阅读说明：本技术 环糊精-金属有机骨架在制备吸入剂中的应用、吸入剂 (Application of cyclodextrin-metal organic framework in preparation of inhalant and inhalant ) 是由 陈航平 李峰 王亚龙 赵志明 周奕先 聂金媛 冯地桑 于 2021-01-27 设计创作，主要内容包括：本发明涉及一种环糊精-金属有机骨架在制备吸入剂中的应用、吸入剂。本发明首次发现将环糊精-金属有机骨架(CD-MOFs)作为载体应用于制备吸入剂,所得吸入剂具有高的肺部有效沉积率和良好的空气动力学行为,粒径结构可控、孔道均一有序、孔隙率高,从而可以实现很好的药物肺部递送效率。(The invention relates to application of cyclodextrin-metal organic framework in preparation of an inhalant and the inhalant. The invention discovers for the first time that cyclodextrin-metal organic frameworks (CD-MOFs) are used as carriers for preparing the inhalant, and the obtained inhalant has high effective lung deposition rate, good aerodynamic behavior, controllable particle size structure, uniform and ordered pore channels and high porosity, so that good lung delivery efficiency of the medicine can be realized.)

1. Use of a cyclodextrin-metal organic framework for the preparation of an inhalant.

2. The use according to claim 1, wherein the inhalant is a dry powder inhalation, further wherein the dry powder inhalation is a dry powder inhalant.

3. Use according to claim 1, wherein the metal ions in the cyclodextrin-metal organic framework material are selected from Li⁺、Na⁺、K⁺、Rb⁺、Cs⁺、Mg²⁺、Ba²⁺、Sr²⁺And Ca²⁺At least one of; and/or the cyclodextrin in the cyclodextrin-metal organic framework material is selected from at least one of alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin.

4. The use according to any one of claims 1 to 3, wherein the inhalant comprises the cyclodextrin-metal organic framework material, and a drug loaded on the cyclodextrin-organic framework material;

further, the drug is selected from at least one of budesonide, salbutamol sulfate, ipratropium bromide, beclomethasone, fluticasone, flunisolide, ciclesonide, formoterol, salmeterol, mometasone, ketoprofen, indomethacin, naproxen, busulfan, lansoprazole, ibuprofen, celecoxib, fenbufen, diazepam, metronidazole, nifedipine, prednisolone, diclofenac sodium, acetaminophen, tolbutamide, meloxicam, clenbuterol, fluconazole, captopril, salicylic acid, curcumin, pseudolaric acid, indapamide, prooxicam, caffeine, adriamycin, cisplatin, prodrugs, topotecan, 5-fluorouracil, azidothymidine mono/triphosphate, cidofovir, nimesulide and procainamide hydrochloride.

5. An inhalant, characterized in that it comprises a cyclodextrin-metal organic framework and a drug carried thereby; the cyclodextrin-metal organic framework is prepared from raw materials including cyclodextrin, alkali metal hydroxide and a surfactant;

the molar ratio of the cyclodextrin to the alkali metal hydroxide is 1: (2-20); the molar ratio of the cyclodextrin to the medicament is (1-4): (1-4).

6. The inhalant according to claim 5,

the drug is selected from at least one of budesonide, salbutamol sulfate, ipratropium bromide, beclomethasone, fluticasone, flunisolide, ciclesonide, formoterol, salmeterol, mometasone, ketoprofen, indomethacin, naproxen, busulfan, lansoprazole, ibuprofen, celecoxib, fenbufen, diazepam, metronidazole, nifedipine, prednisolone, diclofenac sodium, acetaminophen, tolbutamide, meloxicam, clenbuterol, fluconazole, captopril, salicylic acid, curcumin, pseudolaric acid, indapamide, prooxicam, caffeine, doxorubicin, cisplatin, topotecan, 5-fluorouracil, azidothymidine monophosphate/triphosphate, cidofovir, nimesulide and procainamide hydrochloride;

and/or, the metal ions in the alkali metal hydroxide are selected from Li⁺、Na⁺、K⁺、Rb⁺、Cs⁺、Mg²⁺、Ba²⁺、Sr²⁺And Ca²⁺At least one of;

and/or the cyclodextrin is selected from at least one of alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin.

7. The inhalant as claimed in claim 6, wherein the cyclodextrin is γ -cyclodextrin, the metal ion is potassium ion, and the drug is ketoprofen or curcumin.

8. An inhalant as claimed in any one of claims 5 to 7, wherein the surfactant is selected from at least one of cetyltrimethylammonium bromide, polyethylene glycol 200-; preferably, the surfactant is cetyltrimethylammonium bromide.

9. A process for the preparation of an inhalant as claimed in any one of claims 5 to 8, comprising the steps of:

(1) dissolving cyclodextrin and alkali metal hydroxide with water to obtain a mixed solution;

(2) dissolving the medicine in an organic solvent, mixing with the mixed solution obtained in the step (1), adding a surfactant and the organic solvent, and standing;

(3) and (3) carrying out solid-liquid separation on the mixture obtained in the step (2), and drying the solid.

10. The method according to claim 9, wherein the organic solvent in step (2) is an alcohol solvent, further methanol;

and/or the mixing temperature in the step (2) is 20-100 ℃, preferably 40-60 ℃, and further 50 +/-5 ℃.

Technical Field

The invention relates to the field of medicines, in particular to application of a cyclodextrin-metal organic framework in preparation of an inhalant and the inhalant.

Background

Metal-organic frameworks (MOFs) are a new porous material with a lattice structure formed by connecting Metal ions or Metal ion clusters and organic ligands through coordination bonds. Compared with the traditional porous material, the metal organic framework has the characteristics of large specific surface area, high porosity, various structures, strong adjustability, easy functionalization and the like, and is widely applied to the fields of catalysis, gas storage, separation, sensing, drug delivery and the like. The cyclodextrin-metal organic frameworks (CD-MOFs) composed of potassium ions and gamma-cyclodextrin have good biocompatibility, can increase the solubility and dissolution rate of insoluble drugs, and are considered to have great application value in the field of biological medicines. However, the existing research shows that the administration route of the metal organic framework is intravenous injection or oral administration, and the administration route is single, so that the development of the metal organic framework in the field of drug delivery is limited.

In recent years, the lung administration attracts the attention of researchers, compared with intravenous injection and oral administration, the lung administration has unique advantages, ultra-thin alveolar epithelial cells (about 0.2 mu m) of the lung, huge alveolar absorption area (about 100m2) and rich pulmonary capillary vascular network are beneficial to the diffusion of the medicine into the blood, and the medicine effect is exerted. For pulmonary delivery systems, the effective deposition rate in the lung directly affects the efficacy. Studies have shown that the aerodynamic properties of an inhaled vehicle are closely related to the effective deposition rate in the lungs, and that poor aerodynamic properties greatly affect the efficiency of drug delivery to the lungs. The aerodynamic behaviour and the effective lung deposition rate can generally be improved by modifying the size and morphological structure of the inhaled vehicle. Wherein the carrier is subjected to porous modification, so that the density of the carrier can be obviously reduced, and the method is a strategy for effectively improving aerodynamic behavior. However, in the existing research, a recrystallization method, a salt filtration method, an osmotic pressure method, a thermosensitive agent pore-forming method and other methods are mainly adopted to prepare the porous carrier, the porous structure is uncontrollable, the uniformity of the porosity is poor, and the accurate delivery of the lung drug is limited. The development lag of the pulmonary drug delivery carrier seriously limits the development of a pulmonary drug delivery system, and the development of a novel pulmonary drug delivery carrier with high effective deposition rate of the lung and good aerodynamic performance is urgently needed.

Disclosure of Invention

Based on the situation, the invention aims to provide the application of the cyclodextrin-metal organic framework in the preparation of the inhalant, and the prepared inhalant has high lung effective deposition rate and good aerodynamic performance.

The specific technical scheme is as follows:

use of a cyclodextrin-metal organic framework for the preparation of an inhalant.

In some embodiments, the inhalation is a dry powder inhalation, further wherein the dry powder inhalation is a dry powder inhalation.

In some of these embodiments, the metal ion in the cyclodextrin-metal organic framework material is selected from Li⁺、Na⁺、K⁺、Rb⁺、Cs⁺、Mg²⁺、Ba²⁺、Sr²⁺And Ca²⁺At least one of (1).

In some of these embodiments, the cyclodextrin in the cyclodextrin-metal organic framework material is selected from at least one of alpha-cyclodextrin, beta-cyclodextrin, and gamma-cyclodextrin.

In some embodiments, the inhalant comprises the cyclodextrin-metal organic framework material, and a drug loaded on the cyclodextrin-organic framework material, further the drug is selected from budesonide, salbutamol sulfate, ipratropium bromide, beclomethasone, fluticasone, flunisolide, ciclesonide, formoterol, salmeterol, mometasone, ketoprofen, indomethacin, naproxen, busulfan, lansoprazole, ibuprofen, celecoxib, fenbufen, diazepam, metronidazole, nifedipine, prednisolone, diclofenac sodium, acetaminophen, tolbutamide, meloxicam, clenbuterol, fluconazole, captopril, salicylic acid, curcumin, pseudolaric acid, indapamide, prixicam, caffeine, adriamycin, cisplatin prodrug, topotecan, 5-fluorouracil, fluxolone, and other drugs, At least one of mono/tri-phosphate-azidothymidine, cidofovir, nimesulide and procainamide hydrochloride.

It is another object of the present invention to provide an inhalant comprising a cyclodextrin-metal organic framework and a drug carried thereby; the cyclodextrin-metal organic framework is prepared from raw materials including cyclodextrin, alkali metal hydroxide and a surfactant;

the molar ratio of the cyclodextrin to the alkali metal hydroxide is 1: (2-20); the molar ratio of the cyclodextrin to the medicament is (1-4): (1-4).

In some of these embodiments, the cyclodextrin and alkali metal hydroxide are present in a molar ratio of 1: (5-15), which can form CD-MOFs fine particles better.

In some of these embodiments, the inhalant is administered by placement in an inhaler.

In some embodiments, the drug is selected from at least one of budesonide, salbutamol sulfate, ipratropium bromide, beclomethasone, fluticasone, flunisolide, ciclesonide, formoterol, salmeterol, mometasone, ketoprofen, indomethacin, naproxen, busulfan, lansoprazole, ibuprofen, celecoxib, fenbufen, diazepam, metronidazole, nifedipine, prednisolone, diclofenac sodium, acetaminophen, tolbutamide, meloxicam, clenbuterol, fluconazole, captopril, salicylic acid, curcumin, pseudolaric acid, indapamide, proxicam, caffeine, doxorubicin, a prodrug, topotecan, 5-fluorouracil, azidothymidine mono/triphosphate, cidofovir, nimesulide and procainamide hydrochloride.

In some of these embodiments, the metal ion in the alkali metal hydroxide is selected from Li⁺、Na⁺、K⁺、Rb⁺、Cs⁺、Mg²⁺、Ba²⁺、Sr²⁺And Ca²⁺At least one of (1).

In some of these embodiments, the cyclodextrin is selected from at least one of alpha-cyclodextrin, beta-cyclodextrin, and gamma-cyclodextrin.

In some of these embodiments, the cyclodextrin is γ -cyclodextrin, the metal ion is a potassium ion, and the drug is ketoprofen or curcumin. By selecting the combination of the gamma-cyclodextrin and the potassium ion, an inhalant with good aerodynamic behavior can be prepared.

In some of these embodiments, the surfactant is selected from at least one of cetyltrimethylammonium bromide, polyethylene glycol 200-.

Another object of the present invention is to provide a method for preparing the above inhalant, comprising the steps of:

(1) dissolving cyclodextrin and alkali metal hydroxide with water to obtain a mixed solution;

(2) mixing the organic solution of the medicine with the mixed solution obtained in the step (1), adding a surfactant and an organic solvent, and standing;

(3) and (3) carrying out solid-liquid separation on the mixture obtained in the step (2), and drying the solid.

In some embodiments, the organic solvent in step (2) is at least one of an alcohol solvent, acetonitrile, and dichloromethane, and further the alcohol solvent is methanol, ethanol, propanol, isopropanol, or n-butanol, preferably methanol.

In some of the embodiments, the temperature of the mixing in the step (2) is 20 to 100 ℃, preferably 40 to 60 ℃.

In some embodiments, the concentration of cyclodextrin in the mixed solution is 30-35 mg-mL^-1The concentration of the alkali metal hydroxide is 8 to 15 mg/mL^-1。

In some of the embodiments, the molar concentration of potassium hydroxide in the mixed solution of step (1) is 0.2 mmol/mL.

In some of these embodiments, the organic solvent is an alcoholic solvent, further methanol. The concentration of the medicine dissolved in the organic solvent is 18.11-393.70 mu mol/mL.

The volume ratio of the organic solvent added in the step (2) to the water in the step (1) is (0.1-10): 1, preferably (5-6): 10.

in some of the embodiments, the drying in step (3) further comprises a step of washing with a washing solvent, wherein the washing solvent is at least one of methanol, ethanol, propanol, isopropanol, n-butanol, acetonitrile and dichloromethane, and preferably isopropanol.

In some embodiments, the solid-liquid separation method in step (3) is centrifugation, the rotation speed of the centrifugation is 1000-10000rpm, and the time of the centrifugation is 1-60min, further, the rotation speed of the centrifugation is 2000-60000rpm, and the time of the centrifugation is 1-10 min.

In some of these embodiments, the method of drying of step (3) comprises at least one of vacuum drying, spray drying, and freeze drying.

Compared with the prior art, the invention has the following beneficial effects:

the inventor of the invention discovers for the first time that cyclodextrin-metal organic frameworks (CD-MOFs) are used as carriers for preparing inhalants, and the cyclodextrin-metal organic frameworks have the advantages of high lung effective deposition rate, good aerodynamic behavior, controllable particle size structure, uniform and ordered pore channels and high porosity, so that good lung delivery efficiency of medicaments can be realized.

In addition, the inhalant prepared from the cyclodextrin-metal organic framework also has good biocompatibility, and the preparation method is simple, mild in condition, stable in process and good in repeatability, and is expected to realize industrial production.

Drawings

FIG. 1 is a powder X-ray diffraction (PXRD) pattern of a ketoprofen-loaded cyclodextrin-metal organic matrix dry powder inhaler prepared in example 1;

FIG. 2 is a PXRD pattern of the curculin-loaded cyclodextrin-metal organic matrix dry powder inhaler prepared in example 2;

FIG. 3 is a scanning electron micrograph of a ketoprofen-loaded cyclodextrin-metal organic matrix dry powder inhaler prepared in example 1;

figure 4 is a scanning electron micrograph of the curculin-loaded cyclodextrin-metal organic matrix dry powder inhaler prepared in example 2;

FIG. 5 is a graph showing the in vitro deposition profile (NGI,60L/min,4s) of the ketoprofen-loaded cyclodextrin-metal organic matrix dry powder inhaler prepared in example 1;

figure 6 is an in vitro deposition profile (NGI,60L/min,4s) of the curculin-loaded cyclodextrin-metal organic matrix dry powder inhaler prepared in example 2;

figure 7 is a graph of the saturation solubility of the curculin-loaded cyclodextrin-metal organic matrix dry powder inhaler prepared in example 2;

figure 8 is a graph of the in vitro release of the curculin-loaded cyclodextrin-metal organic matrix dry powder inhaler prepared in example 2 and the micronized curcumin dry powder inhaler prepared in comparative example 1.

Detailed Description

Experimental procedures according to the invention, in which no particular conditions are specified in the following examples, are generally carried out under conventional conditions, or under conditions recommended by the manufacturer. The various chemicals used in the examples are commercially available.

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. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

The terms "comprising" and "having," and any variations thereof, are intended to cover non-exclusive inclusions. For example, a process, method, apparatus, article, or device that comprises a list of steps is not limited to only those steps or modules listed, but may alternatively include other steps not listed or inherent to such process, method, article, or device.

The "plurality" referred to in the present invention means two or more. "and/or" describes the association relationship of the associated objects, meaning that there may be three relationships, e.g., a and/or B, which may mean: a exists alone, A and B exist simultaneously, and B exists alone. The character "/" generally indicates that the former and latter associated objects are in an "or" relationship.

The present invention will be described in further detail with reference to specific examples.

EXAMPLE 1 preparation of ketoprofen-loaded Cyclodextrin-Metal organic framework (KET-CD-MOF) Dry powder inhalants

The content of gamma-cyclodextrin and potassium hydroxide is 32.4 mg/mL respectively^-1And 11.2 mg. mL^-1Dissolved in 50mL of deionized water, and the two solutions were completely dissolved and then filtered through a 0.8 μm filter. Then, 30mL of ketoprofen methanol solution (20 mg. mL) was added to the filtrate^-1) And moving the mixture into a water bath with the temperature of 50 ℃ to heat for 0.5 h. Then 30mL of methanol and cetyltrimethylammonium bromide (concentration 2 mg. multidot.mL after addition) were added^-1) After the hexadecyl trimethyl ammonium bromide is completely dissolved, standing for 2 hours at room temperature. Finally, the cyclodextrin-metal organic framework (KET-CD-MOF) loaded with ketoprofen is collected by centrifugation (rotation speed is 4000rpm, centrifugation time is 5min), washed with isopropanol, and the obtained solid is dried in vacuum overnight.

The PXRD pattern of the prepared ketoprofen-loaded cyclodextrin-metal organic framework (KET-CD-MOF) dry powder inhalant is shown in figure 1 (measured by a powder X-ray diffractometer, the voltage is 30kV, the current is 10mA, and the Cu K alpha copper target). Referring to fig. 3, it can be seen that the particle morphology is similar to a cube, and has better dispersibility.

Example 2 preparation of Cyclodextrin-Metal organic framework Dry powder inhaler entrapping curcumin

The content of gamma-cyclodextrin and potassium hydroxide is 32.4 mg/mL respectively^-1And 11.2 mg. mL^-1Dissolved in 50mL of deionized water, and the two solutions were completely dissolved and then filtered through a 0.8 μm filter. Then, 35mL of a solution having a mass concentration of 6.67 mg/mL was added to the filtrate^-1The methanol solution of curcumin is transferred into a water bath with the temperature of 50 ℃ to be heated for 0.5 h. However, the device is not suitable for use in a kitchenThen 75mL of methanol and cetyltrimethylammonium bromide (2 mg. mL after addition)^-1) After the hexadecyl trimethyl ammonium bromide is completely dissolved, standing for 2 hours at room temperature. And finally, centrifuging (the rotating speed is 4000rpm, the centrifuging time is 5min), collecting the cyclodextrin-metal organic framework (Cur-CD-MOF) carrying the curcumin, washing with isopropanol, and vacuum-drying the solid overnight.

The PXRD pattern of the prepared curcumin-loaded cyclodextrin-metal organic framework (Cur-CD-MOF) dry powder inhaler is shown in fig. 2 (measured by a powder X-ray diffractometer, the voltage is 30kV, the current is 10mA, and the Cu K α copper target), and the scanning electron microscope pattern is shown in fig. 4, and it can be seen in fig. 4 that the particle morphology is in a cube-like shape and has relatively good dispersibility.

Comparative example 1

Preparation of micronized curcumin dry powder inhalant

Pulverizing curcumin of raw material medicine by air flow, micronizing, mixing with commercial dry powder inhalant carrier230 (lactose) are mixed homogeneously. The in vitro release profile of the micronized curcumin dry powder inhaler (Cur) prepared is shown in fig. 8.

In-vitro aerodynamic behavior investigation of ketoprofen-encapsulated cyclodextrin-metal organic framework dry powder inhaler

The respirable Fine Particle Fraction (FPF) is an important index for representing the in-vitro aerodynamic behavior of the dry powder inhalant, and the FPF value is positively correlated with the lung deposition rate. The in vitro aerodynamic behaviour of the ketoprofen-encapsulated cyclodextrin-metal organic matrix dry powder inhalant prepared in example 1 was examined using a new generation particle impactor (model: NGI, Copley Scientific, uk).

After the vacuum pump, the flow controller and the particle impactor are connected, the impact cup is placed in the cup holder, the upper cover of the impactor is fastened, and the positioning pin is screwed. 15mL of deionized water or absolute ethyl alcohol is added into a collecting cup of the preseparator, and the impactor, the preseparator and the right-angle simulated throat are sequentially connected to form a closed system. Starting the vacuum pump to measure the flow rate of the air flowThe flow rate of the gas stream was adjusted to a flow rate of about 60L/min. After determining that the ratio of P2 to P3 was less than 0.5, the assay was started. The adapter of the dry powder inhaler was attached to a right angle simulated throat with both on the same horizontal axis. And (3) putting a capsule filled with a sample to be tested into an inhaler, puncturing the capsule, connecting the dry powder inhaler with the adapter, starting the vacuum pump, and taking out the inhaler after 4 s. Repeatedly sucking 10 capsules, turning off the power supply and dismantling the device. Deionized water or ethanol is used as a collecting solution, samples in the inhalation device and the adapter, the right-angle simulated throat, the preseparator, S1-S7 and the MOC are respectively collected, and the medicine content of each component is measured by high performance liquid chromatography. The experimental result is processed by CITDAS (Version3.00) software, the FPF value of the cyclodextrin-metal organic framework dry powder inhalant loaded with ketoprofen is 25.14 percent and is higher than 10 percent specified in pharmacopoeia, and the aerodynamic behavior is excellent. In vitro aerodynamic behavior examination (in vitro deposition profile) referring to figure 5, it can be seen that a certain amount of particles are deposited in the S3-S7 discs, indicating that this fraction of particles can be deposited in the lungs and that the inhalant has good aerodynamic properties. In this test, selection was madeDry powder inhaler (model:italian pH&T company) and Hydroxypropylmethylcellulose (HPMC) capsules (brand model: 3#, suzhou capsule corporation).

Secondly, in-vitro aerodynamic behavior investigation of curcumin-encapsulated cyclodextrin-metal organic framework dry powder inhalant

The in vitro aerodynamic behavior of the curcumin-entrapped cyclodextrin-metal organic framework dry powder inhaler prepared in example 2 was examined using a new generation of particle impactor (NGI).

After the vacuum pump, the flow controller and the particle impactor are connected, the impact cup is placed in the cup holder, the upper cover of the impactor is fastened, and the positioning pin is screwed. 15mL of a solution was added to the collection cup of the preseparatorThe ion water or 80% ethanol is connected with the impactor, the preseparator and the right-angle simulated throat in sequence, so that the system becomes a closed system. And starting a vacuum pump, measuring the flow rate of the air flow, and adjusting the flow rate of the air flow to enable the flow rate of the air flow to be about 60L/min. The adapter of the dry powder inhaler was attached to a right angle simulated throat with both on the same horizontal axis. And (3) putting a capsule filled with a sample to be tested into an inhaler, puncturing the capsule, connecting the dry powder inhaler with the adapter, starting the vacuum pump, and taking out the inhaler after 4 s. Repeatedly sucking 10 capsules, turning off the power supply and dismantling the device. Deionized water or 80% ethanol is used as a collecting solution, samples in an inhalation device and an adapter, a right-angle simulated throat, a pre-separator, S1-S7 and MOC are respectively collected, and the content of the drugs in each component is determined by high performance liquid chromatography. The experimental result is processed by CITDAS (Version3.00) software, the FPF value of the cyclodextrin-metal organic framework dry powder inhalant loaded with the curcumin is 64.47 percent, which is obviously higher than 10 percent specified in pharmacopoeia, and the aerodynamic behavior is excellent. In vitro aerodynamic behavior examination (in vitro deposition profile) referring to fig. 6, it can be seen from fig. 6 that most of the particles are deposited in the S3-S7 discs, which indicates that the particles can be deposited in the lungs, and thus the inhalant has excellent aerodynamic properties. In the present embodiment, selectionDry powder inhalers and hydroxypropyl methylcellulose (HPMC) capsules (brand model No. 3, suzhou capsule company) were implemented.

Third, saturation solubility of curcumin dry powder inhalant

A sample of drug-loaded cyclodextrin-metal organic framework dry powder inhaler (prepared in example 2) containing the same curcumin content (2mg) and a sample of micronized curcumin dry powder inhaler (prepared in comparative example 1) prepared with lactose carrier were placed in an EP tube and immersed in 30mL of phosphate buffered saline (PBS, pH7.4) at a gas bath system temperature of 37 ℃, shaking speed of 100rpm, and dissolution and release for 24 h. 1mL of fresh dissolution medium was taken at each time point and supplemented with the same volume. The solution taken out was filtered through a 0.22 μm filter and analyzed by High Performance Liquid Chromatography (HPLC) injection.

Phosphate Buffered Saline (PBS) at pH7.4 was used to simulate the environment in lung fluid. Solubility results As shown in FIG. 7, the curcumin solubility of the curcumine-loaded cyclodextrin-metal organic matrix dry powder inhaler prepared in example 2 was about 0.6. mu.g.mL in 24h^-1. The solubility of curcumin in 24h for the micronized curcumin lactose dry powder inhaler prepared in comparative example 1 is below the limit of quantitation (should be below 0.08264 μ g/mL). Dry powder inhalers based on cyclodextrin-metal organic frameworks have been shown to increase the solubility of poorly soluble drugs.

In vitro drug release of curcumin dry powder inhalant

A drug-loaded cyclodextrin-metal organic framework dry powder inhaler sample (prepared in example 2) containing the same curcumin content (429 μ g) and a micronized curcumin dry powder inhaler sample (prepared in comparative example 1) prepared with a lactose carrier were placed in an EP tube, and the samples were immersed in 7mL of phosphate buffer solution (PBS, ph7.4) containing 1% (w/v) Sodium Dodecyl Sulfate (SDS), with a gas bath system temperature of 37 ℃, a shaking speed of 100rpm, and released for 1.5 h. 1mL was taken at each time point and supplemented with the same volume of fresh release medium. The released solution was filtered through a 0.22 μm filter and analyzed by HPLC injection.

The release results are shown in fig. 8, and the curcumin released by the curcumine-loaded cyclodextrin-metal organic framework dry powder inhalant prepared in example 2 is close to 100% within 1.5h, and more specifically, the curcumin released is close to 100% within 10 min. The micronized curcumin lactose dry powder inhalant prepared in comparative example 1 releases less than 70% of curcumin within 1.5h and less than 40% within 10 min. The curcumin-loaded cyclodextrin-metal organic framework dry powder inhalant prepared in example 2 can increase the dissolution rate of insoluble drugs. Proves that the novel cyclodextrin-metal organic framework-based dry powder inhalant has wide prospect in the field of pulmonary delivery of insoluble drugs.

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.