CN106880637B - Ciclesonide formoterol and tiotropium bromide compound dry powder inhalant composition - Google Patents

Ciclesonide formoterol and tiotropium bromide compound dry powder inhalant composition Download PDF

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CN106880637B
CN106880637B CN201510944301.4A CN201510944301A CN106880637B CN 106880637 B CN106880637 B CN 106880637B CN 201510944301 A CN201510944301 A CN 201510944301A CN 106880637 B CN106880637 B CN 106880637B
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ciclesonide
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formoterol
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王淑丽
韩昆颖
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Tianjin Jinyao Group Co Ltd
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Abstract

A ciclesonide formoterol and tiotropium bromide compound dry powder inhalation composition comprises (A) ciclesonide or monohydrate, (B) formoterol fumarate or hydrate thereof, (C) tiotropium bromide or hydrate thereof and a pharmaceutically acceptable carrier, wherein the carrier is a mixture of a carrier A, a carrier B and a carrier C.

Description

Ciclesonide formoterol and tiotropium bromide compound dry powder inhalant composition
Technical Field
The invention relates to a glucocorticoid, a beta 2-receptor agonist and an anticholinergic drug compound dry powder inhalant, in particular to a ciclesonide formoterol and tiotropium bromide compound dry powder inhalant and a preparation method thereof.
Background
The dry powder inhalant belongs to one of respiratory tract administration preparations. In recent years, dry powder inhalants are developed rapidly due to the advantages of targeting, high efficiency, quick action, small toxic and side effects, no pollution and the like. Glucocorticoids, beta 2-receptor agonists and anticholinergic drugs are currently the most common drugs for the treatment of asthma and chronic pulmonary obstruction. Ciclesonide, a novel glucocorticoid, was developed by Altana, germany, and was approved for sale in australia for the treatment of asthma in 2004 as ciclesonide aerosol, and then subsequently marketed in countries and regions of the united states, europe, the day, etc. The company also studied ciclesonide suspension nasal spray, which was ciclesonide suspension nasal spray in 2008
Figure GDA0000975997040000011
First in the united states and then in countries and regions such as europe and the day. Formoterol fumarate is a third-generation β 2-receptor agonist antiasthmatic drug developed by Nippon mountain company, and is marketed in Japan in 3 months in 1988. Tiotropium bromide is a specific and selective anticholinergic drug, and is suitable for the maintenance treatment of Chronic Obstructive Pulmonary Disease (COPD), including chronic bronchitis and emphysema, the maintenance treatment of accompanying dyspnea and the prevention of acute attack. Tiotropium bromide is the only long-acting and high-selectivity M3 receptor retarder at present, can achieve good treatment effect on COPD patients by being inhaled once a day, has good medication compliance and is regularly used for a long timeTiotropium bromide is effective in improving pulmonary ventilation function, hyperinflation and dyspnea, improving exercise tolerance, and reducing acute exacerbation of COPD. In addition, tiotropium bromide in combination with other types of bronchodilators increases bronchodilator efficacy without increasing adverse effects, and is therefore a first-line maintenance drug recommended by guidelines for COPD.
At present, the research work on the crystal form of the drug becomes more and more important, and especially for solid preparations, Chinese patent ZL200580026414.0 discloses that the crystal polymorphic form of a specific drug is often an important judgment factor for the difficulty of preparing the drug, the stability, the solubility, the storage stability, the preparation difficulty and the in vivo pharmacology.
The document JOURNAL OF PHARMACEUTICAL SCIENCES, VOL.97, NO.9,2008, P3765, EP929566, WO2008062450, WO2008035066, WO2007092574, US2010120737, EP2022796 and the like report the existence OF anhydrous ciclesonide amorphous, 4 anhydrous ciclesonide crystal polymorphic forms (I, II, III, IV) and ciclesonide methanol solvate. The XRD spectrum of the ciclesonide crystal form I is shown in figure 1of WO 2008062450. The XRD spectrums of the ciclesonide crystal form II are shown in the attached figures 1of WO2007092574 and 2 of the attached figure of WO 2008062450. The XRD spectrum of the ciclesonide crystal form III is shown in figure 3 of WO 2008062450. The XRD spectrum of ciclesonide crystal form IV is shown in figure 2 of WO 2007092574. There is currently no study or report on ciclesonide monohydrate.
When a ciclesonide bulk drug is developed, the crystal form condition of the ciclesonide bulk drug is deeply researched, and anhydrous ciclesonide amorphous substances, ciclesonide crystal polymorphic forms I and II are prepared by a method of a reference document, and ciclesonide crystal polymorphic forms III and IV are not obtained. For example, by repeating WO2007092574, comparative example1, and examples 2 and 3, it was found that ciclesonide form II was obtained and ciclesonide form IV was not obtained. By repeating WO2008062450, example 8, it was found that crystalline ciclesonide form I was obtained and crystalline ciclesonide form III was not obtained. The ciclesonide polycrystalline type has stable crystal form only of ciclesonide crystal form II and no change of XRD spectrogram through continuous 10-day high-temperature, high-humidity and illumination influence factor experiments (see the attached drawing in the specification for details)1) (ii) a At high temperature, the ciclesonide crystal form I is converted into the ciclesonide crystal form II (see the attached figure 4 in the specification for details); the XRD pattern of the ciclesonide amorphous substance under illumination and high humidity shows obvious diffraction peaks (see the attached figure 5 in the specification). In addition, we filtered and separated the ciclesonide nasal spray sold in the market
Figure GDA0000975997040000021
The ciclesonide raw material in the formula (I) is subjected to X-ray powder diffraction measurement, and is also found to be a crystal form II.
When ciclesonide form II is used as active ingredient for the preparation of dry powder inhalers, a number of difficulties have been found, such as: the ciclesonide crystal form II is easy to generate static electricity when being crushed, and the particles are seriously agglomerated, which is not beneficial to the configuration of a dry powder inhalant. In addition, the lung deposition rate of the prepared ciclesonide dry powder inhalant is not ideal.
When ciclesonide form II is used as active ingredient for the preparation of dry powder inhalers, a number of difficulties have been found, such as: the ciclesonide crystal form II is easy to generate static electricity when being crushed, and the particles are seriously agglomerated, which is not beneficial to the configuration of a dry powder inhalant. In addition, the lung deposition rate of the prepared ciclesonide dry powder inhalant is not ideal.
Disclosure of Invention
The invention provides a ciclesonide formoterol and tiotropium bromide compound dry powder inhalant composition which has higher lung deposition rate.
The invention relates to a ciclesonide formoterol and tiotropium bromide compound dry powder inhalant, which comprises (A) ciclesonide monohydrate or ciclesonide, (B) formoterol fumarate or hydrate thereof, (C) tiotropium bromide or hydrate thereof and a pharmaceutically acceptable carrier, wherein the carrier is a mixture of the carrier A, the carrier B and the carrier C; calculated by weight ratio, the proportion of the carrier A in the carrier mixture is 2-8%, and the d (0.9) of the carrier A is less than 10 μm; the proportion of the carrier B in the carrier mixture is 40-60%, and the d (0.9) of the carrier B is 80-100 μm; the proportion of the carrier C in the carrier mixture is 40-60%, and the d (0.9) of the carrier C is 180-200 μm.
The ciclesonide formoterol and tiotropium bromide compound dry powder inhalant is characterized by containing ciclesonide monohydrate.
The ciclesonide formoterol and tiotropium bromide compound dry powder inhalant is characterized in that ciclesonide monohydrate exists in a crystal form, and has characteristic peaks in diffraction angle 2 theta of 5.1, 9.0, 11.2, 12.8, 15.0, 16.2, 16.9 and 20.7 in X-ray powder diffraction.
The ciclesonide formoterol and tiotropium bromide compound dry powder inhalant is characterized by containing formoterol fumarate dihydrate.
The ciclesonide formoterol and tiotropium bromide compound dry powder inhalant is characterized by containing tiotropium bromide monohydrate.
The ciclesonide formoterol and tiotropium bromide compound dry powder inhalant is characterized in that the carrier is one or more selected from carbohydrate carriers, mannitol and amino acids.
The ciclesonide formoterol and tiotropium bromide compound dry powder inhalant is characterized in that the carrier is one or more selected from maltose, trehalose, cellobiose, lactose, sucrose, fructose, glucose, mannitol and glycine.
The ciclesonide formoterol and tiotropium bromide compound dry powder inhalant is characterized in that the carrier is lactose.
The ciclesonide formoterol and tiotropium bromide compound dry powder inhalant is characterized in that the lactose is selected from one or more of alpha-lactose monohydrate, beta-anhydrous lactose, amorphous spray-dried lactose and crystalline dried lactose.
The ciclesonide formoterol and tiotropium bromide compound dry powder inhalant is characterized in that the lactose is alpha-lactose monohydrate.
Surprisingly, in the process of ciclesonide crystal form research, a brand new ciclesonide monohydrate is discovered, and through stability test investigation, the brand new ciclesonide monohydrate is more convenient to crush than the existing anhydrous ciclesonide, is beneficial to the preparation of dry powder inhalant, and the dry powder inhalant prepared under the same prescription and preparation conditions has higher lung deposition rate, as shown in invention example 6. Therefore, the novel ciclesonide monohydrate raw material drug can become a new choice of ciclesonide preparation products, especially dry powder inhalants.
The chemical structural formula of the ciclesonide monohydrate is shown as the following chart:
Figure GDA0000975997040000041
the ciclesonide monohydrate is characterized in that the compound exists in a crystal form, and has characteristic peaks in diffraction angles 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 by X-ray powder diffraction.
The ciclesonide monohydrate is characterized in that the compound exists in a crystal form, and has characteristic peaks in diffraction angles 2 theta of 5.1 degrees, 9.0 degrees, 11.2 degrees, 12.8 degrees, 15.0 degrees, 16.2 degrees, 16.9 degrees, 20.7 degrees, 21.8 degrees, 24.3 degrees, 29.1 degrees and 32.7 degrees by X-ray powder diffraction.
It should be understood that the diffraction intensity of the characteristic peak may vary slightly from crystal preparation technique, sample mounting method and measurement instrument to crystal preparation technique and should be within the scope of the present invention. In addition, the diffraction angle 2 θ value may be affected by instrument variation and other factors, so that the above-mentioned diffraction angle 2 θ value having characteristic peaks may vary within ± 0.1 ° from the existing value.
The preparation method of the ciclesonide monohydrate is characterized by adopting a supercritical fluid technology for preparation, and comprises the following steps:
preparing ciclesonide solution: completely dissolving 5g of ciclesonide in a mixed solution of 200ml of acetone and 20ml of water at 50 ℃;
the ciclesonide solution configured in the step is connected with a solution pump, and the working pressure is controlled to be 10 MPa;
feeding carbon dioxide: CO in the steel cylinder2Inputting the supercritical fluid anti-solvent equipment system into a crystallization kettle through a booster pump, controlling the flow at 10ml/min, and controllingThe starting temperature is 50 ℃, and the pressure is 10 MPa;
fourthly, rapidly spraying the ciclesonide solution prepared in the step S into a crystallization kettle through a nozzle in a supercritical fluid solvent resisting equipment system by a solution pump, controlling the flow to be 1.5ml/min, controlling the temperature of the nozzle to be 50 ℃, and controlling the spraying distance to be 5 cm; simultaneously, an entrainer ethanol is sprayed into the crystallization kettle through an entrainer solution pump, and the flow is controlled to be 1.5 ml/min; the operation time is 140 min; continuously introducing CO2Cleaning the residual solvent in the crystallization kettle;
fifthly, crystallizing and separating out ciclesonide monohydrate; ciclesonide monohydrate precipitated from the solution was collected at the bottom of the crystallization vessel.
The preparation method of ciclesonide monohydrate is characterized by adding a seed crystal into a saturated solution M of ciclesonide, cooling and crystallizing, wherein the solution M consists of 1 part by volume of ethanol, 0.1-0.15 part by volume of water and 0.1-0.15 part by volume of acetonitrile, and the X-ray powder diffraction of the seed crystal has characteristic peaks at diffraction angles 2 theta of 5.1 degrees, 9.0 degrees, 11.2 degrees, 12.8 degrees, 15.0 degrees, 16.2 degrees, 16.9 degrees, 20.7 degrees, 21.8 degrees, 24.3 degrees, 29.1 degrees and 32.7 degrees.
The ciclesonide monohydrate of the invention is determined to contain a crystal water by thermogravimetric differential thermal analysis research. The DTA spectrogram has an endothermic peak at 132 ℃ in the range of room temperature to 200 ℃, the corresponding TG spectrum is a step-shaped weight loss line, the weight loss is 3.1 percent, and the amount of one crystal water is calculated to be 3.2 percent, which proves that one crystal water exists.
In the studies, it was found that recrystallization using a mixed solvent of one or more organic solvents (methanol, ethanol, isopropanol, n-propanol, t-butanol, acetone, acetonitrile, tetrahydrofuran, etc.) and water makes it difficult to obtain ciclesonide monohydrate even under very mild room temperature vacuum drying conditions. Ciclesonide monohydrate crystals are unexpectedly obtained by supercritical fluid technology, and the crystals can be used as seed crystals for the next reaction after being crushed. By way of study, it has surprisingly been found that in the above-mentioned process for the preparation of ciclesonide monohydrate, the volume ratio of ethanol/water/acetonitrile in the mixed solvent M required for recrystallization is important, for example: when the volume ratio of ethanol/water/acetonitrile is out of the above range, the obtained product is anhydrous ciclesonide even if the ciclesonide monohydrate seed crystal is added, for example, comparative example 1. On the other hand, it is also important to add a seed crystal of ciclesonide monohydrate, and anhydrous ciclesonide is also obtained without adding a seed crystal under the same other preparation conditions, for example, comparative example 2.
As can be seen from inventive example 6, the completely new ciclesonide monohydrate has a higher lung deposition rate than the existing anhydrous ciclesonide crystal form II, and the dry powder inhalant prepared under the same prescription and preparation conditions has a higher lung deposition rate.
In addition, the results of influence factors, accelerated tests and long-term stability test investigation of 24-month room temperature sample retention show that the ciclesonide monohydrate has no obvious change in all detection items (characters, contents and related substances) and good stability, and the results of X-ray powder diffraction tests show that the crystal form is not changed and can keep good stability.
The powder diffraction instrument used in the present invention is Rigaku D/max-2500 powder diffraction instrument, a product of Japan science Co. The thermogravimetric-differential thermal analyzer used in the present invention is a japanese physical standard type TG-DTA analyzer.
Description of the drawings:
FIG. 1 shows the X-ray powder diffraction pattern and 10-day effect factor experiment results of ciclesonide form II prepared in comparative example 14
FIG. 2 is an X-ray powder diffraction pattern of ciclesonide monohydrate prepared in inventive example1
FIG. 3 is a schematic diagram of the connection and flow of supercritical fluid anti-solvent equipment in example1of the present invention.
Wherein, 1 is ciclesonide solution, 2 is a solution pump, 3 is a nozzle, 4 is a crystallization kettle, 5 is a gas-liquid separation kettle, 6 is a gas discharge outlet, 7 is a residual liquid collector, 8 is a booster pump, 9 is CO 210 is entrainer solution pump, P1 is equipment system pressure, P2 is crystallization kettle working pressure
FIG. 4 shows the X-ray powder diffraction pattern and 10-day effect factor experiment results of ciclesonide form I obtained in comparative example 15
FIG. 5 is an X-ray powder diffraction pattern of ciclesonide amorphous form obtained in comparative example 12 and 10-day influence factor experiment results
The specific implementation mode is as follows:
the invention will now be further described by way of the following examples, which are not intended to limit the scope of the invention in any way. It will be understood by those skilled in the art that equivalent substitutions for the technical features of the present invention, or corresponding modifications, can be made within the scope of the present invention.
The same lot numbers were used for the same reagents and reagents in the following examples.
Inventive example1 preparation of ciclesonide monohydrate by supercritical method
Preparing ciclesonide solution 1: completely dissolving 5g of ciclesonide in a mixed solution of 200ml of acetone and 20ml of water at 50 ℃;
the ciclesonide solution 1 configured in the step is connected with a solution pump 2, and the working pressure is controlled to be 10 MPa;
feeding carbon dioxide: CO in the steel cylinder2Inputting the supercritical fluid anti-solvent equipment system through a booster pump 8, and feeding the supercritical fluid anti-solvent equipment system into a crystallization kettle 4, wherein the flow is controlled at 10ml/min, the starting temperature is controlled at 50 ℃, and the pressure is 10 MPa;
fourthly, rapidly spraying the ciclesonide solution 1 configured in the step S into a crystallization kettle 4 through a nozzle 3 in a supercritical fluid solvent resisting equipment system by a solution pump 2, wherein the flow rate is controlled to be 1.5ml/min, the temperature of the nozzle is 50 ℃, and the spraying distance is 5 cm; simultaneously, an entrainer ethanol is sprayed into the crystallization kettle 4 through an entrainer solution pump 10, and the flow is controlled to be 1.5 ml/min; the operation time is 140 min; continuously introducing CO2Cleaning the residual solvent in the crystallization kettle 4;
fifthly, crystallizing and separating out ciclesonide monohydrate; ciclesonide monohydrate precipitated from the solution is collected at the bottom 4 of the crystallization vessel.
Sixthly, processing the residue by a gas-liquid separation kettle 5, discharging gas through a gas discharge port 6, and enabling the residual liquid to flow into a residual liquid collector 7.
The dried crystals were analyzed by TG-DTA, and weight loss was about 3.1%, and ciclesonide monohydrate was confirmed. The obtained crystal was subjected to X-ray powder diffraction measurement, and characteristic peak positions were found to be 5.1 °, 9.0 °, 11.2 °, 12.8 °, 15.0 °, 16.2 °, 16.9 °, 20.7 °, 21.8 °, 24.3 °, 29.1 °, and 32.7 °, as shown in fig. 2.
The ciclesonide monohydrate crystals prepared in inventive example1 were crushed in a mortar and used as seeds for inventive examples 2 to 5.
Inventive example 2 preparation of ciclesonide monohydrate
Adding 5g of ciclesonide into a mixed solution of 100ml of ethanol, 10ml of water and 10ml of acetonitrile, heating to 50 ℃, filtering out insoluble substances by heat filtration, cooling to 30 ℃ (if crystals are precipitated, taking supernatant liquid), then adding the seed crystal prepared in the invention example1, stirring for 30 minutes under heat preservation, precipitating a large amount of crystals, cooling to 0-5 ℃, filtering, drying, analyzing the dried crystals by TG-DTA, losing weight by about 3.1%, and confirming that the ciclesonide monohydrate. The obtained crystal was subjected to X-ray powder diffraction measurement, and characteristic peak positions were found to be 5.1 °, 9.0 °, 11.2 °, 12.8 °, 15.0 °, 16.2 °, 16.9 °, 20.7 °, 21.8 °, 24.3 °, 29.1 °, and 32.7 °.
Inventive example 3 preparation of ciclesonide monohydrate
Adding 5g of ciclesonide into a mixed solution of 100ml of ethanol, 10ml of water and 15ml of acetonitrile, heating to 50 ℃, filtering out insoluble substances by heat filtration, cooling to 30 ℃ (if crystals are precipitated, taking supernatant liquid), then adding the seed crystal prepared in the invention example1, stirring for 30 minutes under heat preservation, precipitating a large amount of crystals, cooling to 0-5 ℃, filtering, drying, analyzing the dried crystals by TG-DTA, losing weight by about 3.1%, and confirming that the ciclesonide monohydrate. The obtained crystal was subjected to X-ray powder diffraction measurement, and characteristic peak positions were found to be 5.1 °, 9.0 °, 11.2 °, 12.8 °, 15.0 °, 16.2 °, 16.9 °, 20.7 °, 21.8 °, 24.3 °, 29.1 °, and 32.7 °.
Inventive example 4 preparation of ciclesonide monohydrate
Adding 5g of ciclesonide into a mixed solution of 100ml of ethanol, 15ml of water and 10ml of acetonitrile, heating to 50 ℃, filtering out insoluble substances by heat filtration, cooling to 30 ℃ (if crystals are precipitated, taking supernatant liquid), then adding the seed crystal prepared in the invention example1, stirring for 30 minutes under heat preservation, precipitating a large amount of crystals, cooling to 0-5 ℃, filtering, drying, analyzing the dried crystals by TG-DTA, losing weight by about 3.1%, and confirming that the ciclesonide monohydrate. The obtained crystal was subjected to X-ray powder diffraction measurement, and characteristic peak positions were found to be 5.1 °, 9.0 °, 11.2 °, 12.8 °, 15.0 °, 16.2 °, 16.9 °, 20.7 °, 21.8 °, 24.3 °, 29.1 °, and 32.7 °.
Inventive example 5 preparation of ciclesonide monohydrate
Adding 5g of ciclesonide into a mixed solution of 100ml of ethanol, 15ml of water and 15ml of acetonitrile, heating to 50 ℃, filtering out insoluble substances by heat filtration, cooling to 30 ℃ (if crystals are precipitated, taking supernatant liquid), then adding the seed crystal prepared in the invention example1, stirring for 30 minutes under heat preservation, precipitating a large amount of crystals, cooling to 0-5 ℃, filtering, drying, analyzing the dried crystals by TG-DTA, losing weight by about 3.1%, and confirming that the ciclesonide monohydrate. The obtained crystal was subjected to X-ray powder diffraction measurement, and characteristic peak positions were found to be 5.1 °, 9.0 °, 11.2 °, 12.8 °, 15.0 °, 16.2 °, 16.9 °, 20.7 °, 21.8 °, 24.3 °, 29.1 °, and 32.7 °.
EXAMPLE 6 preparation of ciclesonide formoterol tiotropium bromide Compound Dry powder inhaler and Lung deposition Rate study
Examples 6-1 to 6-20 used ciclesonide monohydrate, formoterol fumarate dihydrate and tiotropium bromide monohydrate as active ingredients. The active ingredients adopted in examples 6-21 to 6-40 were ciclesonide crystal form II, formoterol fumarate dihydrate and tiotropium bromide monohydrate. Ciclesonide monohydrate d (0.9) ═ 5.3 μm, and the charged amount was 4.13g (4.0 g based on ciclesonide). Ciclesonide form II had d (0.9) ═ 5.1 μm, and the charged amount was 4.0 g. Formoterol fumarate dihydrate d (0.9) ═ 5.3 μm, charged amounts were 0.123g each, tiotropium bromide monohydrate d (0.9) ═ 5.0 μm, charged amounts were 0.184g each.
The preparation process comprises the following steps: premixing the active ingredient and the carrier through a three-dimensional mixer according to the prescription, and then mixing by adopting a high-speed mixer to obtain a dry powder mixture of the active ingredient and the carrier. The high-speed mixer is characterized in that two mixing blades are arranged in a mixing cavity of the high-speed mixer and move in the horizontal direction and the vertical direction respectively. The prepared mixture was quantitatively filled into a multi-dose reservoir type dry powder administration device. Each product employs the same dry powder inhalation device.
The deposition rates of ciclesonide (in each case ciclesonide), formoterol fumarate and tiotropium bromide were determined using a new generation pharmaceutical impactor (NGI). Sequentially assembling a vacuum pump, a flow control meter, a new-generation medical impactor, a suction nozzle adapter and a flowmeter, adjusting the flow of the vacuum pump to 60L/min +/-2L/min, setting the air extraction time to 4s, taking down the flowmeter, forcibly and vertically shaking the sample for three times, connecting the adapter and the sample, pressing once, starting the vacuum pump, starting the test of the flow control meter, and continuously operating for 10 times. Adding a proper amount of sample dissolving liquid into a new generation of suction nozzle adapter, the throat part of the medicinal impactor, the preseparator and the collection disc respectively, testing the content after extraction, calculating the deposition rate of the effective part (namely the proportion of the medicine smaller than 5 microns in the recovered medicine) by using calculation software, and obtaining a detection result shown in table 2.
TABLE 1 examples 6-1 to 6-40 formulations
Figure GDA0000975997040000091
Figure GDA0000975997040000101
TABLE 2 examples 6-1 to 6-40 Lung deposition rates
Figure GDA0000975997040000102
Figure GDA0000975997040000111
Figure GDA0000975997040000121
D (0.9) of lactose A, mannitol A and glycine A is less than 10 μm; d (0.9) of lactose B, mannitol B and glycine B is 80-100 μm; the d (0.9) of lactose C, mannitol C and glycine C is 180-200. mu.m. Lactose a, lactose B and lactose C are all alpha-lactose monohydrate.
Comparative example preparation of Anhydrous ciclesonide
Comparative example1
Adding 5g of ciclesonide into a mixed solution of 100ml of ethanol, 10ml of water and 20ml of acetonitrile, heating to 50 ℃, filtering out insoluble substances by heat filtration, cooling to 30 ℃ (if crystals are precipitated, taking supernatant liquid), then adding the seed crystal prepared in the invention example1, stirring for 30 minutes under heat preservation, precipitating a large amount of crystals, cooling to 0-5 ℃, filtering, drying in vacuum at room temperature, measuring the water content of the dried crystals by using a Karl Fischer method, and confirming that the ciclesonide anhydrous compound is obtained.
Comparative example 2
Adding 5g of ciclesonide into a mixed solution of 100ml of ethanol, 10ml of water and 10ml of acetonitrile, heating to 50 ℃, filtering out insoluble substances by heat filtration, cooling for crystallization, filtering, vacuum drying at room temperature, measuring the water content of the dried crystal by using a Karl Fischer method, and confirming the ciclesonide anhydrous compound.
Comparative example 3
Comparative example 3-1
Ciclesonide 0.5g was dissolved in 1.8mL of acetonitrile, and 0.3mL of pure water was added under stirring and refluxing, and the mixture was cooled to room temperature, crystallized, filtered, and vacuum-dried at room temperature, and the water content of the dried crystals was measured by the Karl Fischer method to confirm that ciclesonide anhydrous compound was obtained.
Comparative example 3-2
Ciclesonide 0.5g was dissolved in 1.5mL of acetonitrile, and 0.2mL of pure water was added under stirring and refluxing, and the mixture was cooled to room temperature, crystallized, filtered, and vacuum-dried at room temperature, and the water content of the dried crystals was measured by the Karl Fischer method to confirm that ciclesonide anhydrous compound was obtained.
Comparative example 4
The master thesis by zhang bin, P23, of asthma treatment-22R ciclesonide, P23:
dissolving 1g of ciclesonide in 5mL of absolute ethyl alcohol, adding 0.2 time of activated carbon, stirring and refluxing for 30 minutes, filtering while hot, concentrating the filtrate under reduced pressure to obtain the rest 4 times of ethyl alcohol, heating, adding 0.2mL of pure water under reflux, standing and cooling, filtering after crystal precipitation, washing with 50% ethyl alcohol/water, drying in vacuum at room temperature, measuring the water content of the dried crystal by using a Karl Fischer method, and determining that the ciclesonide anhydrous compound is obtained.
Comparative example 5
Comparative example 5-1
Dissolving 0.5g of ciclesonide in 5mL of acetone, adding 0.3mL of pure water under stirring and refluxing, standing, naturally cooling, filtering after crystallization, drying in vacuum at room temperature, and measuring the water content of the dried crystal by using a Karl Fischer method to confirm that the ciclesonide anhydrous compound is obtained.
Comparative example 5-2
Dissolving 0.5g of ciclesonide in 2.5mL of acetone, adding 0.2mL of pure water under stirring and refluxing, standing for natural cooling, filtering after crystallization, drying in vacuum at room temperature, and determining the water content of the dried crystal by using a Karl Fischer method to obtain the ciclesonide anhydrous compound.
Comparative examples 5 to 3
The master thesis by zhang bin, P23, of asthma treatment-22R ciclesonide, P23:
dissolving 2g of ciclesonide in 5.6mL of acetone, adding 1.2mL of pure water under stirring reflux, standing, naturally cooling, filtering after crystal precipitation, washing with 75% acetone/water, vacuum drying at room temperature, measuring the water content of the dried crystal by using a Karl Fischer method, and determining that the ciclesonide anhydrous compound is obtained.
Comparative example 6
Adding 5g of ciclesonide into a mixed solution of 200ml of methanol and 10ml of water, heating to 50 ℃, filtering out insoluble substances by heat filtration, cooling for crystallization, filtering, drying in vacuum at room temperature, and measuring the water content of the dried crystal by using a Karl Fischer method to confirm that the ciclesonide anhydrous compound is obtained.
Comparative example 7
Adding 5g of ciclesonide into a mixed solution of 50ml of ethanol, 10ml of water and 50ml of acetone, heating to 50 ℃, filtering out insoluble substances by heat filtration, cooling for crystallization, filtering, vacuum drying at room temperature, measuring the water content of the dried crystal by using a Karl Fischer method, and confirming the ciclesonide anhydrous compound.
Comparative example 8
Heating and dissolving 0.5g of ciclesonide in 1.5mL of isopropanol, adding 0.4mL of pure water under stirring and refluxing, cooling to room temperature, filtering after crystallization, drying in vacuum at room temperature, and determining the water content of the dried crystal by using a Karl Fischer method to determine that the ciclesonide anhydrous compound is obtained.
Comparative example 9
And adding 5g of ciclesonide into a mixed solution of 10ml of water and 500ml of n-propanol, heating to 50 ℃, filtering out insoluble substances by hot filtration, cooling, crystallizing, filtering, drying in vacuum at room temperature, and measuring the water content of the dried crystal by using a Karl Fischer method to confirm that the ciclesonide anhydrous compound is obtained.
Comparative example 10
And adding 5g of ciclesonide into a mixed solution of 3ml of water and 50ml of tetrahydrofuran, heating to 50 ℃, filtering out insoluble substances by heat filtration, cooling for crystallization, filtering, drying in vacuum at room temperature, and measuring the water content of the dried crystals by using a Karl Fischer method to confirm that the ciclesonide anhydrous compound is obtained.
Comparative example 11
Taking out the commercial products
Figure GDA0000975997040000141
(ciclesonide suspension type nasal spray), filtering, washing the filtrate with water, drying in vacuum at room temperature, measuring the water content of the dried crystal by using a Karl Fischer method, and confirming that the ciclesonide anhydrous compound is obtained. The obtained ciclesonide crystals were subjected to X-ray powder diffraction measurement, and characteristic peak positions thereof were found to be 2 θ ═ 5.3 °, 6.7 °, 8.1 °, 10.6 °, 12.3 °, 14.7 °, 16.8 °, 17.2 °, 18.2 ° (degrees of X-ray diffraction)And the crystal form II is confirmed.
Comparative example 12
Specific method refer to WO2008062450, example 9, the final product is vacuum dried at room temperature, and the water content of the dried product is measured by karl fischer method, and ciclesonide is confirmed as anhydrous. The ciclesonide crystals obtained were confirmed to be amorphous by X-ray powder diffraction measurement, and the XRD spectrum and the influence factor results are shown in fig. 5 after 10 days.
Comparative example 13
Specific method referring to WO2007092574 comparative example1 (synthetic example 1: repetition of example1of EP929566), the final product was dried under vacuum at room temperature, and the water content of the dried crystals was measured by Karl Fischer method to confirm that ciclesonide was anhydrous. The obtained ciclesonide crystals were subjected to X-ray powder diffraction measurement, and characteristic peak positions of 2 θ ═ 5.3 °, 6.7 °, 8.1 °, 10.6 °, 12.3 °, 14.7 °, 16.8 °, 17.2 °, 18.2 °, and identified as ciclesonide crystal form II.
Comparative example 14
Specific method refer to WO2007092574 example 2, the final product is dried in vacuum at room temperature, and the water content of the dried crystal is measured by karl fischer method, and ciclesonide anhydrous compound is confirmed. The ciclesonide crystals obtained were subjected to X-ray powder diffraction measurement, and characteristic peak positions of 2 θ ═ 5.3 °, 6.7 °, 8.1 °, 10.6 °, 12.3 °, 14.7 °, 16.8 °, 17.2 °, 18.2 ° were determined as ciclesonide form II, and the results of the XRD spectrum and the influence factors for 10 days were shown in fig. 1.
Comparative example 15
Specific methods refer to WO2008062450, example 8. The ciclesonide crystal obtained was confirmed to be ciclesonide crystal form I by X-ray powder diffraction measurement, and the XRD spectrum and the influence factor results for 10 days are shown in fig. 4.

Claims (10)

1. A ciclesonide formoterol and tiotropium bromide compound dry powder inhalant contains (A) ciclesonide monohydrate or ciclesonide, (B) formoterol fumarate or hydrate thereof, (C) tiotropium bromide or hydrate thereof and a pharmaceutically acceptable carrier, wherein the carrier is a mixture of the carrier A, the carrier B and the carrier C; calculated by weight ratio, the proportion of the carrier A in the carrier mixture is 2-8%, and the d (0.9) of the carrier A is less than 10 μm; the proportion of the carrier B in the carrier mixture is 40-60%, and the d (0.9) of the carrier B is 80-100 μm; the proportion of the carrier C in the carrier mixture is 40-60%, and the d (0.9) of the carrier C is 180-200 μm; the carrier is selected from saccharide carrier, mannitol or amino acid.
2. The ciclesonide formoterol and tiotropium bromide compound dry powder inhaler according to claim 1, characterized by comprising ciclesonide monohydrate.
3. The ciclesonide formoterol and tiotropium compound dry powder inhaler according to claim 2, characterized in that the ciclesonide monohydrate exists in a crystal form, and has characteristic peaks in X-ray powder diffraction at diffraction angles 2 θ of 5.1 °, 9.0 °, 11.2 °, 12.8 °, 15.0 °, 16.2 °, 16.9 ° and 20.7 °.
4. The ciclesonide formoterol and tiotropium compound dry powder inhaler according to claim 2, characterized in that the ciclesonide monohydrate exists in a crystal form and has characteristic peaks in X-ray powder diffraction at diffraction angles 2 θ of 5.1 °, 9.0 °, 11.2 °, 12.8 °, 15.0 °, 16.2 °, 16.9 °, 20.7 °, 21.8 °, 24.3 °, 29.1 ° and 32.7 °.
5. The compound dry powder inhaler of claim 1, characterized by containing formoterol fumarate dihydrate.
6. The ciclesonide formoterol and tiotropium bromide compound dry powder inhaler according to claim 1, characterized by comprising tiotropium bromide monohydrate.
7. The compound dry powder inhaler of ciclesonide formoterol and tiotropium bromide according to any one of claims 1 to 6, characterized in that the carrier is one or more selected from maltose, trehalose, cellobiose, lactose, sucrose, fructose, glucose, mannitol and glycine.
8. The compound dry powder inhaler of claim 7, wherein the carrier is lactose.
9. The ciclesonide formoterol and tiotropium bromide compound dry powder inhaler according to claim 8, characterized in that the lactose is selected from one or more of alpha-lactose monohydrate, beta-lactose anhydrous, amorphous lactose spray-dried and crystalline lactose dried.
10. The ciclesonide formoterol and tiotropium bromide compound dry powder inhaler according to claim 9, characterized in that the lactose is α -lactose monohydrate.
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