CN106692115A - Ciclesonide suspension nasal spray composition - Google Patents
Ciclesonide suspension nasal spray composition Download PDFInfo
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- CN106692115A CN106692115A CN201510779859.1A CN201510779859A CN106692115A CN 106692115 A CN106692115 A CN 106692115A CN 201510779859 A CN201510779859 A CN 201510779859A CN 106692115 A CN106692115 A CN 106692115A
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Abstract
A ciclesonide suspension nasal spray composition is disclosed, and the ciclesonide suspension nasal spray composition comprises ciclesonide monohydrate and a pharmaceutically acceptable carrier. The ciclesonide monohydrate is existed in a crystal form, and characteristic peaks are shown at diffraction angle 2*theta of 5.1 degrees, 9.0 degrees, 11.2 degrees, 12.8 degrees, 15.0 degrees, 16.2 degrees, 16.9 degrees and 20.7 degrees in X ray powder diffraction.
Description
Technical field：
The present invention relates to a kind of sugared glucocorticoid steroid hormone suspension nasal spray, more particularly to ciclesonide monohydrate suspension nasal spray composition.Belong to pharmaceutical technology field.
Background technology：
People's nasal cavity is effective organ that pharmacological activity component absorbs.From the eighties, with the continuous improvement of scientific and technological level, via intranasal application mucosal absorption is rapid to play the Progress in research and development of the novel formulation-general designation nasal drug delivery system (Nasal Drug Delirery System) of the locally or systemically therapeutic action of pharmacological activity component.
Nasal mist (Nasal Spray) is the research of new dosage forms for nasal administration of developed recently.Pharmacological activity component and auxiliary material solution (or suspension) are filling to be administered in high atomisation and container with accurate quantification valve at one using manual pressing.Nasal mist has the advantages that easy to use, effect is rapid, absorbs good.So, the appearance of nasal mist novel form is spoken highly of by many patients and clinician.
Sugared glucocorticoid steroid hormone is to treat one of the most frequently used medicine of anaphylactia.The prevention and treatment of anaphylaxis (including seasonal or Out of season) rhinitis are successfully used for using the nasal mist containing hormonal medicaments.For example, there is conventional budesonide nasal spray, mometasone furoate as nasal spray, fluticasone propionate nasal spray etc..
Ciclesonide is a kind of new glucocorticoid, is researched and developed by German Altana companies, and Ciclesonide aerosol in 2004 is listed in countries and regions such as U.S., Europe, days successively afterwards in Australia's approval listing.The said firm is investigated ciclesonide suspension nasal spray, ciclesonide suspension nasal spray in 2008Listed in the U.S. first, listed in countries and regions such as Europe, days successively afterwards.
The crystal formation research work of current medicine has become more and more important, Chinese patent ZL200580026414.0 discloses difficulty or ease, stability, solubility, the storage stability of the crystalline polymorphs often medicine preparation of certain drug, 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. report ciclesonide and there is anhydrous ciclesonide amorphous substance, 4 kinds of anhydrous ciclesonide crystalline polymorphs (I, II, III, IV) and ciclesonide Methanol Solvate.The XRD spectra of ciclesonide crystal formation I is as shown in WO2008062450 accompanying drawings 1.The XRD spectra of ciclesonide crystal formation II is as shown in WO2007092574 accompanying drawings 1 and WO2008062450 accompanying drawings 2.The XRD spectra of ciclesonide crystal formation III is as shown in WO2008062450 accompanying drawings 3.The XRD spectra of ciclesonide crystal formation IV is as shown in WO2007092574 accompanying drawings 2.Currently without the research on ciclesonide monohydrate and report.
We are when ciclesonide bulk drug is developed, its crystal formation situation is conducted in-depth research, and the method for bibliography is prepared for anhydrous ciclesonide amorphous substance, ciclesonide crystalline polymorphs I and II, does not obtain ciclesonide crystalline polymorphs III and IV.For example, by repeating WO2007092574 comparative examples 1 and embodiment 2 and 3, that discovery is obtained is all ciclesonide crystal formation II, does not obtain ciclesonide crystal formation IV.By repeating WO2008062450 embodiments 8, that discovery is obtained is ciclesonide crystal formation I, does not obtain ciclesonide crystal formation III.Tested by the influence factor of continuous 10 days high temperature, high humidity, illumination and found, in above-mentioned ciclesonide polymorphic, the only stable crystal form of ciclesonide crystal formation II, XRD spectra does not change (refer to Figure of description 1)；Ciclesonide crystal formation I can change (referring to Figure of description 4) to ciclesonide crystal formation II at high temperature；The XRD spectra of ciclesonide amorphous substance occurs obvious diffraction maximum (referring to Figure of description 5) under illumination and high humidity.In addition, we filter to isolate commercially available ciclesonide nasal sprayIn ciclesonide raw material, carry out X-ray powder diffraction measure, find its also be crystal formation II.
Through overtesting, the suspension nasal spray prepared using ciclesonide crystal formation II is found, at 25 DEG C ± 2 DEG C, stored 24 months under 60%RH ± 5%RH relative humidity, agglomeration occur.Therefore, preparing a kind of stability ciclesonide suspension nasal spray higher becomes extremely important.
The invention aims to the above-mentioned technical problem for overcoming ciclesonide nasal spray to exist.
The content of the invention
The invention provides a kind of ciclesonide suspension nasal spray composition, investigated by stability test, the brand-new ciclesonide monohydrate suspension nasal spray shows more preferable stability, the reduction of medicine reunion degree compared with suspension nasal spray prepared by ciclesonide crystal formation II.
The present invention relates to a kind of ciclesonide suspension nasal spray composition, it is characterized in that containing the ciclesonide monohydrate as active component, water, suspending agent and other auxiliary materials, described other auxiliary materials are selected from one or more in pH adjusting agent, osmotic pressure regulator, surfactant, bacteriostatic agent.
Described a kind of ciclesonide suspension nasal spray, it is characterised in that described ciclesonide monohydrate 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.
A kind of described ciclesonide suspension nasal spray composition, it is characterized in that can also be containing one or more additional active components, the additional active ingredients are selected from decongestant, antihistaminic, mast cell stabilizers or the cholinolytic class medicine being locally administered suitable for nasal cavity.
Described a kind of ciclesonide suspension nasal spray composition, it is characterized in that described decongestant is selected from ephedrine, xylometazoline, naphazoline, tetrahydrozoline or oxymetazoline；The antihistaminic is selected from diphenhydramine, chlorphenamine, cetirizine, RMI 9918, FEXOFENADINE (fenofexadine), astemizole, norastemizole, histimet, azelastine, olopatadine or Ah Zhas and replaces fourth (azatidine)；The mast cell stabilizers are selected from nasmil, Nedocromil；The cholinolytic class medicine is selected from Ipratropium Bromide, glycopyrronium bromide and Tiotropium Bromide.
Described a kind of ciclesonide suspension nasal spray composition, it is characterized in that the antihistaminic is selected from azelastine and its salt.
Described a kind of ciclesonide suspension nasal spray composition, it is characterized in that the antihistaminic is azelastine hydrochloride.
Described a kind of ciclesonide suspension nasal spray composition, it is characterized in that the often spray content of azelastine hydrochloride is 137 μ g.
Any described a kind of ciclesonide suspension nasal spray composition, it is characterised in that in terms of ciclesonide, the often spray content of ciclesonide is 50 μ g.
Any described a kind of ciclesonide suspension nasal spray composition, it is characterised in that the suspending agent is selected from one or more in sodium hyaluronate, microcrystalline cellulose-sodium carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, carboxy vinyl polymer, dextran, PVP, Carbomer.
Any described a kind of ciclesonide suspension nasal spray composition, it is characterised in that described surfactant is selected from one or more in Tween-80, Emulsifier EL-60 60, HCO60, polyethylene glycol-stearate, polyethylene glycol, lecithin, sucrose ester, polyoxyethylene alkyl ether, polyoxy stearate, polyoxyethylene polyoxypropylene glycol, tyloxapol.
Any described a kind of ciclesonide suspension nasal spray composition, it is characterised in that the bacteriostatic agent is selected from one or more in benzalkonium chloride, benzalkonium bromide, polyquaternium, natrium adetate, mosatil, benzethonium chloride, sorbic acid, phenmethylol, benzyl carbinol, potassium sorbate, methyl p-hydroxybenzoate, propylparaben, chlorobutanol.
Described a kind of ciclesonide suspension nasal spray composition, it is characterised in that the bacteriostatic agent is selected from benzalkonium chloride, natrium adetate and its mixture.
Any described a kind of ciclesonide suspension nasal spray composition, it is characterised in that the osmotic pressure regulator is selected from glucose, glycerine, propane diols, sodium chloride, potassium chloride, D-sorbite, mannitol.
Described a kind of ciclesonide suspension nasal spray composition, it is characterised in that the osmotic pressure regulator is selected from glycerine or mannitol.
Any described a kind of ciclesonide suspension nasal spray composition, it is characterised in that the pH adjusting agent is selected from one or more in 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, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus, tromethamine.
Ciclesonide is adrenocortical hormone compound, it is more difficult to be dissolved in water, therefore it is the suspension type aqueous solution that the nasal spray containing ciclesonide is first-selected, thus a certain amount of suspending agent need to be added to keep the stability of suspension type water solution system；Additionally, in view of ciclesonide solubility in water is extremely low, a certain amount of surfactant need to be added to reduce surface tension, maintenance system stabilization.To reduce said preparation in use to the excitant of schneiderian membrance, a certain amount of osmotic pressure regulator need to be added to keep isotonic with body fluid；In view of stability of the ciclesonide during storage and use, the suspension type water solution system pH value need to be adjusted to acidity, pH value is adjusted to 3.5~6.5 by the results show, and ciclesonide stability is preferable.
In ciclesonide crystal formation research process is carried out, it was found that a kind of brand-new ciclesonide monohydrate.Investigated by stability test at present, the brand-new ciclesonide monohydrate is compared with existing anhydrous ciclesonide and easily facilitates crushing, and there is content higher in obtained nasal spray stability placement process under identical prescription and preparation condition and drug content and smaller granularity is often sprayed, as shown in inventive embodiments 7 and 8.Therefore this brand-new ciclesonide monohydrate bulk drug can turn into the new selection of ciclesonide formulation products.
Ciclesonide monohydrate chemical structural formula is as 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 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 °, 21.8 °, 24.3 °, 29.1 °, 32.7 °.
Should be understood to the diffracted intensity of characteristic peak with crystal preparing technology, sample mounting procedure and measuring instrument difference can micro change, also should be within the scope of the invention.Additionally, the difference and other factors of instrument may influence the θ values of the angle of diffraction 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 being to be prepared using supercritical fluid technique, step is as follows：
(1) ciclesonide solution is configured：5g ciclesonides are completely dissolved in the mixed solution of 200ml acetone and 20ml water at 50 DEG C；
(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 by configuration in above-mentioned steps (1) is rapidly sprayed into crystallization kettle by solution pump through nozzle in supercritical fluid anti-solvent equipment system, flow is controlled to 1.5ml/min, 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 ciclesonide monohydrate separated out from solution is collected at crystallization kettle bottom.
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, the acetonitrile composition of 0.1~0.15 parts by volume, the X-ray powder diffraction of the crystal seed 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 °, 21.8 °, 24.3 °, 29.1 °, 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 have an endothermic peak at 132 DEG C in the range of room temperature~200 DEG C, and corresponding TG spectrums are scalariform weightlessness line, and weightlessness is 3.1%, and it is 3.2% to calculate an amount for the crystallization water, it was demonstrated that there is a crystallization water.
Find under study for action, recrystallized with the mixed solvent of water using one or more organic solvent (methyl alcohol, ethanol, isopropanol, normal propyl alcohol, the tert-butyl alcohol, acetone, acetonitrile, tetrahydrofuran etc.), even if also being difficult to obtain ciclesonide monohydrate under room temperature in vacuo drying condition as mild as a dove.Ciclesonide hydrate crystallization has surprisingly been obtained by supercritical fluid technique, can be used as the crystal seed of the next step after the crystallization is crushed.Surprised to find by research, in the preparation method of above-mentioned ciclesonide monohydrate, the volume ratio of ethanol/water/acetonitrile is critically important in mixed solvent M needed for recrystallization, for example：When the volume ratio of ethanol/water/acetonitrile is not in above range, even if adding the crystal seed of ciclesonide monohydrate, the product for obtaining also is anhydrous ciclesonide, such as comparative examples 1.On the other hand, the addition of the crystal seed of ciclesonide monohydrate is also critically important, and in the case of crystal seed, but other preparation condition identicals is added without, what is obtained is also anhydrous ciclesonide, such as comparative examples 2.
Be can be seen that from inventive embodiments 7 and 8, the brand-new ciclesonide monohydrate is compared with existing anhydrous ciclesonide crystal formation II, obtained suspension nasal spray has content higher in stability placement process and often sprays drug content under identical prescription and preparation condition, but granularity is smaller, medicine reunion degree is lower.
Investigate result and show carrying out influence factor, accelerated test and 24 months room temperatures long-term stable experiment that keeps sample in addition, there are not significant changes in this each detection project of ciclesonide monohydrate (proterties, content, relevant material), with good stability, X-ray powder diffraction test is additionally carried out, result shows that crystal formation does not change, and the crystal formation can keep good stability.
Powder diffraction instrument used is that Rigaku D/max-2500 powder diffractometers are Rigaku Products in the present invention.TG-DTA analysis instrument used is Rigaku standard type TG-DTA analyzers in the present invention.
Brief description of the drawings：
Fig. 1 is the X-ray powder diffraction spectrogram and 10 days influence factor experimental results of ciclesonide crystal formation II obtained in comparative examples 14
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, 5 is gas-liquid separation kettle, and 6 is gas discharge outlet, and 7 is raffinate collector, and 8 is booster pump, 9 is CO2, and 10 is entrainment agent solution pump, and P1 is equipment system pressure, and P2 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 factor experimental results
Fig. 5 is the unbodied X-ray powder diffraction spectrogram of ciclesonide obtained in comparative examples 12 and 10 days influence factor experimental results
Specific embodiment：
Below will by embodiment, the invention will be further described, these descriptions are not that present invention is further limited.It should be understood by those skilled in the art that the equivalent made to technical characteristic of the invention, or be correspondingly improved, still fall within protection scope of the present invention.
Same reagent, reagent and nasal spray Brown Glass Brown glass bottles and jars only 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 the mixed solution of 200ml acetone and 20ml water at 50 DEG C；
(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 rapidly sprayed into crystallization kettle 4 by solution pump 2 through nozzle 3 in supercritical fluid anti-solvent equipment system, flow is controlled to 1.5ml/min, 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；Operating time is 140min；CO2 is continually fed into clean remaining solvent in crystallization kettle 4；
(5) ciclesonide hydrate crystallization is separated out；The ciclesonide monohydrate separated out from solution is collected at crystallization kettle bottom 4.
(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.The crystal that will be obtained carries 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, the crystal seed of inventive embodiments 2-5 is done.
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 DEG C in the mixed solution of the acetonitrile of 10ml, heat filtering filters off insoluble matter, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), the crystal seed of the preparation of inventive embodiments 1 is subsequently adding, insulated and stirred 30 minutes separates out a large amount of crystal, it is cooled to 0~5 DEG C, filtering, is dried, and dried crystal is analyzed using TG-DTA, weightless about 3.1%, confirm as ciclesonide monohydrate.The crystal that will be obtained carries 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 °.
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 DEG C in the mixed solution of the acetonitrile of 15ml, heat filtering filters off insoluble matter, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), the crystal seed of the preparation of inventive embodiments 1 is subsequently adding, insulated and stirred 30 minutes separates out a large amount of crystal, it is cooled to 0~5 DEG C, filtering, is dried, and dried crystal is analyzed using TG-DTA, weightless about 3.1%, confirm as ciclesonide monohydrate.The crystal that will be obtained carries 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 °.
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 DEG C in the mixed solution of the acetonitrile of 10ml, heat filtering filters off insoluble matter, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), the crystal seed of the preparation of inventive embodiments 1 is subsequently adding, insulated and stirred 30 minutes separates out a large amount of crystal, it is cooled to 0~5 DEG C, filtering, is dried, and dried crystal is analyzed using TG-DTA, weightless about 3.1%, confirm as ciclesonide monohydrate.The crystal that will be obtained carries 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 °.
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 DEG C in the mixed solution of the acetonitrile of 15ml, heat filtering filters off insoluble matter, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), the crystal seed of the preparation of inventive embodiments 1 is subsequently adding, insulated and stirred 30 minutes separates out a large amount of crystal, it is cooled to 0~5 DEG C, filtering, is dried, and dried crystal is analyzed using TG-DTA, weightless about 3.1%, confirm as ciclesonide monohydrate.The crystal that will be obtained carries 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 °.
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 crushing, feed size 80-100 mesh, and the granularity d (0.9) for crushing for five times carries out average again；
6.2 groups is ciclesonide crystal formation II 500g prepared by comparative examples 14, is equally divided into ten crushing, feed size 80-100 mesh, and the granularity d (0.9) for crushing for five times carries out 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 granularity that will be obtained is：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 to crush, due to crushing the electrostatic for producing, particle aggregation is serious.
The ciclesonide monohydrate suspension type nasal spray of inventive embodiments 7 and ciclesonide crystal formation II suspension nasal spray stability and quality versus' research
The ciclesonide suspension type nasal spray prescription of table 1
With reference to commercially available ciclesonide nasal sprayPrescription, is prepared for ciclesonide monohydrate suspension type nasal spray (A groups) and ciclesonide crystal formation II suspension types nasal spray (B groups), and carry out stability property amount comparative study.A groups employ micronizing ciclesonide monohydrate, are detected with laser particle analyzer, and granularity is D (0.99)=3.758 μm.B groups employ micronizing ciclesonide crystal formation II, are detected with laser particle analyzer, and granularity is D (0.99)=3.789 μm.The preparation method of two groups of suspensions is：
(1) after suspending agent is with appropriate purifying water dissolves, osmotic pressure regulator, pH adjusting agent, bacteriostatic agent are added, stirring and dissolving obtains auxiliary material solution；
(2) with after appropriate water dissolves, addition ciclesonide monohydrate or ciclesonide crystal formation II stirrings disperse it to surfactant, obtain main ingredient suspension；
(3) main ingredient suspension is transferred in auxiliary material solution, is stirred after the purified water for adding surplus, the suspension type aqueous solution is obtained, in the filling Brown Glass Brown glass bottles and jars only to nasal spray.
7.1 stability
Every group takes 10 bottles, at 25 DEG C ± 2 DEG C, is stored under 60%RH ± 5%RH relative humidity 24 months, when surveying storage 0 respectively, 3 months, 6 months, 12 months, the content (in terms of ciclesonide) of 18 months and 24 months measures result and see the table below 2；When 0 and 24 the end of month, 1 bottle of test sample is taken, according to the assay method that drug content is often sprayed in Chinese Pharmacopoeia, repeat injection 10 times, often spray drug content (in terms of ciclesonide) is detected respectively, often sprayed drug content result and see the table below 3；With reference to particle size determination in American Pharmacopeia fluticasone propionate nasal spray standard, when 0 and 24 the end of month detection ciclesonide granularities, ciclesonide particle size results see the table below 4：
The ciclesonide content of table 2 investigates result (X ± s, n=10)
| Group | When 0 | 3 months | 6 months | 12 months | 18 months | 24 months |
| A groups | 100.2±0.98 | 99.8±0.96 | 100.5±0.95 | 99.4±1.01 | 98.8±0.98 | 99.0±0.96 |
| B groups | 99.8±0.92 | 99.7±0.90 | 99.6±0.94 | 99.2±0.99 | 98.5±0.93 | 98.1±0.98 |
The ciclesonide of table 3 often sprays drug content investigates result
The ciclesonide granularity of table 4 investigates result
By the result of 2~table of upper table 4 it can be found that it is long-term place during two groups of samples relatively stablize, but sample prepared by ciclesonide crystal formation II, during long-term placement ciclesonide content and often spray drug content decline it is more.After long-term placement 24 months, two groups often spray drug content and have decline, and wherein A groups (ciclesonide monohydrate group) often spray drug contentIt is 96.2 ± 1.44,10 data for determining every time are basic between the 95%~105% of average value, and B groups (ciclesonide crystal formation II groups) often spray drug contentIt is 94.8 ± 3.41,10 data for determining every time are basic between the 90%~110% of average value；Granularity investigates result, it was also found that granularity has the trend of growth after placing 24 months for a long time simultaneously, but B groups (ciclesonide crystal formation II groups) become apparent from compared with the increase of A groups (ciclesonide monohydrate group) granularity.
The preparation of the ciclesonide monohydrate suspension nasal spray of inventive embodiments 8 and compound ciclesonide monohydrate suspension nasal spray and study on the stability
The suspension nasal spray prescription of table 5
The ciclesonide of a groups is ciclesonide crystal formation II in embodiment 8-1~8-9, inventory is 0.5g, ciclesonide in b groups is ciclesonide monohydrate, and inventory is also 0.5g (in terms of ciclesonide), and the preparation method of embodiment 8-1~8-9 is referring to embodiment 7.
The ciclesonide of a groups is ciclesonide crystal formation II in embodiment 8-10, inventory is 0.5g, ciclesonide in b groups is ciclesonide monohydrate, inventory is also 0.5g (in terms of ciclesonide), the inventory of the azelastine hydrochloride in a groups and b groups is 1.0g, and preparation method is：
(1) after azelastine hydrochloride and suspending agent are with appropriate purifying water dissolves, osmotic pressure regulator, pH adjusting agent, bacteriostatic agent are added, stirring and dissolving obtains solution A；
(2) with after appropriate water dissolves, addition ciclesonide monohydrate or ciclesonide crystal formation II stirrings disperse it to surfactant；
(3) suspension of ciclesonide monohydrate or ciclesonide crystal formation II is transferred in solution A, adds excess water, stirred, the suspension type aqueous solution is obtained, in the filling Brown Glass Brown glass bottles and jars only to nasal spray.
8.1 stability
Every group takes 10 bottles, at 25 DEG C ± 2 DEG C, is stored under 60%RH ± 5%RH relative humidity 24 months, when surveying storage 0 respectively, 3 months, 6 months, 12 months, the content (in terms of ciclesonide) of 18 months and 24 months measures result and see the table below 6；When 0 and 24 the end of month, 1 bottle of test sample is taken, repeat injection totally 10 detections often spray drug content (in terms of ciclesonide), often sprayed drug content result and see the table below 7；With reference to particle size determination in American Pharmacopeia fluticasone propionate nasal spray standard, when 0 and 24 the end of month detection ciclesonide granularities, ciclesonide particle size results see the table below 8.
By result it can be found that it is long-term place during two groups of samples relatively stablize, but under identical prescription and preparation technology, sample prepared by ciclesonide crystal formation II, during long-term placement ciclesonide content and often spray drug content decline it is more.It is long-term place 24 months after two groups often spray drug content and have decline, wherein ciclesonide crystal formation II groups decline many compared with ciclesonide monohydrate group, and 10 data when often spraying drug content are determined every time, ciclesonide crystal formation II groups are basic between the 95%~105% of average value, and ciclesonide monohydrate group to determine 10 data when often spraying drug content every time basic between the 97%~103% of average value；Simultaneously granularity investigate result, it was also found that after placing 24 months for a long time two groups there is agglomeration, but agglomeration occur compared with ciclesonide monohydrate group more serious for ciclesonide crystal formation II groups.
The ciclesonide content of table 6 investigation result (N=10)
The ciclesonide of table 7 often sprays drug content investigates result
The ciclesonide granularity of table 8 investigates result
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 DEG C in the mixed solution of the acetonitrile of 20ml, heat filtering filters off insoluble matter, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), it is subsequently adding the crystal seed of the preparation of inventive embodiments 1, insulated and stirred 30 minutes, separates out a large amount of crystal, is cooled to 0~5 DEG C, filtering, 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 2
The ethanol that 5g ciclesonides add 100ml is taken, the water of 10ml is heated to 50 DEG C in the mixed solution of the acetonitrile of 10ml, heat filtering filters off insoluble matter, cooling crystallization, filtering, 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 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 hydrate.
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 hydrate.
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 pages：
Ciclesonide 1g is dissolved in 5mL absolute ethyl alcohols, 0.2 times of activated carbon is added, is stirred at reflux 30 minutes, filter while hot, filtrate decompression is concentrated into remainings 4 times of ethanol, heating, and backflow is lower to add 0.2mL pure water, stand cooling, crystallization and filtration to be separated out, is washed with 50% ethanol/water, and room temperature in vacuo is dried, dried crystal is utilized into Karl_Fischer method measured moisture content, ciclesonide is confirmed as 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, 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 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, 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 ciclesonide 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 pages：
2g ciclesonides are dissolved in 5.6mL acetone, lower addition 1.2mL pure water is stirred at reflux, Temperature fall is stood, crystallization and filtration to be separated out, 75% acetone/water washing, room temperature in vacuo is dried, dried crystal is utilized into Karl_Fischer method measured moisture content, ciclesonide is confirmed as 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 filters off insoluble matter, cooling crystallization, filtering, room temperature in vacuo is dried, dried crystal is utilized into Karl_Fischer method measured moisture content, ciclesonide is confirmed as 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, cooling crystallization, filtering, 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 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 ciclesonide without hydrate.
Comparative examples 9
The water that 5g ciclesonides add 10ml is taken, 50 DEG C are heated in the mixed solution of the normal propyl alcohol of 500ml, heat filtering filters off insoluble matter, cooling crystallization, filtering, room temperature in vacuo is dried, dried crystal is utilized into Karl_Fischer method measured moisture content, ciclesonide is confirmed as without hydrate.
Comparative examples 10
The water that 5g ciclesonides add 3ml is taken, 50 DEG C are heated in the mixed solution of the tetrahydrofuran of 50ml, heat filtering filters off insoluble matter, cooling crystallization, filtering, room temperature in vacuo is dried, dried crystal is utilized into Karl_Fischer method measured moisture content, ciclesonide is confirmed as without hydrate.
Comparative examples 11
Take commercially available product(ciclesonide suspension type nasal spray), filtering, much filtrate is washed, and room temperature in vacuo is dried, 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, 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 °, confirms as crystal formation II.
Comparative examples 12
Specific method refers to WO2008062450 embodiments 9, and finished product room temperature in vacuo is dried, and 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 diffraction and determines to confirm as that ciclesonide is amorphous, and 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, 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 °, confirms as ciclesonide crystal formation II.
Comparative examples 14
Specific method refers to WO2007092574 embodiments 2, and 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, 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 and 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 suspension nasal spray composition, it is characterised in that contain the strop as active component
How moral monohydrate, water, suspending agent and other auxiliary materials, described other auxiliary materials be selected from pH adjusting agent, infiltration
Pressure conditioning agent, surfactant, one or more in bacteriostatic agent.
2. a kind of ciclesonide suspension nasal spray composition as claimed in claim 1, 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 °.
3. a kind of ciclesonide suspension nasal spray composition as described in claim 1 and 2, it is characterised in that
Can also be containing one or more additional active components, the additional active ingredients are selected from and are applied to nasal cavity
The local decongestant being administered, antihistaminic, mast cell stabilizers or cholinolytic class medicine.
4. a kind of ciclesonide suspension nasal spray composition as described in claim 1 and 2, it is characterized in that institute
The decongestant stated is selected from ephedrine, xylometazoline, naphazoline, tetrahydrozoline or oxymetazoline；It is described anti-
Histamine agent be selected from diphenhydramine, chlorphenamine, cetirizine, RMI 9918, FEXOFENADINE (fenofexadine),
Astemizole, norastemizole, histimet, azelastine, olopatadine or Ah Zhas replace fourth
(azatidine)；The mast cell stabilizers are selected from nasmil, Nedocromil；The cholinolytic class medicine choosing
From Ipratropium Bromide, glycopyrronium bromide and Tiotropium Bromide.
5. a kind of ciclesonide suspension nasal spray composition as described in claim 4 is any, it is characterised in that
In terms of ciclesonide, the often spray content of ciclesonide is 50 μ g.
6. a kind of ciclesonide suspension nasal spray composition as described in claim 1,2,5 is any, it is special
Levy is that the suspending agent is selected from sodium hyaluronate, microcrystalline cellulose-sodium carboxymethylcellulose, carboxymethylcellulose calcium
Sodium, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, carboxylic ethene gather
One or more in compound, dextran, PVP, Carbomer.
7. a kind of ciclesonide suspension nasal spray composition as described in claim 1,2,5 is any, it is special
Levy is that described surfactant is selected from Tween-80, Emulsifier EL-60 60, polyethylene glycol hydrogenated castor-oil plant
Oil 60, polyethylene glycol-stearate, polyethylene glycol, lecithin, sucrose ester, polyoxyethylene alkyl ether,
One or more in polyoxy stearate, the polyoxypropylene diols of polyoxyethylene one, tyloxapol.
8. a kind of ciclesonide suspension nasal spray composition as described in claim 1,2,5 is any, it is special
Levy is that the bacteriostatic agent is selected from benzalkonium chloride, benzalkonium bromide, polyquaternium, natrium adetate, Ca-EDTA
Sodium, benzethonium chloride, sorbic acid, phenmethylol, benzyl carbinol, potassium sorbate, methyl p-hydroxybenzoate, to hydroxyl
One or more in yl benzoic acid propyl ester, chlorobutanol.
9. a kind of ciclesonide suspension nasal spray composition as described in claim 1,2,5 is any, it is special
Levy is that the osmotic pressure regulator is selected from glucose, glycerine, propane diols, sodium chloride, potassium chloride, sorbose
Alcohol, mannitol.
10. a kind of ciclesonide suspension nasal spray composition as described in claim 1,2,5 is any, it is special
Levy be the pH adjusting agent 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, sulfuric acid, hydrochloric acid, NaOH, potassium hydroxide, sodium carbonate, potassium carbonate, carbonic acid
One or more in hydrogen sodium, saleratus, tromethamine.
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