figure 2.
After ciclesonide hydrate crystallization mortar prepared by inventive embodiments 1 pulverizes, it is inventive embodiments 2-5's
Crystal seed.
The preparation of the ciclesonide monohydrate of inventive embodiments 2
The ethanol that 5g ciclesonides add 100ml is taken, the water of 10ml is heated to 50 in the mixed solution of the acetonitrile of 10ml
DEG C, heat filtering filters off insoluble matter, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), is subsequently adding inventive embodiments 1 and makes
Standby crystal seed, insulated and stirred 30 minutes separates out a large amount of crystal, is cooled to 0~5 DEG C, and filtering is dried, by dried crystal profit
Analyzed with TG-DTA, weightless about 3.1%, confirm as ciclesonide monohydrate.The crystal that will be obtained carries out X-ray powder diffraction
Determine, measure characteristic peak positions for 2 θ=5.1 °, 9.0 °, 11.2 °, 12.8 °, 15.0 °, 16.2 °, 16.9 °, 20.7 °, 21.8 °,
24.3°、29.1°、32.7°。
The preparation of the ciclesonide monohydrate of inventive embodiments 3
The ethanol that 5g ciclesonides add 100ml is taken, the water of 10ml is heated to 50 in the mixed solution of the acetonitrile of 15ml
DEG C, heat filtering filters off insoluble matter, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), is subsequently adding inventive embodiments 1 and makes
Standby crystal seed, insulated and stirred 30 minutes separates out a large amount of crystal, is cooled to 0~5 DEG C, and filtering is dried, by dried crystal profit
Analyzed with TG-DTA, weightless about 3.1%, confirm as ciclesonide monohydrate.The crystal that will be obtained carries out X-ray powder diffraction
Determine, measure characteristic peak positions for 2 θ=5.1 °, 9.0 °, 11.2 °, 12.8 °, 15.0 °, 16.2 °, 16.9 °, 20.7 °, 21.8 °,
24.3°、29.1°、32.7°。
The preparation of the ciclesonide monohydrate of inventive embodiments 4
The ethanol that 5g ciclesonides add 100ml is taken, the water of 15ml is heated to 50 in the mixed solution of the acetonitrile of 10ml
DEG C, heat filtering filters off insoluble matter, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), is subsequently adding inventive embodiments 1 and makes
Standby crystal seed, insulated and stirred 30 minutes separates out a large amount of crystal, is cooled to 0~5 DEG C, and filtering is dried, by dried crystal profit
Analyzed with TG-DTA, weightless about 3.1%, confirm as ciclesonide monohydrate.The crystal that will be obtained carries out X-ray powder diffraction
Determine, measure characteristic peak positions for 2 θ=5.1 °, 9.0 °, 11.2 °, 12.8 °, 15.0 °, 16.2 °, 16.9 °, 20.7 °, 21.8 °,
24.3°、29.1°、32.7°。
The preparation of the ciclesonide monohydrate of inventive embodiments 5
The ethanol that 5g ciclesonides add 100ml is taken, the water of 15ml is heated to 50 in the mixed solution of the acetonitrile of 15ml
DEG C, heat filtering filters off insoluble matter, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), is subsequently adding inventive embodiments 1 and makes
Standby crystal seed, insulated and stirred 30 minutes separates out a large amount of crystal, is cooled to 0~5 DEG C, and filtering is dried, by dried crystal profit
Analyzed with TG-DTA, weightless about 3.1%, confirm as ciclesonide monohydrate.The crystal that will be obtained carries out X-ray powder diffraction
Determine, measure characteristic peak positions for 2 θ=5.1 °, 9.0 °, 11.2 °, 12.8 °, 15.0 °, 16.2 °, 16.9 °, 20.7 °, 21.8 °,
24.3°、29.1°、32.7°。
The preparation of the ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation of inventive embodiments 6 and pulmonary deposition ratio are examined
Examine
The active component that embodiment 6-1~6-20 is used is hydrated for ciclesonide monohydrate, formoterol fumarate two
Thing and tiotropium bromide monohydrate.The active component that embodiment 6-21~6-40 is used is ciclesonide crystal formation II, fumaric acid good fortune
Mo Teluo dihydrates and tiotropium bromide monohydrate.The d (0.9)=5.3 μm of ciclesonide monohydrate, inventory is
4.13g (is calculated as 4.0g) with ciclesonide.The d (0.9)=5.1 μm of ciclesonide crystal formation II, inventory is 4.0g.Fumaric acid
The d (0.9)=5.3 μm of Formoterol dihydrate, inventory is 0.123g, and the d (0.9) of tiotropium bromide monohydrate=
5.0 μm, inventory is 0.184g.
Preparation technology：Active component and carrier are premixed by three-dimensional mixer according to prescription, then using mixed at high speed
Machine is mixed to get the powder mixture of active component and carrier.Described high-speed mixer, its mixing chamber is contained within two kinds and mixes
Blade is closed, is both horizontally and vertically being moved respectively.The mixture quantitative filling that will be prepared in multiple dose reservoir devices dry powder to
In medicine device.Each product uses identical powder inhaler.
Medicinal ram (NGI) of new generation is used to determine ciclesonide (each embodiment is in terms of ciclesonide), fumaric acid
The active component deposition of Formoterol and Tiotropium Bromide.Vavuum pump, flow control meter, medicinal shock of new generation are assembled successively
Device, nozzle adapter, flowmeter, regulation vacuum pump flow rate is 60L/min ± 2L/min, and setting pumpdown time is 4s, by flow
Meter is removed, and sample is exerted oneself vertically to shake three times, connects adapter and sample, presses pressure once, opens vavuum pump, flow control meter
Start test, operate continuously 10 times.By nozzle adapter of new generation, the throat of medicinal ram, preseparator is each in catch tray
Appropriate sample solution is added, content is tested after extraction, and active component deposition is calculated (i.e. less than 5 microns with software for calculation
Medicine accounts for the ratio of the medicine of recovery), testing result is shown in Table 2.
The embodiment 6-1 of table 1~6-40 prescriptions
The embodiment 6-1 of table 2~6-40 pulmonary deposition ratios
The d (0.9) of lactose A, mannitol A and glycine A is less than 10 μm；The d (0.9) of lactose B, mannitol B and glycine B
It is 80-100 μm；The d (0.9) of lactose C, mannitol C and glycine C is 180-200 μm.Lactose A, lactose B, lactose C be α-
Lactose monohydrate.
The preparation of the anhydrous ciclesonide of comparative examples
Comparative examples 1
The ethanol that 5g ciclesonides add 100ml is taken, the water of 10ml is heated to 50 in the mixed solution of the acetonitrile of 20ml
DEG C, heat filtering filters off insoluble matter, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), is subsequently adding inventive embodiments 1 and makes
Standby crystal seed, insulated and stirred 30 minutes separates out a large amount of crystal, is cooled to 0~5 DEG C, and filtering, room temperature in vacuo is dried, after drying
Crystal utilize Karl_Fischer method measured moisture content, confirm as ciclesonide without hydrate.
Comparative examples 2
The ethanol that 5g ciclesonides add 100ml is taken, the water of 10ml is heated to 50 in the mixed solution of the acetonitrile of 10ml
DEG C, heat filtering filters off insoluble matter, and cooling crystallization, filtering, room temperature in vacuo is dried, and dried crystal is surveyed using Karl_Fischer method
Water content, confirms as ciclesonide without hydrate.
Comparative examples 3
Comparative examples 3-1
0.5g ciclesonides are dissolved in 1.8mL acetonitriles, lower addition 0.3mL pure water is stirred at reflux, are cooled to room temperature, crystallization,
Filtering, room temperature in vacuo is dried, and dried crystal is utilized into Karl_Fischer method measured moisture content, confirms as ciclesonide without hydration
Thing.
Comparative examples 3-2
0.5g ciclesonides are dissolved in 1.5mL acetonitriles, lower addition 0.2mL pure water is stirred at reflux, are cooled to room temperature, crystallization,
Filtering, room temperature in vacuo is dried, and dried crystal is utilized into Karl_Fischer method measured moisture content, confirms as ciclesonide without hydration
Thing.
Comparative examples 4
Below with reference to the Master's thesis of document Zhang Debin《The study on the synthesis of asthma medications -22R ciclesonides》, P23
Page：
Ciclesonide 1g is dissolved in 5mL absolute ethyl alcohols, 0.2 times of activated carbon is added, 30 minutes is stirred at reflux, while hot mistake
Filter, filtrate decompression is concentrated into remainings 4 times of ethanol, heating, and backflow is lower to add 0.2mL pure water, stands cooling, the mistake after crystallization is separated out
Filter, is washed with 50% ethanol/water, and room temperature in vacuo is dried, and dried crystal is utilized into Karl_Fischer method measured moisture content, is confirmed as
Ciclesonide is without hydrate.
Comparative examples 5
Comparative examples 5-1
0.5g ciclesonides are dissolved in 5mL acetone, lower addition 0.3mL pure water is stirred at reflux, Temperature fall is stood, wait to analyse
Go out crystallization and filtration, room temperature in vacuo is dried, and dried crystal is utilized into Karl_Fischer method measured moisture content, confirms as ciclesonide
Without hydrate.
Comparative examples 5-2
0.5g ciclesonides are dissolved in 2.5mL acetone, lower addition 0.2mL pure water is stirred at reflux, Temperature fall is stood, treated
Crystallization and filtration is separated out, room temperature in vacuo is dried, and dried crystal is utilized into Karl_Fischer method measured moisture content, how confirms as strop
Moral is without hydrate.
Comparative examples 5-3
Below with reference to the Master's thesis of document Zhang Debin《The study on the synthesis of asthma medications -22R ciclesonides》, P23
Page：
2g ciclesonides are dissolved in 5.6mL acetone, lower addition 1.2mL pure water is stirred at reflux, Temperature fall is stood, wait to analyse
Go out crystallization and filtration, 75% acetone/water washing, room temperature in vacuo dries, dried crystal surveyed using Karl_Fischer method and is contained
Water, confirms as ciclesonide without hydrate.
Comparative examples 6
The methyl alcohol that 5g ciclesonides add 200ml is taken, 50 DEG C, heat filtering filter are heated in the mixed solution of the water of 10ml
Go insoluble matter, cooling crystallization, filtering, room temperature in vacuo to dry, dried crystal is utilized into Karl_Fischer method measured moisture content, confirm
It is ciclesonide without hydrate.
Comparative examples 7
The ethanol that 5g ciclesonides add 50ml is taken, the water of 10ml is heated to 50 DEG C in the mixed solution of the acetone of 50ml,
Heat filtering filters off insoluble matter, and cooling crystallization, filtering, room temperature in vacuo is dried, and dried crystal is surveyed using Karl_Fischer method and is contained
Water, confirms as ciclesonide without hydrate.
Comparative examples 8
The heating of 0.5g ciclesonides is dissolved in 1.5mL isopropanols, lower addition 0.4mL pure water is stirred at reflux, room temperature is down to,
Crystallization and filtration to be separated out, room temperature in vacuo is dried, and dried crystal is utilized into Karl_Fischer method measured moisture content, confirms as strop
Nai De is without hydrate.
Comparative examples 9
The water that 5g ciclesonides add 10ml is taken, 50 DEG C, heat filtering filter are heated in the mixed solution of the normal propyl alcohol of 500ml
Go insoluble matter, cooling crystallization, filtering, room temperature in vacuo to dry, dried crystal is utilized into Karl_Fischer method measured moisture content, confirm
It is ciclesonide without hydrate.
Comparative examples 10
The water that 5g ciclesonides add 3ml is taken, 50 DEG C, heat filtering filter are heated in the mixed solution of the tetrahydrofuran of 50ml
Go insoluble matter, cooling crystallization, filtering, room temperature in vacuo to dry, dried crystal is utilized into Karl_Fischer method measured moisture content, confirm
It is ciclesonide without hydrate.
Comparative examples 11
Take commercially available product(ciclesonide suspension type nasal spray), filtering, much filtrate is washed, room temperature in vacuo
Dry, dried crystal is utilized into Karl_Fischer method measured moisture content, confirm as ciclesonide without hydrate.The strop that will be obtained
How moral crystal carries out X-ray powder diffraction measure, measures characteristic peak positions for 2 θ=5.3 °, 6.7 °, 8.1 °, 10.6 °, 12.3 °,
14.7 °, 16.8 °, 17.2 °, 18.2 °, confirm as crystal formation II.
Comparative examples 12
Specific method refers to WO2008062450 embodiments 9, and finished product room temperature in vacuo is dried, by dried product utilization
Karl_Fischer method measured moisture content, confirms as ciclesonide without hydrate.The ciclesonide crystal that will be obtained carries out x-ray powder and spreads out
Penetrate measure and confirm as that ciclesonide is amorphous, XRD spectra and 10 days results of influence factor are as shown in Figure 5.
Comparative examples 13
Specific method refers to (the comparative example1 of WO2007092574 comparative examples 1：repetition
Of example1of EP929566), finished product is dried using room temperature in vacuo, and dried crystal is surveyed using Karl_Fischer method
Water content, confirms as ciclesonide without hydrate.The ciclesonide crystal that will be obtained carries out X-ray powder diffraction measure, measures
Characteristic peak positions are 2 θ=5.3 °, 6.7 °, 8.1 °, 10.6 °, 12.3 °, 14.7 °, 16.8 °, 17.2 °, 18.2 °, confirm as strop
How moral crystal formation II.
Comparative examples 14
Specific method refers to WO2007092574 embodiments 2, and finished product is dried using room temperature in vacuo, by dried crystal
Using Karl_Fischer method measured moisture content, ciclesonide is confirmed as without hydrate.The ciclesonide crystal that will be obtained carries out X-ray powder
Last diffraction, measures characteristic peak positions for 2 θ=5.3 °, 6.7 °, 8.1 °, 10.6 °, 12.3 °, 14.7 °, 16.8 °, 17.2 °,
18.2 °, ciclesonide crystal formation II is confirmed as, XRD spectra and 10 days results of influence factor are as shown in Figure 1.
Comparative examples 15
Specific method refers to WO2008062450 embodiments 8.The ciclesonide crystal that will be obtained carries out X-ray powder diffraction
Measure confirms as ciclesonide crystal formation I, and XRD spectra and 10 days results of influence factor are as shown in Figure 4.
Claims (10)
1. a kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation, contains (A) ciclesonide monohydrate or ring
Suo Naide, (B) formoterol fumarate or its hydrate, (C) Tiotropium Bromide or its hydrate and pharmaceutically acceptable load
Body, described carrier is the mixture of carrier A, carrier B and support C；Calculated with weight ratio meter, the carrier A is in carrier mixture
Middle proportion is 2-8%, and the d (0.9) of carrier A is less than 10 μm；Carrier B proportion in carrier mixture is 40-
60%, the d (0.9) of carrier B is 80-100 μm；Support C proportion in carrier mixture is 40-60%, support C
D (0.9) is 180-200 μm.
2. a kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation as claimed in claim 1, it is characterized in that containing
There is ciclesonide monohydrate.
3. a kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation as claimed in claim 2, it is characterized in that institute
The ciclesonide monohydrate stated with crystal form exist, its X-ray powder diffraction θ=5.1 ° of the angle of diffraction 2,9.0 °,
11.2 °, 12.8 °, 15.0 °, 16.2 °, 16.9 °, have characteristic peak at 20.7 °.
4. a kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation as claimed in claim 1, it is characterized in that containing
There is formoterol fumarate dihydrate.
5. a kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation as claimed in claim 1, it is characterized in that containing
There is tiotropium bromide monohydrate.
6. a kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation as described in Claims 1 to 5 is any, it is special
Levy be the carrier be selected from carbohydrate carrier, mannitol, amino acid in one or more.
7. a kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation as claimed in claim 6, it is characterized in that institute
The carrier stated is selected from maltose, trehalose, cellobiose, lactose, sucrose, fructose, glucose, mannitol, glycine
Plant or several.
8. a kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation as claimed in claim 7, it is characterized in that institute
The carrier stated is lactose.
9. ciclesonide monohydrate, structure is shown below
10. ciclesonide monohydrate as claimed in claim 9, it is characterized in that described compound exists with crystal form,
Its X-ray powder diffraction has at θ=5.1 ° of the angle of diffraction 2,9.0 °, 11.2 °, 12.8 °, 15.0 °, 16.2 °, 16.9 °, 20.7 °
Characteristic peak.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101264092A (en) * | 2008-04-11 | 2008-09-17 | 北京润德康医药技术有限公司 | Compound preparations with ciclesonide and formoterol as active component and preparation and application thereof |
| CN103687483A (en) * | 2011-05-17 | 2014-03-26 | 珍珠治疗公司 | Compositions, methods & systems for respiratory delivery of two or more active agents |
| CN104918604A (en) * | 2012-10-23 | 2015-09-16 | 西普拉有限公司 | Pharmaceutical composition |
| CN106692163A (en) * | 2015-11-13 | 2017-05-24 | 天津金耀集团有限公司 | Ciclesonide suspension composition for inhalation |
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2015
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101264092A (en) * | 2008-04-11 | 2008-09-17 | 北京润德康医药技术有限公司 | Compound preparations with ciclesonide and formoterol as active component and preparation and application thereof |
| CN103687483A (en) * | 2011-05-17 | 2014-03-26 | 珍珠治疗公司 | Compositions, methods & systems for respiratory delivery of two or more active agents |
| CN104918604A (en) * | 2012-10-23 | 2015-09-16 | 西普拉有限公司 | Pharmaceutical composition |
| CN106692163A (en) * | 2015-11-13 | 2017-05-24 | 天津金耀集团有限公司 | Ciclesonide suspension composition for inhalation |
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