CN106692163A - Ciclesonide suspension composition for inhalation - Google Patents
Ciclesonide suspension composition for inhalation Download PDFInfo
- Publication number
- CN106692163A CN106692163A CN201510779995.0A CN201510779995A CN106692163A CN 106692163 A CN106692163 A CN 106692163A CN 201510779995 A CN201510779995 A CN 201510779995A CN 106692163 A CN106692163 A CN 106692163A
- Authority
- CN
- China
- Prior art keywords
- ciclesonide
- suction
- acid
- crystal
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dispersion Chemistry (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Inorganic Chemistry (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a ciclesonide suspension composition for inhalation. The composition contains a ciclesonide hydrate and a pharmaceutically acceptable carrier, wherein the ciclesonide hydrate exists in a form of crystal.
Description
Technical field：
The present invention relates to a kind of suction ciclesonide monohydrate suspension solution composition.Belong to pharmaceutical technology field.
Background technology：
Medicinal atomized inhalation therapy, as a kind of novel method for the treatment of, is using high speed air-flow that medicine atomisation is straight
Punching to bronchium, eventually end bronchus and alveolar is connect, medicine is directly contacted lesion, so that local drug concentration is improved,
Play a part of expansion bronchus and anti-inflammatory, it is possible to keep air flue moistening, desaturation sputum to be beneficial to expectoration, therefore, to above exhaling
Inhaling road infection, tracheae and bronchitis, pneumonia, bronchial astehma, bronchiectasis also has its important clinical meaning；Not only
In this way, research finds, the treatment of other disease also has obvious therapeutic effect by medicinal atomized inhalation therapy.It is conventional
Neulized inhalation have three kinds, i.e. Ultrasonic atomising taring, compression atomized inhalation (compression atomized inhalation include：Compression atomizing device is sucked
With oxygen inhalation system Neulized inhalation), steam atomization suction.
Glucocorticoid is that treatment asthma and chronic pulmonary hinder most common medicine at present.Ciclesonide swashs for adrenal cortex
Chlorins compound, it is more difficult to be dissolved in water, is researched and developed by German Altana companies, and Ciclesonide aerosol in 2004 is ratified in Australia
Listing, lists in countries and regions such as U.S., Europe, days successively afterwards.The said firm is investigated ciclesonide suspension nasal spray, 2008
Year ciclesonide suspension nasal sprayListed in the U.S. first, afterwards successively on the countries and regions such as Europe, day
City.
The crystal formation research work of current medicine has become more and more important, and Chinese patent ZL200580026414.0 is disclosed
The crystalline polymorphs of certain drug are often difficulty or ease, stability, solubility, the storage stability of medicine preparation, preparation difficulty or ease
With 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 and penetrate
Line powder diffraction is determined, it is found that it is also crystal formation II.
For preparing the Neulized inhalation suspension that contained drug is water-insoluble compound, generally all need for bulk drug to enter micro-
Efflorescence, the Neulized inhalation suspension prepared using the ciclesonide crystal formation II after micronizing, the minuteness particle point in placement process
Number (determining less than 5 μm percentage granules, referred to as FPF by medicinal ram device of new generation) constantly declines.It can be seen that, there is provided
A kind of ciclesonide suction suspension solution solves above-mentioned deficiency, particularly important.
The content of the invention：
The invention provides a kind of suction suspension solution of ciclesonide monohydrate.With ciclesonide crystal formation II preparations
Suction suspension compares, and during stability is placed, suction suspension solution prepared by ciclesonide monohydrate is more steady
Fixed, granularity is smaller, and FPF values are higher.
The present invention relates to a kind of suction ciclesonide suspension composite, it is characterised in that containing as active component
Ciclesonide monohydrate, water and other auxiliary materials, described other auxiliary materials are selected from pH adjusting agent, osmotic pressure regulator, surface work
One or more in property agent, chelating agent.
Ciclesonide suspension composite is used in a kind of described suction, it is characterised in that described ciclesonide 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 °, 16.2 °,
16.9 °, have characteristic peak at 20.7 °.
Ciclesonide suspension composite is used in a kind of described suction, it is characterised in that described surfactant is selected from and tells
Temperature -80, Emulsifier EL-60 60, HCO60, polyethylene glycol-stearate, polyethylene glycol, lecithin
One kind in fat, sucrose ester, polyoxyethylene alkyl ether, polyoxy stearate, polyoxyethylene polyoxypropylene glycol, tyloxapol
Or it is several.
Ciclesonide suspension composite use in a kind of described suction, it is characterised in that the chelating agent selected from edetic acid(EDTA) or
One or more in its pharmaceutically acceptable sodium salt or sylvite.
Ciclesonide suspension composite is used in a kind of described suction, it is characterised in that the chelating agent is selected from edetic acid(EDTA) two
Sodium or mosatil and its mixture.
Ciclesonide suspension composite is used in a kind of described suction, it is characterised in that the osmotic pressure regulator is selected from Portugal
Grape sugar, glycerine, propane diols, sodium chloride, potassium chloride, D-sorbite or mannitol.
Ciclesonide suspension composite is used in a kind of described suction, it is characterised in that the osmotic pressure regulator is selected from chlorine
Change sodium, glycerine or glucose.
Ciclesonide suspension composite use in a kind of described suction, it is characterised in that the pH adjusting agent selected from phosphoric acid and
Its salt, boric acid and its salt, citric acid and its salt, acetic acid and its salt, tartaric acid and its salt, sulfuric acid, hydrochloric acid, NaOH, hydrogen-oxygen
Change potassium, sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus, one or more in tromethamine.
Ciclesonide suspension composite use in a kind of described suction, it is characterised in that the pH adjusting agent for citric acid and
Its salt.
In ciclesonide crystal formation research process is carried out, it was found that a kind of brand-new ciclesonide monohydrate.Pass through at present
Overstability experiment investigation, the brand-new ciclesonide monohydrate is compared with existing anhydrous ciclesonide and easily facilitates powder
It is broken, and obtained suction suspension solution has FPF values higher, such as inventive embodiments 7 under identical prescription and preparation condition
With shown in 8.Therefore this brand-new ciclesonide monohydrate bulk drug can turn into the new choosing that ciclesonide sucks suspension
Select.
Ciclesonide monohydrate chemical structural formula is shown below：
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 configuration in step (1) 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,
Into crystallization kettle, flow control controls 50 DEG C of start-up temperature in 10ml/min, and pressure is 10MPa；
(4) the ciclesonide solution of configuration in above-mentioned steps (1) is passed through into solution pump through supercritical fluid anti-solvent equipment
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；CO2 is continually fed into clean remaining solvent in crystallization kettle；
(5) ciclesonide hydrate crystallization is separated out；The water of ciclesonide one separated out from solution is collected at crystallization kettle bottom
Compound.
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 7 and 8 as can be seen that the brand-new ciclesonide monohydrate and existing anhydrous ciclesonide
Crystal formation II is compared, under identical prescription and preparation condition it is obtained suction suspension it is more stable, with FPF values higher.
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 Rigaku D/max-2500 powder diffractometers for Rigaku company produces 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
The X-ray powder diffraction spectrogram of ciclesonide monohydrate obtained in Fig. 2 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, and 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, reagent, polyethylene bottle use same lot number in following examples.
The supercritical methanol technology of inventive embodiments 1 prepares ciclesonide monohydrate
(1) configuration ciclesonide solution 1：5g ciclesonides are completely dissolved in 200ml acetone and 20ml water at 50 DEG C
In mixed solution；
(2) the ciclesonide solution 1 by configuration in step (1) is connected with solution pump 2, and operating pressure is controlled to 10MPa；
(3) feed carbon dioxide：CO2 in steel cylinder is input into supercritical fluid anti-solvent equipment system 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；
(4) the ciclesonide solution 1 by configuration in above-mentioned steps (1) is set by solution pump 2 through supercritical fluid anti-solvent
Nozzle 3 is rapidly sprayed into crystallization kettle 4 in standby system, and flow is controlled to 1.5ml/min, and nozzle temperature is 50 DEG C, its jet length
It is 5cm；Entrainer ethanol is sprayed into crystallization kettle 4 by entrained solution pump 10 simultaneously, flow is controlled to 1.5ml/min；Operation
Time is 140min；CO2 is continually fed into clean remaining solvent in crystallization kettle 4；
(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 and spreads out
Penetrate 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°。
The ciclesonide of inventive embodiments 6 crushes experiment
Experimental facilities：WLFM-P-85 type airslide disintegrating mills Beijing Wei Ling Hu Xin Mechanical Equipment Co., Ltd
Granulometry instrument：Easysizer20 laser particle analyzers Zhuhai OMEC Technology Co., Ltd.
Sample is grouped：
6.1 groups is the made ciclesonide hydrate crystallization 500g of the method for inventive embodiments 2, is equally divided into ten wheat-middlings
It is broken, feed size 80-100 mesh, five times crushing granularity d (0.9) carry out it is average again；
6.2 groups of ciclesonide crystal formation II 500g prepared for comparative examples 14, are equally divided into ten crushing, feed grain
Degree 80-100 mesh, five times crushing granularity d (0.9) carry out it is average again.
Pulverization conditions：Crush air-flow 1.0Mpa
Charging rate 0.5kg/h
Above-mentioned 6.1 groups and 6.2 groups of samples are carried out into air-flow crushing according to above-mentioned pulverization conditions respectively, the product grain that will be obtained
Spend and be：6.1 groups of average d (0.9)=5.1 μm of sample, 6.2 groups of sample average d (0.9)=10.5 μm.When 6.2 groups of samples continue
During crushing, due to crushing the electrostatic for producing, particle aggregation is serious.
The ciclesonide monohydrate of inventive embodiments 7 sucks suspension solution and ciclesonide crystal formation II suction suspension solution systems
Standby and stability study
Table 1 sucks suspension solution prescription
According to above-mentioned prescription, it is prepared for ciclesonide monohydrate suction suspension solution (A groups) and ciclesonide suction is mixed
Outstanding solution (B groups), and be compared for stability.A groups employ the aseptic ciclesonide monohydrate of micronizing, use laser
Particle size analyzer detects that granularity is D (0.9)=4.812 μm.B groups employ the aseptic ciclesonide crystal formation II of micronizing, use laser
Particle size analyzer detects that granularity is D (0.9)=4.823 μm.The preparation method of two groups of suspensions is：
(1) after pressing conditioning agent, pH adjusting agent and chelating agent with appropriate purified water stirring and dissolving by surfactant, thoroughly,
By the solution by 0.22 μm of film aseptic filtration, auxiliary material solution is obtained；
(2) aseptic ciclesonide monohydrate or ciclesonide crystal formation II is added in auxiliary material solution, high-speed stirred makes it
Dispersion, obtains the suspension aqueous solution, is subsequently adding surplus and crosses 0.22 μm of degerming purified water of film.
(3) high-speed stirred is changed to low rate mixing, keeps low rate mixing, the aqueous solution that will be suspended is filling in polyethylene bottle.
7.1 stability
Two groups of samples are placed 24 months at 30 DEG C ± 2 DEG C under 40%RH ± 5%RH relative humidity, to system in placement process
Agent quality is detected.
(1) content
Using HPLC methods, when 0,3 months, 6 months, 12 months, 18 months and 24 the end of month detections, two groups of samples
Product content, as a result see the table below, and be learnt by contrast, and two groups of ciclesonide contents of sample are relatively stablized, but ciclesonide crystal formation
The drug content of II groups (B groups) slightly has reduction at 24 the end of month.
The ciclesonide content of table 2 investigation result (N=10)
| Group | When 0 | 3 months | 6 months | 12 months | 18 months | 24 months |
| A groups | 98.4±0.93 | 98.1±1.01 | 98.1±0.89 | 98.0±0.89 | 97.5±0.91 | 97.8±0.97 |
| B groups | 98.7±0.87 | 98.4±0.97 | 98.0±1.00 | 97.7±0.95 | 97.6±0.96 | 97.3±0.89 |
(2) granularity
24 the end of month determination sample granularities are placed in 0 when and for a long time using Coulter-counter (Coulter Counter),
Method is as follows：Take ciclesonide monohydrate and suck suspension solution (A groups) in right amount, put and (take sodium chloride containing 200ml blank solutions
40g, Triton X-1001.0g, the 1000ml that adds water make dissolving, add ciclesonide monohydrate to be allowed into saturation while stirring
Solution, continues to stir above-mentioned saturated solution 12 hours, is filtered with 0.2 μm of filter membrane) beaker in, ultrasound 15 minutes, using storehouse
You determine special counter (Coulter Counter).The measure of ciclesonide suction suspension solution (B groups) granularity refers to above-mentioned side
Method.
Result see the table below, and be learnt by contrast, and during long-term placement, two groups of samples occur main ingredient agglomeration,
Ciclesonide crystal formation II groups (B groups) is more serious compared with ciclesonide monohydrate group (A groups) agglomeration.
The granularity of table 3 investigates result
(3) the effective deposition of lung is investigated
With 24 the end of month of placement for a long time when 0, medicinal ram of new generation is used using the pairing of Aeroneb ultrasonic atomizers
(NGI), air-flow velocity 30L/min, HPLC external standard method calculate two with each level medication amount of calculated by peak area with NGI software for calculation
The minuteness particle percentage (FPF) of the diameter less than 5 microns of group sample, as a result see the table below, and be learnt by contrast, when 0, A groups
FPF values are higher than B groups；At 24 months, the FPF values of two groups of samples have decline, and ciclesonide crystal formation II groups (B groups) is compared with ciclesonide
The FPF values of monohydrate group (A groups) decline more.
The effective deposition of the lung of table 4 investigates result
The ciclesonide of inventive embodiments 8 sucks suspension solution and stability study
The ciclesonide of table 5 sucks suspension solution prescription
Main ingredient in embodiment 8-1a~8-10a is the aseptic ciclesonide monohydrate of micronizing, uses laser particle analyzer
Detection, granularity is D (0.9)=4.812 μm, and inventory is 0.25g (in terms of ciclesonide), the master in 8-1b~8-10b groups
Medicine is the aseptic ciclesonide crystal formation II of micronizing, is detected with laser particle analyzer, and granularity is D (0.9)=4.823 μm, inventory
Also 0.25g is, preparation method is referring to embodiment 7.
8.1 stability
By each group sample at 30 DEG C ± 2 DEG C, placed 24 months under 40%RH ± 5%RH relative humidity, it is right in placement process
The quality of the pharmaceutical preparations is detected.
(1) content
Using HPLC methods, when 0,3 months, 6 months, 12 months, 18 months and 24 the end of month detections, two groups of samples
Product content, as a result see the table below, and from result, during long-term placement, sample is relatively stablized, prepared by ciclesonide crystal formation II
Sample, during long-term placement content decline it is more.
The content of table 6 investigation result (N=10)
| Group | When 0 | 3 months | 6 months | 12 months | 18 months | 24 months |
| 8-1a | 99.2±0.86 | 98.8±1.01 | 98.7±0.94 | 98.4±0.91 | 98.4±1.00 | 98.6±0.83 |
| 8-1b | 99.0±0.99 | 98.7±0.86 | 98.4±0.83 | 98.5±1.01 | 98.2±0.94 | 98.0±0.88 |
| 8-2a | 99.0±1.03 | 98.8±0.97 | 98.7±0.92 | 98.5±0.89 | 98.4±0.86 | 98.3±0.91 |
| 8-2b | 98.7±0.83 | 98.4±0.92 | 98.3±0.91 | 97.9±0.88 | 97.4±0.84 | 97.2±1.00 |
| 8-3a | 99.2±0.85 | 99.0±0.91 | 99.1±0.86 | 98.7±0.84 | 98.5±0.96 | 98.3±0.95 |
| 8-3b | 99.4±0.91 | 99.1±0.88 | 98.8±0.83 | 98.2±0.92 | 97.8±0.87 | 97.1±0.87 |
| 8-4a | 99.0±0.94 | 98.8±0.86 | 98.5±0.98 | 98.4±0.92 | 98.1±1.00 | 97.8±0.88 |
| 8-4b | 99.1±0.94 | 98.6±0.88 | 98.4±0.92 | 98.1±0.99 | 97.6±0.84 | 97.1±0.91 |
| 8-5a | 99.0±0.87 | 98.8±0.86 | 98.7±0.95 | 98.6±0.88 | 98.4±0.99 | 98.2±0.86 |
| 8-5b | 100.0±0.83 | 99.6±0.94 | 99.2±0.84 | 98.8±0.94 | 98.1±1.01 | 97.6±0.91 |
| 8-6a | 99.5±0.94 | 99.5±0.83 | 99.8±0.97 | 99.4±0.90 | 98.5±0.89 | 98.6±0.94 |
| 8-6b | 99.3±0.87 | 99.1±0.99 | 98.9±0.91 | 98.2±0.88 | 97.8±0.92 | 97.2±0.83 |
| 8-7a | 99.6±0.93 | 99.2±0.87 | 98.7±1.03 | 98.5±0.82 | 98.8±0.99 | 98.6±1.01 |
| 8-7b | 99.5±0.92 | 99.1±0.88 | 98.7±0.99 | 98.4±0.86 | 98.1±1.01 | 97.6±0.92 |
| 8-8a | 99.5±0.91 | 99.5±0.96 | 99.3±0.87 | 99.5±1.03 | 99.2±0.97 | 98.9±0.91 |
| 8-8b | 99.6±0.88 | 99.8±1.02 | 99.2±1.00 | 98.7±0.92 | 98.4±0.99 | 97.7±0.86 |
| 8-9a | 99.4±0.99 | 99.2±0.98 | 99.1±1.01 | 98.8±0.93 | 98.5±0.84 | 98.6±0.96 |
| 8-9b | 99.6±0.82 | 99.5±1.01 | 99.2±0.98 | 99.0±0.84 | 98.7±0.93 | 98.3±0.84 |
| 8-10a | 99.3±0.87 | 99.2±0.99 | 99.0±0.91 | 98.9±0.88 | 98.8±0.92 | 98.6±0.83 |
| 8-10b | 99.1±0.84 | 98.8±0.81 | 98.5±0.92 | 97.8±0.84 | 97.6±0.92 | 97.3±1.00 |
(2) granularity
24 the end of month determination sample granularities are placed in 0 when and for a long time using Coulter-counter (Coulter Counter),
Method reference implementation example 7, as a result see the table below, and from result, during long-term placement, two groups of samples occur main ingredient reunion
Phenomenon, ciclesonide crystal formation II groups (b groups) is more serious compared with ciclesonide monohydrate group (a groups) agglomeration.
The granularity of table 7 investigates result
(3) the effective deposition of lung is investigated
With 24 the end of month of placement for a long time when 0, medicinal ram of new generation is used using the pairing of Aeroneb ultrasonic atomizers
(NGI), air-flow velocity 30L/min, HPLC external standard method calculate ten with each level medication amount of calculated by peak area with NGI software for calculation
The minuteness particle percentage (FPF) of the diameter less than 5 microns of group sample, as a result see the table below, and learn that when 0, how is strop by contrast
The FPF values of moral monohydrate group are higher than ciclesonide crystal formation II groups；At 24 months, the FPF values of two groups of samples have decline, strop
How moral crystal formation II groups are more compared with the FPF values decline of ciclesonide monohydrate group.
The effective deposition of the lung of table 4 investigates result
| As a result | When 0 | 24 months |
| 8-1a | 49.80% | 45.70% |
| 8-1b | 44.10% | 38.60% |
| 8-2a | 48.90% | 44.10% |
| 8-2b | 45.30% | 39.60% |
| 8-3a | 48.20% | 43.60% |
| 8-3b | 44.20% | 38.40% |
| 8-4a | 48.30% | 45.10% |
| 8-4b | 43.80% | 38.80% |
| 8-5a | 48.10% | 43.00% |
| 8-5b | 44.70% | 38.40% |
| 8-6a | 48.60% | 45.80% |
| 8-6b | 43.10% | 38.40% |
| 8-7a | 47.80% | 44.20% |
| 8-7b | 42.20% | 37.20% |
| 8-8a | 48.80% | 43.90% |
| 8-8b | 45.50% | 39.60% |
| 8-9a | 48.50% | 44.70% |
| 8-9b | 43.90% | 39.10% |
| 8-10a | 50.10% | 46.30% |
| 8-10b | 46.70% | 40.20% |
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 are heated in the mixed solution of the water of 10ml, heat filtering is filtered off
Insoluble matter, cooling crystallization, filtering, 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 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 example1 of EP929566), finished product is dried using room temperature in vacuo, and dried crystal is utilized into Karl_Fischer method
Measured moisture content, confirms as ciclesonide without hydrate.The ciclesonide crystal that will be obtained carries out X-ray powder diffraction measure, surveys
It is 2 θ=5.3 ° to obtain characteristic peak positions, 6.7 °, 8.1 °, 10.6 °, 12.3 °, 14.7 °, 16.8 °, 17.2 °, 18.2 °, confirms as ring
Suo Naide crystal formations 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 (9)
1. ciclesonide suspension composite is used in a kind of suction, it is characterised in that contain the water of ciclesonide one as active component
Compound, water and other auxiliary materials, described other auxiliary materials are selected from pH adjusting agent, osmotic pressure regulator, surfactant, chelating agent
One or more.
2. ciclesonide suspension composite is used in a kind of suction as claimed in claim 1, it is characterised in that how is described strop
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 °, 16.2 °, 16.9 °, have characteristic peak at 20.7 °.
3. ciclesonide suspension composite is used in a kind of suction as described in claim 1,2 is any, it is characterised in that described
Surfactant is selected from Tween-80, Emulsifier EL-60 60, HCO60, polyethylene glycol-stearic acid
Ester, polyethylene glycol, lecithin, sucrose ester, polyoxyethylene alkyl ether, polyoxy stearate, the polyoxypropylene diols of polyoxyethylene one,
One or more in tyloxapol.
4. ciclesonide suspension composite is used in a kind of suction as described in claim 3 is any, it is characterised in that the chelating
Agent is selected from one or more in edetic acid(EDTA) or its pharmaceutically acceptable sodium salt or sylvite.
5. ciclesonide suspension composite is used in a kind of suction as claimed in claim 4, it is characterised in that the chelating agent choosing
From natrium adetate or mosatil and its mixture.
6. ciclesonide suspension composite is used in a kind of suction as described in claim 1,2,4 is any, it is characterised in that described
Osmotic pressure regulator is selected from glucose, glycerine, propane diols, sodium chloride, potassium chloride, D-sorbite, mannitol.
7. ciclesonide suspension composite is used in a kind of suction as claimed in claim 6, it is characterised in that the osmotic pressure is adjusted
Section agent is selected from sodium chloride, glycerine or glucose.
8. ciclesonide suspension composite is used in a kind of suction as described in claim 1,2,4,7 is any, it is characterised in that institute
State pH adjusting agent and be selected from phosphoric acid and its salt, boric acid and its salt, citric acid and its salt, acetic acid and its salt, tartaric acid and its salt, sulphur
One kind in acid, hydrochloric acid, NaOH, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus, tromethamine
Or it is several.
9. ciclesonide suspension composite is used in a kind of suction as claimed in claim 8, it is characterised in that the pH adjusting agent
It is citric acid and its salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510779995.0A CN106692163A (en) | 2015-11-13 | 2015-11-13 | Ciclesonide suspension composition for inhalation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510779995.0A CN106692163A (en) | 2015-11-13 | 2015-11-13 | Ciclesonide suspension composition for inhalation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106692163A true CN106692163A (en) | 2017-05-24 |
Family
ID=58931471
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510779995.0A Pending CN106692163A (en) | 2015-11-13 | 2015-11-13 | Ciclesonide suspension composition for inhalation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106692163A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106880636A (en) * | 2015-12-15 | 2017-06-23 | 天津金耀集团有限公司 | A kind of ciclesonide folk prescription and compound dry powder inhalation composition |
| CN106883283A (en) * | 2015-12-15 | 2017-06-23 | 天津金耀集团有限公司 | Ciclesonide monohydrate and its crystal formation and preparation method |
| CN106880635A (en) * | 2015-12-15 | 2017-06-23 | 天津金耀集团有限公司 | A kind of ciclesonide Foradil composition |
| CN106880637A (en) * | 2015-12-15 | 2017-06-23 | 天津金耀集团有限公司 | A kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation composition |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1890256A (en) * | 2003-12-16 | 2007-01-03 | 奥坦纳医药公司 | Aqueous suspensions of ciclesonide for nebulisation |
| CN103565741A (en) * | 2012-07-25 | 2014-02-12 | 天津金耀集团有限公司 | Glucocorticoid ophthalmic water suspension having redispersibility |
-
2015
- 2015-11-13 CN CN201510779995.0A patent/CN106692163A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1890256A (en) * | 2003-12-16 | 2007-01-03 | 奥坦纳医药公司 | Aqueous suspensions of ciclesonide for nebulisation |
| CN103565741A (en) * | 2012-07-25 | 2014-02-12 | 天津金耀集团有限公司 | Glucocorticoid ophthalmic water suspension having redispersibility |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106880636A (en) * | 2015-12-15 | 2017-06-23 | 天津金耀集团有限公司 | A kind of ciclesonide folk prescription and compound dry powder inhalation composition |
| CN106883283A (en) * | 2015-12-15 | 2017-06-23 | 天津金耀集团有限公司 | Ciclesonide monohydrate and its crystal formation and preparation method |
| CN106880635A (en) * | 2015-12-15 | 2017-06-23 | 天津金耀集团有限公司 | A kind of ciclesonide Foradil composition |
| CN106880637A (en) * | 2015-12-15 | 2017-06-23 | 天津金耀集团有限公司 | A kind of ciclesonide Formoterol Tiotropium Bromide compound dry powder inhalation composition |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7267813B2 (en) | Inhalation particles incorporating a combination of two or more active ingredients | |
| CN106692163A (en) | Ciclesonide suspension composition for inhalation | |
| DE60225242T2 (en) | PROCESS FOR PRODUCING NANOPARTICLES | |
| US7172752B2 (en) | Combination particles for the treatment of asthma | |
| CN106279324A (en) | Loteprednol etabonate monohydrate and crystal formation thereof and preparation method | |
| EP1242048B2 (en) | INHALATION PARTICLES: method of preparation | |
| Zhao et al. | Preparation of microsized spherical aggregates of ultrafine ciprofloxacin particles for dry powder inhalation (DPI) | |
| CN101185611B (en) | Technique for preparing silybin fine particles by using supercritical fluid crystallization technology | |
| CN101798308A (en) | Preparation process and products of oridonin fine particles | |
| CN106478524A (en) | A kind of preparation method of ambroxol hydrochloride impurity standard substance | |
| CN106692115A (en) | Ciclesonide suspension nasal spray composition | |
| CN106692164A (en) | Ciclesonide azelastine compound composition | |
| CN107260665A (en) | Momestasone furoate suspension composite is used in one kind suction | |
| CN106880635A (en) | A kind of ciclesonide Foradil composition | |
| CN106883283B (en) | Ciclesonide monohydrate, crystal form and preparation method thereof | |
| CN106880637B (en) | Ciclesonide formoterol and tiotropium bromide compound dry powder inhalant composition | |
| Zhiyi et al. | Preparation of tetracycline microparticles suitable for inhalation administration by supercritical fluid expansion depressurization | |
| CN115400103B (en) | Porous respiratory particle and preparation method thereof | |
| CN106880636A (en) | A kind of ciclesonide folk prescription and compound dry powder inhalation composition | |
| CN106892953A (en) | Loteprednol etabonate monohydrate and its crystal formation and preparation method | |
| CN117180235A (en) | Amorphous Lei Fen narasin inhalation preparation | |
| CN107951893B (en) | Mometasone furoate powder inhalant composition | |
| CN106265502A (en) | A kind of stable Loteprednol etabonate suspension eye drop composition | |
| CN117285458A (en) | Amorphous Lei Fen narasin and preparation method thereof | |
| WO2003002111A1 (en) | Inhalation particles |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170524 |
|
| RJ01 | Rejection of invention patent application after publication |