Salmeteroxaphthoate and ciclesonide co-amorphous substance as well as preparation method and application of salmeteroxaphthoate and ciclesonide co-amorphous substance

Abstract

The invention provides a salmeteroxaphthoate and ciclesonide co-amorphous substance as well as a preparation method and application thereof. Specifically, the invention provides a salmeteroxinaphthenate / ciclesonide co-amorphous substance, the co-amorphous substance is an amorphous substance formed by salmeteroxinaphthenate and ciclesonide according to a molar ratio of 1: (0.4-4.1), and the invention further provides a nano-crystallized co-amorphous substance of the salmeteroxinaphthenate / ciclesonide co-amorphous substance. The amorphous substance provided by the invention has better solubility, stability and pharmacokinetic and pharmacodynamic properties than the salmeteroxaphthoate and ciclesonide, can enhance the synergistic effect of the salmeteroxaphthoate and ciclesonide, and is very suitable for being used as an API of a salmeteroxaphthoate and ciclesonide combined drug.

Description

Technical Field

[0001] The invention relates to a salmeterol xinafoate and ciclesonide co-amorphous substance and a preparation method and application thereof. Background Art

[0002] The chemical name of salmeterol xinafoate (SX) is 2-hydroxymethyl-4-[1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl]phenol, 1-hydroxy-2-naphthoate, CAS No.: 94749-08-3, molecular weight: 603.75, structure:

[0003]

[0004] Salmeterol xinafoate is a long-acting selective β2-adrenergic receptor agonist with significant bronchodilator effect when administered by inhalation. It is often used in combination with inhaled glucocorticoids to treat reversible airway obstructive airway diseases, including asthma in adults and children. Salmeterol xinafoate has good lipid solubility due to its long alkyl chain. After administration, it easily enters the cell membrane to form a reservoir and exerts a unique long-acting effect.

[0005] The chemical name of ciclesonide (CIC) is (11β, 16α)-16,17-[[(R)cyclohexylmethylene]bis(oxy)]-11-hydroxy-21-(2-methyl-1-oxopropoxy)pregna-1,4-diene-3,20-dione, the CAS number is 126544-47-6, the molecular weight is 540.69, and the structure is as shown in Formula II:

[0006]

[0007] Ciclesonide is an inhaled glucocorticoid with good affinity to glucocorticoid receptors. It has good local anti-inflammatory efficacy and long-lasting effect when inhaled, has a complete first-pass effect, and can significantly reduce the systemic adverse reactions of inhaled glucocorticoids. In clinical practice, aerosols are often used and can be used to treat obstructive airway diseases through oral inhalation.

[0008] When long-acting β2 receptor agonists are combined with inhaled glucocorticoids for the treatment of bronchial asthma, glucocorticoids can increase the expression of β2 receptors in airway smooth muscle cells, reduce the desensitization and tolerance of β2 receptors, and long-acting β2 receptor agonists can pre-activate glucocorticoid receptors after binding to receptors, thereby enhancing the anti-inflammatory effect. Compared with the use of long-acting β2 receptor agonists or glucocorticoids alone, combined medication can have a synergistic anti-inflammatory and antiasthmatic effect, reduce the use of glucocorticoids, and thus reduce the adverse reactions that may be caused by the use of glucocorticoids.

[0009] Since salmeterol xinafoate and ciclesonide have extremely low water solubility and dispersibility, the combined administration of salmeterol xinafoate and ciclesonide becomes difficult. Therefore, there is an urgent need in the art to provide a combined administration method of salmeterol xinafoate and ciclesonide that is more conducive to the pharmaceutical process. Summary of the invention

[0010] The purpose of the present invention is to provide a salmeterol xinafoate and ciclesonide co-amorphous substance and a preparation method and application thereof.

[0011] In a first aspect of the present invention, a salmeterol xinafoate / ciclesonide co-amorphous material is provided, wherein the co-amorphous material is an amorphous material formed by salmeterol xinafoate and ciclesonide in a molar ratio of 1:(0.4-4.1).

[0012] In another preferred embodiment, the powder X-ray diffraction pattern of the co-amorphous material has no crystal diffraction peaks and exhibits a hump characteristic of amorphous material.

[0013] In another preferred embodiment, the glass transition temperature of the co-amorphous material is 8-75°C.

[0014] In another preferred embodiment, in the co-amorphous material, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(0.5±0.1), 1:(1±0.1), 1:(1.5±0.1), 1:(2±0.1), 1:(3±0.1) or 1:(4±0.1).

[0015] In another preferred embodiment, in the co-amorphous material, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(1.5±0.1), and the glass transition temperature of the co-amorphous material is 52.67±3°C (preferably ±2°C or ±1°C).

[0016] In another preferred embodiment, the mass ratio of salmeterol xinafoate to ciclesonide is 7.25:(10±0.5).

[0017] In another preferred embodiment, the infrared spectrum of the co-amorphous material is 1721±5cm -1 , 1500±5cm -1 (Preferably ±2cm -1 or ±1cm -1 ) has an absorption peak.

[0018] In another preferred embodiment, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(1.5±0.05), more preferably 1:(1.5±0.01).

[0019] In another preferred embodiment, in the co-amorphous material, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(0.5±0.1), and the glass transition temperature of the co-amorphous material is 9.29±3°C (preferably ±2°C or ±1°C).

[0020] In another preferred embodiment, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(0.5±0.05), more preferably 1:(0.5±0.01).

[0021] In another preferred embodiment, in the co-amorphous material, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(1±0.1), and the glass transition temperature of the co-amorphous material is 43.64±3°C (preferably ±2°C or ±1°C).

[0022] In another preferred embodiment, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(1±0.05), more preferably 1:(1±0.01).

[0023] In another preferred embodiment, in the co-amorphous material, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(2±0.1), and the glass transition temperature of the co-amorphous material is 57.76±3°C (preferably ±2°C or ±1°C).

[0024] In another preferred embodiment, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(2±0.05), more preferably 1:(2±0.01).

[0025] In another preferred embodiment, in the co-amorphous material, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(3±0.1), and the glass transition temperature of the co-amorphous material is 64.91±3°C (preferably ±2°C or ±1°C).

[0026] In another preferred embodiment, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(3±0.05), more preferably 1:(3±0.01).

[0027] In another preferred embodiment, in the co-amorphous material, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(4±0.1), and the glass transition temperature of the co-amorphous material is 72.76±3°C (preferably ±2°C or ±1°C).

[0028] In another preferred embodiment, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(4±0.05), more preferably 1:(4±0.01).

[0029] The second aspect of the present invention provides a method for preparing the salmeterol xinafoate / ciclesonide co-amorphous material as described in the first aspect of the present invention, comprising the steps of: providing a mixed solution of salmeterol xinafoate and ciclesonide, and removing the solvent by rotary evaporation to obtain the co-amorphous material.

[0030] In another preferred embodiment, the solvent of the mixed solution is selected from the following group: methanol, ethanol, tetrahydrofuran, chloroform, dichloromethane, or a combination thereof, preferably methanol.

[0031] In another preferred embodiment, the temperature of the rotary evaporation is 20-60°C, preferably 30±5°C.

[0032] In another preferred embodiment, in the mixed solution, the concentration of salmeterol xinafoate is 5-50 mg / mL, preferably 14.5 mg / mL to 29 mg / mL, such as 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL or 30 mg / mL.

[0033] In another preferred embodiment, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(0.4-4.1), preferably 1:(0.5-4), more preferably 1:(0.5±0.1), 1:(1±0.1), 1:(1.5±0.1), 1:(2±0.1), 1:(3±0.1) or 1:(4±0.1).

[0034] The third aspect of the present invention provides a method for preparing the salmeterol xinafoate / ciclesonide co-amorphous material as described in the first aspect of the present invention, comprising the steps of: adding a solvent to salmeterol xinafoate and ciclesonide in a container and then grinding to obtain the salmeterol xinafoate / ciclesonide co-amorphous material.

[0035] In another preferred embodiment, the solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran, chloroform, dichloromethane, or a combination thereof, preferably methanol.

[0036] In another preferred embodiment, the grinding temperature is 4-40°C, preferably 20±5°C.

[0037] In another preferred embodiment, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(0.4-4.1), preferably 1:(0.5-4), more preferably 1:(0.5±0.1), 1:(1±0.1), 1:(1.5±0.1), 1:(2±0.1), 1:(3±0.1) or 1:(4±0.1).

[0038] In a fourth aspect, the present invention provides a salmeterol xinafoate / ciclesonide nano-co-amorphous material, wherein:

[0039] In the nano-co-amorphous material, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(0.4-4.1).

[0040] In another preferred embodiment, in the nano-co-amorphous material, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(0.5±0.1), 1:(1±0.1), 1:(1.5±0.1), 1:(2±0.1), 1:(3±0.1) or 1:(4±0.1).

[0041] In another preferred embodiment, the powder X-ray diffraction pattern of the salmeterol xinafoate / ciclesonide nano-co-amorphous material has no crystal diffraction peaks and exhibits a hump characteristic of amorphous material.

[0042] In another preferred embodiment, the nano-co-amorphous material is spherical nanoparticles.

[0043] In another preferred embodiment, in the nano-co-amorphous material, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(1.5±0.1), and the glass transition temperature of the co-amorphous material is 28.28±3°C (preferably ±2°C or ±1°C).

[0044] In another preferred embodiment, the particle size of the nano-co-amorphous material is 172.5±25 nm, the polydispersity coefficient is 0.119±0.015, and the Zeta potential is -51.5±2 mV.

[0045] In another preferred embodiment, the particle size of the nano-co-amorphous material is 172.5±21.03 nm, the polydispersity coefficient is 0.119±0.013, and the Zeta potential is -51.5±1.55 mV.

[0046] In a fifth aspect, the present invention provides a method for preparing the salmeterol xinafoate / ciclesonide nano-co-amorphous material as described in the fifth aspect of the present invention, wherein the method is an emulsified solvent freeze-drying method, and preferably the method comprises the steps of mixing an organic solution of salmeterol xinafoate and ciclesonide with water or an aqueous solution of a stabilizer (such as sodium deoxycholate) to obtain a mixed solution, and then freeze-drying to obtain the nano-co-amorphous material.

[0047] In another preferred embodiment, in the organic solution, the solvent is selected from the following group: methanol, ethanol, isopropanol, or a combination thereof, preferably methanol.

[0048] In another preferred embodiment, the volume ratio of the organic solvent to water in the mixed solution is 1:10-50, preferably 1:30-40, such as 1:15, 1:20, 1:25, 1:30, 1:35, 1:40 or 1:45.

[0049] In another preferred embodiment, the freeze-drying time is 12-24 hours.

[0050] In another preferred embodiment, the concentration of sodium deoxycholate in the aqueous solution is between 0.1wt% and 1.0wt%, such as 0.2wt%, 0.3wt%, 0.4wt%, 0.5wt%, 0.6wt%, 0.8wt%.

[0051] In another preferred embodiment, in the organic solution, the concentration of salmeterol xinafoate is 5-50 mg / mL, preferably 14.5 mg / mL to 29 mg / mL, such as 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL or 30 mg / mL.

[0052] In another preferred embodiment, in the nano-co-amorphous material, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(0.4-4.1), such as 1:(0.5±0.1), 1:(1±0.1), 1:(1.5±0.1), 1:(2±0.1), 1:(3±0.1) or 1:(4±0.1).

[0053] In the sixth aspect of the present invention, a pharmaceutical composition is provided, comprising the salmeterol xinafoate / ciclesonide co-amorphous material as described in the first aspect of the present invention or the salmeterol xinafoate / ciclesonide nano-co-amorphous material as described in the fifth aspect of the present invention, and a pharmaceutically acceptable carrier.

[0054] The seventh aspect of the present invention provides use of the salmeterol xinafoate / ciclesonide co-amorphous material as described in the first aspect of the present invention or the salmeterol xinafoate / ciclesonide nano-co-amorphous material as described in the fifth aspect of the present invention in the preparation of a medicament for preventing or treating obstructive airway diseases.

[0055] In another preferred embodiment, the obstructive airway disease is selected from the group consisting of asthma, nocturnal asthma, exercise-induced asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infection and upper respiratory tract disease.

[0056] In the seventh aspect of the present invention, a method for preventing or treating obstructive airway disease is provided, comprising the steps of administering the salmeterol xinafoate / ciclesonide co-amorphous compound described in the first aspect of the present invention or the salmeterol xinafoate / ciclesonide nano-co-amorphous compound described in the fifth aspect of the present invention to a subject in need, thereby preventing or treating obstructive airway disease.

[0057] In another preferred embodiment, the subject is a human or non-human mammal, such as a rat or a mouse.

[0058] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 The powder X-ray diffraction pattern of salmeterol xinafoate / ciclesonide co-amorphous (molar ratio 1:1.5);

[0060] Figure 2 The powder X-ray diffraction patterns of salmeterol xinafoate / ciclesonide co-amorphous (molar ratios of 2:1, 1:1, 1:2, 1:3 and 1:4, respectively);

[0061] Figure 3 The differential scanning calorimetry spectrum was modulated for salmeterol xinafoate / ciclesonide co-amorphous (molar ratio 1:1.5);

[0062] Figure 4 Modulation differential scanning calorimetry spectra for salmeterol xinafoate / ciclesonide co-amorphous (molar ratios of 2:1, 1:1, 1:2, 1:3, and 1:4, respectively);

[0063] Figure 5 It is the liquid H NMR spectrum of salmeterol xinafoate / ciclesonide co-amorphous;

[0064] Figure 6 This is the solid infrared absorption spectrum of salmeterol xinafoate / ciclesonide co-amorphous compound;

[0065] Figure 7 The powder X-ray diffraction patterns of salmeterol xinafoate / ciclesonide co-amorphous and ciclesonide amorphous after being placed under the conditions of temperature 25±2°C and relative humidity 60±5% for 30 days;

[0066] Figure 8 The X-ray diffraction pattern of salmeterol xinafoate / ciclesonide nano-co-amorphous powder;

[0067] Fig. 9 is the particle size distribution of salmeterol xinafoate / ciclesonide nanoco-amorphous;

[0068] Fig.10 This is a transmission electron micrograph of salmeterol xinafoate / ciclesonide nanoco-amorphous material;

[0069] Fig.11 Modulation differential scanning calorimetry for salmeterol xinafoate / ciclesonide nanoco-amorphous;

[0070] Fig.12 The powder X-ray diffraction spectrum of the salmeterol xinafoate / ciclesonide nano-co-amorphous material after being placed under sealed conditions at a temperature of 4±1°C for 120 days;

[0071] Fig.13 The graph of particle size change of salmeterol xinafoate / ciclesonide nano-co-amorphous material after being placed at a temperature of 4±1°C and sealed for 120 days;

[0072] Fig.14 The in vitro dissolution profiles of salmeterol xinafoate / ciclesonide co-amorphous, salmeterol xinafoate and ciclesonide;

[0073] Fig.15 The in vitro dissolution profiles of salmeterol xinafoate / ciclesonide nanoco-amorphous, salmeterol xinafoate / ciclesonide co-amorphous, salmeterol xinafoate and ciclesonide;

[0074] Fig.16 The powder X-ray diffraction pattern of the in vitro dissolution process of salmeterol xinafoate / ciclesonide nano-co-amorphous body;

[0075] Fig.17 is the apparent permeability coefficient of salmeterol xinafoate / ciclesonide nanoco-amorphous compound, salmeterol xinafoate, and ciclesonide;

[0076] Fig.18 The levels of tumor necrosis factor-α in the lipopolysaccharide-induced in vitro inflammation model treated with different concentrations of salmeterol xinafoate / cicklesonide nanoco-amorphous, salmeterol xinafoate / cicklesonide co-amorphous, salmeterol xinafoate, and ciclesonide. DETAILED DESCRIPTION

[0077] The inventors have conducted extensive and in-depth research, and through a large number of screenings and tests, have provided a salmeterol xinafoate and ciclesonide co-amorphous material and a preparation method and application thereof. More specifically, the present invention prepares salmeterol xinafoate and ciclesonide into a co-amorphous form for the first time, and provides a salmeterol xinafoate and ciclesonide co-amorphous material and a co-amorphous material in the form of nanoparticles. Surprisingly, the amorphous material of the present invention has better solubility, stability and pharmacokinetic and pharmacodynamic properties than salmeterol xinafoate and ciclesonide, can enhance the synergistic effect of salmeterol xinafoate and ciclesonide, and is very suitable as an API for the combined use of salmeterol xinafoate and ciclesonide. The present invention has been completed on this basis.

[0078] the term

[0079] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0080] As used herein, when used in reference to a specific recited numerical value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0081] As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0082] As used herein, the term "room temperature" or "normal temperature" refers to a temperature of 4-40°C, preferably, 25±5°C.

[0083] Active ingredients

[0084] The active ingredients of the present invention include salmeterol xinafoate and ciclesonidena.

[0085] More specific are the co-amorphous forms of salmeterol xinafoate and ciclesonidena of the present invention.

[0086] More preferably, further nano-sizing on the basis of co-amorphization can achieve further improvement in drug solubility, and can be taken up by cells to achieve long-term retention in the lungs, showing good anti-inflammatory activity and asthma treatment effects.

[0087] Salmeterol xinafoate and ciclesonide are both drugs with good lipophilicity, with limited solubility in water, wherein salmeterol xinafoate is slightly soluble in water, and ciclesonide is almost insoluble in water. The present invention is firstly prepared into a co-amorphous substance by salmeterol xinafoate and ciclesonide, on the one hand, its amorphous stability can be improved, on the other hand, the co-amorphous substance can significantly improve the solubility and dissolution rate of these two components in water, is conducive to the onset of the drug, helps to achieve the synchronous release of the two components, thereby achieving better synergistic anti-inflammatory and antiasthmatic effects. Further preparing salmeterol xinafoate and ciclesonide into a nano co-amorphous substance can not only achieve the significant optimization of dissolution performance, but also can realize the increase of drug effect by improving its behavior in vivo.

[0088] Co-amorphous and preparation method thereof

[0089] Co-amorphous refers to a uniform single-phase amorphous system formed by a combination of two or more small molecules. For drug co-amorphous, the other component can be selected as a small molecule excipient or a drug molecule with a synergistic effect. The present invention prepares two drug molecules with synergistic pharmacological effects into co-amorphous, which can improve the solubility and dissolution performance of the drug on the one hand, and on the other hand, the synchronous release of different component drugs in the co-amorphous is conducive to achieving its synergistic effect.

[0090] Specifically, the present invention provides a salmeterol xinafoate / ciclesonide co-amorphous material, characterized in that the co-amorphous material is an amorphous material formed by salmeterol xinafoate and ciclesonide in a molar ratio of 1:(0.4-4.1).

[0091] In another preferred embodiment, the powder X-ray diffraction pattern of the co-amorphous material has no crystal diffraction peaks and exhibits a hump characteristic of amorphous material.

[0092] In another preferred embodiment, the glass transition temperature of the co-amorphous material is 8-75°C.

[0093] In another preferred embodiment, in the co-amorphous material, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(0.5±0.1), 1:(1±0.1), 1:(1.5±0.1), 1:(2±0.1), 1:(3±0.1) or 1:(4±0.1).

[0094] The present invention also provides a method for preparing the salmeterol xinafoate / ciclesonide co-amorphous material as described in the present invention, comprising the steps of providing a mixed solution of salmeterol xinafoate and ciclesonide, and removing the solvent by rotary evaporation to obtain the co-amorphous material.

[0095] In another preferred embodiment, the solvent of the mixed solution is selected from the following group: methanol, ethanol, tetrahydrofuran, chloroform, dichloromethane, or a combination thereof, preferably methanol.

[0096] In another preferred embodiment, the temperature of the rotary evaporation is 20-60°C, preferably 30±5°C.

[0097] Another method for preparing the salmeterol xinafoate / ciclesonide co-amorphous material of the present invention comprises the steps of: adding a solvent to salmeterol xinafoate and ciclesonide in a container and then grinding to obtain the salmeterol xinafoate / ciclesonide co-amorphous material.

[0098] In another preferred embodiment, the solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran, chloroform, dichloromethane, or a combination thereof, preferably methanol. The amount of solvent added is appropriately added according to a conventional grinding crystallization method until the solvent is completely volatilized to obtain the co-amorphous material of the present invention.

[0099] In another preferred embodiment, the grinding temperature is 4-40°C, preferably 20±5°C.

[0100] Nano-co-amorphous

[0101] Furthermore, the present invention provides a salmeterol xinafoate / ciclesonide nano-co-amorphous material, wherein the molar ratio of salmeterol xinafoate to ciclesonide is 1:(0.4-4.1).

[0102] In another preferred embodiment, in the nano-co-amorphous material, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(0.5±0.1), 1:(1±0.1), 1:(1.5±0.1), 1:(2±0.1), 1:(3±0.1) or 1:(4±0.1).

[0103] In another preferred embodiment, the powder X-ray diffraction pattern of the salmeterol xinafoate / ciclesonide nano-co-amorphous material has no crystal diffraction peaks and exhibits a hump characteristic of amorphous material.

[0104] In another preferred embodiment, the nano-co-amorphous material is spherical nanoparticles.

[0105] Nanosizing generally refers to the process of preparing drugs into carrier-free drug particles with a size less than 1 micron.

[0106] The present invention greatly increases the specific surface area of ​​the drug particles and improves the surface energy by preparing the nano-co-amorphous, so that the water solubility and dissolution rate of the drug particles can be significantly improved. On the other hand, the nano-scale particles can improve the concentration of the drug in the lesion site and increase the efficacy by improving the biofilm adhesion performance and physiological barrier penetration ability in the body. For pulmonary inhalation administration, the nano-co-amorphous of the present invention is also conducive to improving its aerodynamic performance, increasing its effective deposition in the lungs, so that more drugs can exert their efficacy in the lungs.

[0107] The nano-sized co-amorphous material of the present invention can be in the form of dry powder after the solvent is removed by freeze drying or spray drying.

[0108] In particular, the present invention provides a method for preparing the salmeterol xinafoate / ciclesonide nano co-amorphous material as described in the present invention, the method is an emulsified solvent freeze-drying method, and the preferred method comprises the steps of mixing an organic solution of salmeterol xinafoate and ciclesonide with water or an aqueous solution of a stabilizer (such as sodium deoxycholate) to obtain a mixed solution, and then freeze-drying to obtain the nano co-amorphous material. The present invention also aims to protect the nano co-amorphous material prepared by the preparation method of the present invention.

[0109] In another preferred embodiment, in the organic solution, the solvent is selected from the following group: methanol, ethanol, isopropanol, or a combination thereof, preferably methanol.

[0110] use

[0111] In the present invention, salmeterol xinafoate is a selective long-acting β2 receptor agonist, and ciclesonide is an inhaled glucocorticoid. The combination of the long-acting β2 receptor agonist and the glucocorticoid can exert a synergistic anti-inflammatory and antiasthmatic effect.

[0112] Those skilled in the art will appreciate that the co-amorphous material of the present invention has the basic activities and action targets of salmeterol xinafoate, ciclesonide, and a combination thereof. Surprisingly, the present invention achieves improved dissolution performance and synergistic release effects of the two components by preparing the salmeterol xinafoate / ciclesonide co-amorphous material.

[0113] Furthermore, the present invention provides the use of the salmeterol xinafoate / ciclesonide co-amorphous material or the salmeterol xinafoate / ciclesonide nano-co-amorphous material in the preparation of a drug for preventing or treating obstructive airway diseases.

[0114] Typically, obstructive airway diseases include (but are not limited to): asthma, nocturnal asthma, exercise-induced asthma, chronic obstructive pulmonary disease (COPD), respiratory tract infections and upper respiratory tract diseases.

[0115] Pharmaceutical compositions and methods of administration

[0116] The present invention provides a pharmaceutical composition, which comprises the salmeterol xinafoate / ciclesonide co-amorphous material or the salmeterol xinafoate / ciclesonide nano-co-amorphous material as described in the present invention, and a pharmaceutically acceptable carrier.

[0117] The pharmaceutical composition of the present invention comprises the active ingredient of the present invention within the safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-500 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0118] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0119] The administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, intratracheal, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0120] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0121] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0122] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0123] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0124] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0125] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0126] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0127] A particularly preferred dosage form is an inhalation dosage form, such as administration by a metered dose inhaler, a dry powder inhaler, a nebulizer, an inhalable powder capsule, etc. The amorphous material of the present invention can be prepared in the form of a powder, a solid dispersion, a solution, a suspension, etc. The carrier for a metered dose inhaler may include a propellant such as hydrofluoroalkane (HFA) 134a and HFA 227; a surfactant such as lecithin, polysorbate 80; a preservative such as benzalkonium chloride; and an antioxidant such as vitamin E. The carrier for a dry powder inhaler (DPIs) may include lactose, microcrystalline cellulose, cyclodextrin or its derivatives; a lubricant such as magnesium stearate; an antistatic agent such as silicone oil; a glidant such as silicon dioxide. The carrier that can be used for a nebulizer (Nebulizers) may include a buffer such as a phosphate buffer; an isotonicity regulator such as sodium chloride; a preservative such as benzyl alcohol, benzalkonium chloride; and an antioxidant such as vitamin E. Carriers for soft mist inhalers (SMIs) may include solvents such as water, ethanol; surfactants such as lecithin, polysorbate 80; preservatives such as benzalkonium chloride; and antioxidants such as vitamin E. Carriers for inhalable powder capsules may include, for example, lactose, microcrystalline cellulose or cyclodextrin or its derivatives; lubricants such as magnesium stearate; antistatic agents such as silicone oil; and glidants such as silicon dioxide.

[0128] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0129] The general range of the therapeutically effective dose of the active ingredient of the present invention will be: about 1-2000mg / day, about 10-about 1000mg / day, about 10-about 500mg / day, about 10-about 250mg / day, about 10-about 100mg / day, or about 10-about 50mg / day. The therapeutically effective dose will be given with one or more doses. However, it should be understood that the specific dose of the compounds of the present invention for any particular patient will depend on multiple factors, for example, the age, sex, body weight, general health, diet, individual response of the patient to be treated, the activity, dosage form, application mode and concomitant drug of the specific compound of the time, the severity of the disease to be treated, the administration. The therapeutically effective amount of a given situation can be determined with routine experiments, and within the scope of the clinician or physician's ability and judgment. In any case, the compound or composition will be given with multiple doses based on the individual situation of the patient and in a manner that allows the delivery of a therapeutically effective amount.

[0130] The main advantages of the present invention include:

[0131] The present invention provides a salmeterol xinafoate / ciclesonide co-amorphous compound (SX-CIC CA) for the first time, and provides a nano-formulation of the salmeterol xinafoate / ciclesonide co-amorphous compound (SX-CIC NCA).

[0132] The salmeterol xinafoate / ciclesonide co-amorphous material of the present invention improves the solubility and stability of the drug, and the dissolution performance of the two components is significantly improved compared with the crystalline raw material, and synchronous release can be achieved, which is conducive to exerting a synergistic drug effect.

[0133] The dissolution performance of salmeterol xinafoate / ciclesonide nano-co-amorphous is further improved compared with that of salmeterol xinafoate / ciclesonide co-amorphous, and it is more easily taken up by cells, showing good anti-inflammatory activity and asthma treatment effect.

[0134] The present invention will be further described below in conjunction with specific implementation. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0135] Example 1. Preparation of Salmeterol Xinafoate / Ciclesonide Co-Amorphous

[0136] Salmeterol xinafoate and ciclesonide were dissolved in methanol at a mass ratio of 7.25:10 (molar ratio 1:1.5), and the solvent was removed by rotary evaporation (20-60° C.) to obtain a salmeterol xinafoate / ciclesonide co-amorphous substance.

[0137] Using the same method as above, except that the molar ratio of salmeterol xinafoate to ciclesonide was 2:1, 1:1, 1:2, 1:3 and 1:4, salmeterol xinafoate / ciclesonide amorphous materials with molar ratios of salmeterol xinafoate to ciclesonide of 2:1, 1:1, 1:2, 1:3 and 1:4 were prepared.

[0138] The salmeterol xinafoate / ciclesonide co-amorphous material in Example 1 was subjected to powder X-ray diffraction analysis, and the operation and analysis steps were as follows:

[0139] Rigaku Ultimate IV PXRD was used with a scanning speed of 20° / min and a scanning range of 5-45°.

[0140] from Figure 1 and 2 It can be seen that the powder X-ray diffraction patterns of the amorphous materials of salmeterol xinafoate / ciclesonide have no crystal diffraction peaks, and all show a hump characteristic of amorphous materials.

[0141] The salmeterol xinafoate / ciclesonide co-amorphous product in Example 1 was subjected to modulated differential scanning calorimetry analysis, and the operation and analysis steps were as follows:

[0142] A TA Q2000 differential scanning calorimeter was used with a N2 atmosphere, a heating rate of 0.5°C / min, and a modulation period of 60 s.

[0143] Figure 3 and Figure 4 is a modulated differential scanning calorimetry spectrum of the salmeterol xinafoate / ciclesonide co-amorphous compound prepared in Example 1, Figure 3 It can be seen that the MDSC curve of the salmeterol xinafoate / ciclesonide co-amorphous material presents a single glass transition temperature, indicating that the prepared co-amorphous material is a uniform single-phase amorphous system.

[0144] The salmeterol xinafoate / ciclesonide co-amorphous substance in Example 1 was subjected to liquid nuclear magnetic resonance analysis, and the operation and analysis steps were as follows:

[0145] About 5 mg of salmeterol xinafoate / ciclesonide co-amorphous was dissolved in 0.5 mL of deuterated DMSO, the spectrum width was set to 8108 Hz, the number of scans was 16, the relaxation time D1 was 1 s, and the measurement was performed at a temperature of 298.15K.

[0146] Figure 5 The liquid nuclear magnetic resonance spectrum of the salmeterol xinafoate / cicklesonide co-amorphous material (molar ratio 1:1.5) prepared in Example 1, the chemical shift of the benign hydrogen of salmeterol xinafoate is 4.65ppm, the chemical shift of the three hydrogens of carbon atom No. 30 of ciclesonide is 0.95ppm, the peak position of the hydrogen of the salmeterol xinafoate / cicklesonide co-amorphous material is consistent with that of the hydrogen of salmeterol xinafoate and ciclesonide, and the number of hydrogens is consistent, indicating that the salmeterol xinafoate and ciclesonide in the co-amorphous material are combined with ciclesonide at a molar ratio of 1:1.5, that is, the mass ratio is 7.25:10. The peak at the chemical shift of salmeterol xinafoate / cicklesonide co-amorphous material at 4.85ppm is shifted to the low field, and the peak at the chemical shift at 6.08ppm is shifted to the high field, indicating that the phenolic hydroxyl group of salmeterol and the carbonyl oxygen or ester oxygen of ciclesonide form an intermolecular hydrogen bond. In addition, the comparison of the H NMR spectrum of the salmeterol xinafoate / ciclesonide co-amorphous material with the raw material drug showed that the prepared co-amorphous material had good purity.

[0147] The salmeterol xinafoate / ciclesonide co-amorphous substance in Example 1 was subjected to infrared spectroscopy analysis, and the operation and analysis steps were as follows:

[0148] The measurements were performed using an Agilent CARY630 FTIR at room temperature in the wavenumber range of 4000-400 cm-1 based on a total of 100 scans with a resolution of 2 cm-1. The powder samples were tested by the direct compression method.

[0149] Figure 6The solid infrared absorption spectrum of the salmeterol xinafoate / ciclesonide co-amorphous material (molar ratio 1:1.5) prepared in Example 1 shows characteristic peaks of ciclesonide and salmeterol xinafoate at 1721 cm-1 and 1500 cm-1, respectively, indicating that the prepared co-amorphous material contains ciclesonide and salmeterol xinafoate. The peak at 3300 cm-1 of the salmeterol xinafoate / ciclesonide co-amorphous material broadens, indicating that the phenolic hydroxyl group of salmeterol xinafoate forms a hydrogen bond; the peak at 1267 cm-1 broadens and the peak at 1132 cm-1 is red-shifted after broadening, indicating that the -COC- structure of ciclesonide participates in the formation of intermolecular hydrogen bonds.

[0150] The salmeterol xinafoate / ciclesonide co-amorphous material in Example 1 was subjected to a stability test, and the operation and analysis steps were as follows:

[0151] The samples were placed at a temperature of 25±2°C and a relative humidity of 60±5%, and samples were taken at predetermined time points for powder X-ray diffraction analysis.

[0152] Figure 7 The powder X-ray diffraction pattern of salmeterol xinafoate / ciclesonide co-amorphous substance (molar ratio 1:1.5) and ciclesonide amorphous substance after being placed at a temperature of 25±2°C and a relative humidity of 60±5% for 30 days is shown in FIG. Figure 7 It can be seen that after being placed at a temperature of 25±2°C and a relative humidity of 60±5% for 30 days, the salmeterol xinafoate / cicklesonide co-amorphous material did not undergo crystal transformation, and its powder X-ray spectrum still had no crystal diffraction peaks, indicating that it had good stability. After being placed at a temperature of 25±2°C and a relative humidity of 60±5% for 30 days, the powder X-ray spectrum of ciclesonide amorphous material showed crystal diffraction peaks at 6.76°, 14.83°, 16.80°, 17.29°, 18.22° (2θ) and other positions, which were consistent with the characteristic peaks of the ciclesonide raw material, indicating that the stability of the single ciclesonide amorphous material was poor, and preparing it into a salmeterol xinafoate / cicklesonide co-amorphous material could significantly improve its stability.

[0153] The solubility test was performed on the salmeterol xinafoate / ciclesonide co-amorphous substance (molar ratio 1:1.5) in Example 1, and the operation and analysis steps were as follows:

[0154] Since the equilibrium solubility of SX and CIC in simulated lung fluid (SILF) is lower than the liquid phase detection limit of 0.1ug / mL, the solubility in SILF of 1% TPGS (vitamin E polyethylene glycol succinate) was measured. The results are shown in the following table. The solubility of ciclesonide and salmeterol xinafoate in the co-amorphous material has been significantly improved. (The simulated lung fluid was prepared according to the following literature: Y.-J. Son, JTMcConville, Development of a standardized dissolution test method for inhaled pharmaceutical formulations, Int. J. Pharm. 382 (2009) 15–22. https: / / doi.org / 10.1016 / j.ijpharm.2009.07.034.)

[0155]

[0156] Example 2 Preparation of Salmeterol Xinafoate / Ciclesonide Co-Amorphous

[0157] Salmeterol xinafoate and ciclesonide were placed in a mortar at a mass ratio of 7.25:10 (molar ratio 1:1.5), and a small amount of methanol was added and ground until the solvent was completely evaporated to obtain a salmeterol xinafoate / ciclesonide co-amorphous substance.

[0158] Example 3 Preparation of Salmeterol Xinafoate / Ciclesonide Nano-Co-Amorphous Material

[0159] 29 mg of salmeterol xinafoate and 40 mg of ciclesonide were weighed and dissolved in 1 mL of methanol, mixed with 40 mL of 0.3% sodium deoxycholate aqueous solution and freeze-dried for 24 hours to obtain salmeterol xinafoate / ciclesonide nano-co-amorphous material.

[0160] The salmeterol xinafoate / ciclesonide nano-co-amorphous material in Example 3 was subjected to powder X-ray diffraction analysis, and the operation and analysis steps were as follows:

[0161] Rigaku Ultimate IV PXRD was used with a scanning speed of 20° / min and a scanning range of 5-45°.

[0162] from Fig. 9 It can be seen that the powder X-ray diffraction pattern of the salmeterol xinafoate / ciclesonide nano-co-amorphous material has no crystal diffraction peaks and exhibits a hump characteristic of amorphous materials.

[0163] The salmeterol xinafoate / ciclesonide nano-co-amorphous material in Example 3 was analyzed for particle size, polydispersity coefficient and Zeta potential. The operation and analysis steps were as follows:

[0164] The particle size, polydispersity coefficient and Zeta potential distribution of the samples were measured at room temperature using a Malvern Zetasizer Nano ZS nanoparticle size analyzer.

[0165] Figure 8 is the particle size distribution diagram of the salmeterol xinafoate / ciclesonide nano-co-amorphous material prepared in Example 3, Figure 7 It can be seen that the particle size of the salmeterol xinafoate / ciclesonide nano-co-amorphous material is 172.5±21.03nm, the polydispersity coefficient is 0.119±0.013, and the Zeta potential is -51.5±1.55mV, indicating that the prepared nano-co-amorphous material has a small particle size, uniform size, and good dispersion stability.

[0166] The salmeterol xinafoate / ciclesonide nano-co-amorphous material in Example 3 was analyzed for its morphological appearance. The operation and analysis steps were as follows:

[0167] The freeze-dried salmeterol xinafoate / ciclesonide nanoco-amorphous material was redispersed in pure water, and 10 μl of the material was dropped onto a copper grid with a carbon support film, and after natural drying, it was observed using a transmission electron microscope.

[0168] Fig.10 is a transmission electron micrograph of the salmeterol xinafoate / ciclesonide nanoco-amorphous material prepared in Example 3. Fig.10 It can be seen that the salmeterol xinafoate / ciclesonide nano-co-amorphous material is a spherical particle.

[0169] The salmeterol xinafoate / ciclesonide co-amorphous product in Example 3 was subjected to modulated differential scanning calorimetry analysis, and the operation and analysis steps were as follows:

[0170] A TA Q2000 differential scanning calorimeter was used with a N2 atmosphere, a heating rate of 0.5°C / min, and a modulation period of 60 s.

[0171] Fig.11 is the modulated differential scanning calorimetry spectrum of the salmeterol xinafoate / ciclesonide nano-co-amorphous material prepared in Example 3, Fig.11 It can be seen that the MDSC curve of the salmeterol xinafoate / ciclesonide co-amorphous nanostructures presents a single glass transition temperature (28.28° C.), indicating that the prepared nano-co-amorphous nanostructures are a uniform single-phase amorphous system.

[0172] The salmeterol xinafoate / ciclesonide co-amorphous material in Example 3 was subjected to a stability test, and the operation and analysis steps were as follows:

[0173] The samples were sealed and placed at 4°C, and samples were taken at predetermined time points for powder X-ray diffraction analysis and particle size distribution measurement.

[0174] Fig.12 The powder X-ray diffraction pattern of salmeterol xinafoate / ciclesonide nano-co-amorphous material after being placed at 4°C for 120 days is shown in FIG. Fig.12 It can be seen that after being placed at a temperature of 4° C. for 120 days, the salmeterol xinafoate / ciclesonide nano-co-amorphous material did not undergo crystal transformation, and its powder X-ray spectrum still had no crystal diffraction peaks, indicating that it had good solid form stability.

[0175] Fig.13 The particle size change of salmeterol xinafoate / ciclesonide nano-co-amorphous material during storage at 4°C for 120 days is shown in Table 1. Fig.13 It can be seen that the particle size of the salmeterol xinafoate / ciclesonide nano-co-amorphous material did not increase significantly when placed at a temperature of 4°C for 120 days, indicating that the prepared nano-co-amorphous material has good particle size stability.

[0176] Example 4

[0177] The in vitro dissolution performance evaluation was performed on the salmeterol xinafoate / ciclesonide co-amorphous material (molar ratio 1:1.5) in Example 1 and the salmeterol xinafoate / ciclesonide nano-co-amorphous material in Example 3. The operation and analysis steps were as follows:

[0178] 10.875 mg of salmeterol xinafoate bulk drug, 15.000 mg of ciclesonide bulk drug, 25.875 mg of salmeterol xinafoate / ciclesonide co-amorphous and 70.875 mg of salmeterol xinafoate / ciclesonide nano-co-amorphous were accurately measured respectively to investigate their release behavior in 1% TPGS SILF (artificial simulated synthetic interstitial lung fluid). The experimental temperature was 37.0 ± 0.1 ° C, and the magnetic stirring speed was 200 rpm. The incompletely dissolved solids were separated by a 50 nm polycarbonate membrane through a vertical Franz diffusion cell. Samples were taken at predetermined time points, and the drug content was determined by HPLC (high performance liquid chromatography) after filtration with a 0.22 micron filter membrane.

[0179] Fig.14The in vitro dissolution curve of ciclesonide in the salmeterol xinafoate / ciclesonide co-amorphous prepared in Example 1 shows that the dissolution rate of ciclesonide in the salmeterol xinafoate / ciclesonide co-amorphous is significantly improved compared with the ciclesonide raw material, and the release amount in 10 min is nearly 5 times that of the ciclesonide raw material, and the equilibrium solubility of ciclesonide in the salmeterol xinafoate / ciclesonide co-amorphous reaches 237.25 μg / mL, while the equilibrium solubility of the ciclesonide raw material is only about 97.91 μg / mL. In addition, in the first 60 min of the dissolution process, the two components in the salmeterol xinafoate / ciclesonide co-amorphous are released substantially synchronously until the ciclesonide therein reaches equilibrium. In summary, the salmeterol xinafoate / ciclesonide co-amorphous material of the present invention improves the stability of the amorphous ciclesonide, significantly improves the solubility and dissolution properties of ciclesonide, and also achieves the synchronous release of salmeterol xinafoate and ciclesonide, which is beneficial to achieve the synergistic efficacy of the drugs.

[0180] Fig.15 The release curve of salmeterol xinafoate and ciclesonide in the salmeterol xinafoate / ciclesonide nano-co-amorphous prepared in Example 3 shows that the cumulative release percentage of salmeterol xinafoate and ciclesonide in the salmeterol xinafoate / ciclesonide nano-co-amorphous is increased by nearly 3 times compared with the salmeterol xinafoate / ciclesonide co-amorphous, and more than 50% is released in 5 minutes, achieving rapid release. The release behavior of the two components is consistent, which is conducive to achieving synergistic synergy.

[0181] Fig.16 The powder X-ray diffraction pattern of the remaining solids during the in vitro dissolution of the salmeterol xinafoate / ciclesonide nano-co-amorphous material prepared in Example 3 shows that the remaining solids are always amorphous during the release process, and have good solid form stability.

[0182] Example 5

[0183] The in vitro mucus penetration ability of the salmeterol xinafoate / ciclesonide co-amorphous material (molar ratio 1:1.5) in Example 1 and the salmeterol xinafoate / ciclesonide nano-co-amorphous material in Example 3 was evaluated, and the operation and analysis steps were as follows:

[0184] 2.9 mg of salmeterol xinafoate bulk drug, 4.0 mg of ciclesonide bulk drug, 6.9 mg of salmeterol xinafoate / ciclesonide co-amorphous and 18.9 mg of salmeterol xinafoate / ciclesonide nano-co-amorphous were accurately measured to investigate their ability to penetrate the 10 mg / mL mucin-PBS solution layer. The experimental temperature was 37.0±0.1℃ and the magnetic stirring speed was 200 rpm. A vertical Franz diffusion cell was used to fix 50 μL of 10 mg / mL mucin-PBS solution with a pair of 3 μm polycarbonate membranes. Samples were taken at predetermined time points and diluted with methanol. The drug concentration was determined by HPLC after filtration with a 0.22 μm filter membrane.

[0185] Fig.17 The apparent permeability coefficient (Papp) of the salmeterol xinafoate / ciclesonide nano-co-amorphous material prepared in Example 3 is significantly increased compared with the salmeterol xinafoate raw material and the ciclesonide raw material, indicating that the preparation of the nano-co-amorphous material significantly improves the mucus penetration ability of salmeterol xinafoate and ciclesonide.

[0186] Example 6

[0187] The in vitro anti-inflammatory activity evaluation was performed on the salmeterol xinafoate / ciclesonide co-amorphous material (molar ratio 1:1.5) in Example 1 and the salmeterol xinafoate / ciclesonide nano-co-amorphous material in Example 3. The operation and analysis steps were as follows:

[0188] RAW264.7 cells were seeded in a 96-well plate at a density of 1×104 cells / well, and cultured for 24 hours to allow the cells to adhere. The culture medium was then replaced, and the co-amorphous material of Example 1, the nano-co-amorphous material of Example 3, salmeterol xinafoate, and ciclesonide were added to each well at different concentrations. After incubation for 2 hours, the culture medium was discarded, and 0.1 mL of serum-free culture medium containing 1 mg / mL lipopolysaccharide (LPS) was added to each well. After incubation for 24 hours, the tumor necrosis factor-α level in the cell culture supernatant was determined using a commercial kit.

[0189] Fig.18The tumor necrosis factor-α levels in the supernatant of RAW264.7 cells treated with different dosing groups after lipopolysaccharide-induced polarization. Compared with the control group, the tumor necrosis factor-α level in the lipopolysaccharide-treated model group was significantly increased, indicating that lipopolysaccharide induced the formation of proinflammatory M1 macrophages, leading to an increase in the secretion of the proinflammatory factor tumor necrosis factor-α. Compared with the salmeterol xinafoate and ciclesonide alone administration groups, the tumor necrosis factor-α level in the salmeterol xinafoate / ciclesonide co-amorphous administration group was significantly reduced, indicating that salmeterol xinafoate / ciclesonide co-amorphous has a better anti-inflammatory effect. The tumor necrosis factor-α level in the salmeterol xinafoate / ciclesonide nano-co-amorphous administration group was further reduced compared with the salmeterol xinafoate / ciclesonide co-amorphous administration group, indicating that the anti-inflammatory activity of the salmeterol xinafoate / ciclesonide nano-co-amorphous was further enhanced.

[0190] The present invention has found that when ciclesonide is dissolved in dichloromethane and the solvent is removed by rotary evaporation, an amorphous ciclesonide is obtained, but when placed at a temperature of 25±2°C and a relative humidity of 60±5% for 30 days, the amorphous ciclesonide is transformed into a crystal; neither the rotary evaporation method nor the ball milling method of salmeterol xinafoate can produce an amorphous substance. This indicates that the amorphous ciclesonide alone is unstable, and salmeterol xinafoate is extremely difficult to form an amorphous substance.

[0191] There are many literatures and patent reports on the combination of long-acting β2 receptor agonists and glucocorticoids for the treatment of bronchial asthma. The present invention is the first to prepare a co-amorphous substance, improve the stability of the amorphous substance, and simultaneously improve the water solubility of salmeterol xinafoate and ciclesonide, so as to achieve synchronous release, so that the two components can exert synergistic efficacy, which is the main purpose of making the two drugs into a co-amorphous substance in the present invention. Based on the physicochemical properties of salmeterol xinafoate and ciclesonide, the present invention has carried out a large number of experimental studies and found a binary co-amorphous substance containing two components of salmeterol xinafoate and ciclesonide, which can not only improve the stability of amorphous ciclesonide, increase the solubility of each of the two components in water, and improve its dissolution performance, but also achieve synchronous release of the two components, which is conducive to the synergistic pharmacological effect of the two components.

[0192] Nano-sizing is also a commonly used method for improving solubility, and is also beneficial for drug particles to escape from the physiological barrier of the lungs, thereby improving drug efficacy. Therefore, the present invention prepares a salmeterol xinafoate / ciclesonide co-amorphous material based on the salmeterol xinafoate / ciclesonide co-amorphous material, further optimizing its in vitro dissolution performance, mucus penetration ability, etc., thereby improving the therapeutic effect.

[0193] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A salmeterol xinafoate / ciclesonide co-amorphous material, characterized in that: The co-amorphous material is an amorphous material formed by salmeterol xinafoate and ciclesonide at a molar ratio of 1:(0.4-4.1).

2. The co-amorphous material according to claim 1, characterized in that The powder X-ray diffraction pattern of the co-amorphous material has no crystal diffraction peaks and exhibits a hump characteristic of amorphous materials.

3. The co-amorphous material according to claim 1, characterized in that In the co-amorphous material, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(1.5±0.1), and the glass transition temperature of the co-amorphous material is 52.67±3°C (preferably ±2°C or ±1°C).

4. A method for preparing the salmeterol xinafoate / ciclesonide co-amorphous material as claimed in claim 1, comprising the steps of: providing a mixed solution of salmeterol xinafoate and ciclesonide, and removing the solvent by rotary evaporation to obtain the co-amorphous material.

5. A method for preparing the salmeterol xinafoate / ciclesonide co-amorphous material as claimed in claim 1, comprising the steps of: adding a solvent to salmeterol xinafoate and ciclesonide in a container and then grinding to obtain the salmeterol xinafoate / ciclesonide co-amorphous material.

6. A salmeterol xinafoate / ciclesonide nano-co-amorphous material, characterized in that: In the nano-co-amorphous material, the molar ratio of salmeterol xinafoate to ciclesonide is 1:(0.4-4.1).

7. The co-amorphous material according to claim 1, characterized in that The powder X-ray diffraction spectrum of the salmeterol xinafoate / ciclesonide nano-co-amorphous material has no crystal diffraction peaks and presents a hump with amorphous characteristics.

8. A method for preparing the salmeterol xinafoate / ciclesonide nano-co-amorphous material as claimed in claim 7, wherein the method is an emulsified solvent freeze-drying method, and preferably the method comprises the steps of mixing an organic solution of salmeterol xinafoate and ciclesonide with water or an aqueous solution of a stabilizer (such as sodium deoxycholate) to obtain a mixed solution, and then freeze-drying to obtain the nano-co-amorphous material.

9. A pharmaceutical composition comprising the salmeterol xinafoate / ciclesonide co-amorphous material according to claim 1 or the salmeterol xinafoate / ciclesonide nano-co-amorphous material according to claim 6, and a pharmaceutically acceptable carrier.

10. Use of the salmeterol xinafoate / ciclesonide co-amorphous material according to claim 1 or the salmeterol xinafoate / ciclesonide nano-co-amorphous material according to claim 6 in the preparation of a medicament for preventing or treating obstructive airway diseases.

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