CN111803471A - Respiratory tract administration preparation based on cyclodextrin-metal organic framework - Google Patents

Abstract

The present invention relates to formulations for respiratory administration based on cyclodextrin-metal organic frameworks. Specifically, the present invention provides a preparation for respiratory tract administration, the preparation for respiratory tract administration comprises a drug-loaded cyclodextrin-metal organic framework; the drug-loaded cyclodextrin-metal organic framework comprises: cyclodextrin - metal organic framework; drug loaded on the cyclodextrin - metal organic framework. In the formulation for respiratory administration of the present invention, the drug-loaded cyclodextrin-metal-organic framework can prevent the drug from being ingested by macrophages, increase the effective absorption of the drug in the lungs, and thereby improve the route of drug administration through the respiratory tract. the medicinal effect.

Description

Respiratory drug delivery formulations based on cyclodextrin-metal organic frameworks

technical field

The invention relates to the technical field of pulmonary administration, in particular to a preparation for respiratory administration based on a cyclodextrin-metal organic framework.

Background technique

A respiratory drug delivery system (eg, a pulmonary drug delivery system) refers to delivering a drug to the respiratory tract, such as the lungs, so that the drug is locally enriched in the respiratory tract, such as the lung, to achieve local or systemic therapeutic effects. Administration in the respiratory tract such as the lung has obvious advantages, including the ability to effectively avoid the first-pass effect, improve the bioavailability of the drug, reduce the destruction of the drug by digestive enzymes, and effectively avoid systemic side effects. At present, the commonly used dosage forms for respiratory tract such as pulmonary administration include Nebulizer, Metered Dose Inhaler and Dry Powder Inhaler (DPI).

However, there are also many shortcomings in the respiratory tract such as the pulmonary drug delivery system. For example, some drugs such as anti-inflammatory drugs are easily phagocytosed and degraded by the surface cells of the respiratory tract such as the lungs, thereby reducing the stability of the drug, thereby reducing the effective availability and efficacy of the drug. etc., how to develop a drug delivery system that can overcome the defects caused by the respiratory tract such as the pulmonary drug delivery system and provide the drug bioavailability and efficacy of the respiratory tract such as the pulmonary drug delivery system has become a research hotspot.

Therefore, there is a need in the art to develop a formulation for respiratory administration that improves the efficacy of the drug.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a preparation for respiratory tract administration, in which the drug-loaded cyclodextrin-metal organic framework can prevent the drug from being ingested by macrophages and improve the effectiveness of the drug in the lungs absorption, thereby improving the efficacy of the drug through the respiratory route of administration.

A first aspect of the present invention provides a preparation for respiratory tract administration, which includes a drug-loaded cyclodextrin-metal organic framework;

The drug-loaded cyclodextrin-metal organic framework includes:

Cyclodextrin-metal organic framework;

A drug supported on the cyclodextrin-metal organic framework.

In another preferred embodiment, the formulation for respiratory tract administration further includes adjuvants acceptable to the formulation for respiratory tract administration.

In another preferred example, the loading method is that the drug enters the inner cavity of the cyclodextrin-metal organic framework and/or the drug is adsorbed on the surface of the cyclodextrin-metal organic framework.

In another preferred embodiment, the drug is loaded on the cyclodextrin-metal organic framework by the following methods: incubation method, co-crystallization method.

In another preferred embodiment, the formulation for respiratory tract administration is dry powder inhaler, spray, powder mist or aerosol.

In another preferred embodiment, the drugs include anti-inflammatory drugs.

In another preferred embodiment, the drug is selected from the group consisting of budesonide, triamcinolone acetonide, ciclesonide, roflumilast, formoterol, mexatrol, beclomethasone, dexamethasone , fluticasone, mometasone, tiotropium bromide, paeonol, curcumin, tanshinone, or a combination thereof.

In another preferred example, the drug comprises nanosilver and one of levofloxacin, budesonide, roflumilast, formoterol, mexaterol, dexamethasone, fluticasone, paeonol, and curcumin A compound composition is formed.

In another preferred embodiment, the weight ratio of the drug-loaded cyclodextrin-metal organic framework to the adjuvant acceptable for the preparation for respiratory tract administration is 0.2-2:0.2-2, preferably 0.5-1.5:0.5- 1.5, more preferably 0.8-1.2:0.8-1.2.

In another preferred embodiment, the formulation for respiratory tract administration further includes adjuvants acceptable for dry powder inhalation, adjuvants acceptable for spray, adjuvant acceptable for powder aerosol and/or adjuvant acceptable for aerosol.

In another preferred embodiment, the adjuvant acceptable to the formulation for respiratory administration is selected from the group consisting of carbohydrates, amino acids, lecithin and phosphatidylcholine, or a combination thereof.

In another preferred embodiment, the adjuvant acceptable to the formulation for respiratory tract administration is selected from the group consisting of lactose, leucine, or a combination thereof.

In another preferred example, the acceptable excipients for the formulation for respiratory administration include lactose with a D ₅₀ particle size of 4-11 μm.

In another preferred example, the acceptable excipients for the formulation for respiratory tract administration include lactose with a D ₅₀ particle size of 4-11 μm and lactose with a D ₅₀ particle size of 70-110 μm.

In another preferred example, the adjuvant acceptable to the formulation for respiratory tract administration is selected from the following group: lactose with a D ₅₀ particle size of 4-11 μm, lactose with a D ₅₀ particle size of 40-70 μm, and a D ₅₀ particle size of 4-11 μm. 70-110 μm of lactose, or a combination thereof.

In another preferred example, the weight ratio of lactose with a _D50 particle size of 4-11 μm and lactose with a _D50 particle size of 70-110 μm is 1-15:30-60, preferably 1.5-10:40-48.5 .

In another preferred example, the molar ratio of the drug to the cyclodextrin-metal organic framework is 0.01-8:1, preferably 0.01-6:1, preferably 0.05-6:1, preferably 0.5-6:1, preferably 1-6:1, most preferably 1.5-6:1.

In another preferred embodiment, the ratio of the weight of the drug-loaded cyclodextrin-metal organic framework to the adjuvant acceptable to the formulation for respiratory tract administration is 1:0.2-120, preferably 1:0.2-60, Preferably 1:0.2-20, preferably 1:0.5-20, preferably 1:0.5-15, preferably 1:0.5-10, preferably 1:0.5-5, preferably 1: 0.8-3, best 1:0.8-1.2.

In another preferred embodiment, the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, or a combination thereof.

In another preferred example, the particle size of the drug-loaded cyclodextrin-metal organic framework is 0.2-10 μm, preferably 1-5 μm.

In another preferred embodiment, the cyclodextrin-metal organic framework is in the form of cubes.

In another preferred example, the particle size of the cyclodextrin-metal organic framework is 1-5 μm.

In another preferred example, the BET specific surface area of the cyclodextrin-metal organic framework is 200-1200m ² /g, preferably 300-1100m ² /g, more preferably 400-1000m ² /g, most Good ground 400-600m ² /g.

In another preferred embodiment, the cyclodextrin-metal-organic framework is selected from the group consisting of surface-unmodified cyclodextrin-metal-organic framework, surface-modified cyclodextrin-metal-organic framework, or a combination thereof.

In another preferred embodiment, the cyclodextrin-metal organic framework is in the form of regular cubes.

In another preferred embodiment, the surface modifier of the surface-modified cyclodextrin-metal organic framework is selected from the group consisting of cholesterol, leucine, poloxamer, pyrene, ferrocene, polypeptide, peroxide compounds, polyisocyanates, glycidyl ethers such as ethylene glycol diglycidyl ether, dibasic or polybasic acids, dibasic or polybasic aldehydes, carbonyl-containing compounds, epoxides, acrylates, succinyl chloride, or a combination thereof.

In another preferred embodiment, the polypeptide is a polypeptide containing a carboxyl group, an acid anhydride and/or an acid chloride.

In another preferred embodiment, the peroxides are selected from the group consisting of benzoyl peroxide, dicumyl peroxide, or a combination thereof.

In another preferred embodiment, the polyisocyanates include isocyanates.

In another preferred embodiment, the dibasic or polybasic acids include citric acid.

In another preferred embodiment, the dibasic or polyvalent aldehydes include glutaraldehyde.

In another preferred embodiment, the carbonyl-containing compound includes diphenyl carbonate and N,N'-carbonyldiimidazole.

In another preferred embodiment, the epoxides include epichlorohydrin.

In another preferred embodiment, the acrylates include ethylene glycol dimethacrylate.

In another preferred embodiment, the cyclodextrin-metal organic framework is prepared by the following method, and the method includes:

(1) providing a first mixed solution, the first mixed solution is a solution containing metal ions and cyclodextrin;

(2) adding the first organic solvent to the first mixed solution to obtain the second mixed solution;

Wherein, the volume ratio of the first organic solvent to the first mixed solution is (0.01-5): 1, preferably (0.1-2): 1, preferably 0.3-1.0: 1, the best Ground is (0.4-0.8): 1;

(3) adding a size regulator to the second mixed solution to form a third mixed solution;

(4) The third mixed solution is cooled and separated to obtain the precipitated cyclodextrin-metal organic framework material.

In another preferred example, in the step (1), the first mixed solution further includes water.

In another preferred example, in the step (1), the first mixed solution is a solution containing metal ions, cyclodextrin and water.

In another preferred embodiment, the metal ion, cyclodextrin and water are mixed and dissolved by heating to form the first mixed solution.

In another preferred example, the heating temperature is 50-80°C.

In another preferred example, in the step (1), the metal ions are selected from the following group: Li ⁺ , K ⁺ , Rb ⁺ , Cs ⁺ , Na ⁺ , Mg ²⁺ , Cd ²⁺ , Sn ²⁺ , Ag ⁺ , Yb ⁺ , Ba ²⁺ , Sr ²⁺ , Ca ²⁺ , Pb ²⁺ , La ³⁺ , or a combination thereof.

In another preferred example, in the step (1), the metal ion is an alkali metal potassium ion.

In another preferred example, in the step (1), the molar ratio of the cyclodextrin to the alkali metal ion is 1:(2-15), preferably 1:(4-12 ), more preferably 1:(6-10).

In another preferred example, in the step (1), the concentration of the cyclodextrin is 10-100mM, preferably 10-60mM, more preferably 10-40mM, more preferably 15-35mM, Optimally 20-30mM.

In another preferred example, in the step (2), the first organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, acetonitrile, or a combination thereof.

In another preferred example, in the step (2), the first mixed solution and the first organic solvent are mixed under heating to obtain a second mixed solution, and the heating temperature 40-60℃.

In another preferred example, in the step (2), the first mixed solution and the first organic solvent are mixed under heating to obtain a second mixed solution, and the heating time for 10-3min.

In another preferred example, in the step (3), the size regulator is selected from the group consisting of polyethylene glycol, povidone, polysorbate, sorbitan monolaurate, poly Oxyethylene lauryl ether, emulsifier OP (nonylphenol polyoxyethylene ether condensate), milk lark A (polyoxyethylene fatty alcohol ether), pluronic (polyoxyethylene polypropylene glycol condensate), dodecane Sodium alkyl sulfate, sodium dodecylbenzenesulfonate, dodecyldimethylbenzylammonium bromide (benzalkonium bromide), or a combination thereof.

In another preferred example, in the step (3), the concentration of the size regulator is 2-20 mg/mL, preferably 3-16 mg/mL, more preferably 6-12 mg/mL.

In another preferred example, in the step (3), the size adjusting agent is selected from polyethylene glycol.

In another preferred example, in the step (3), the molecular weight of the polyethylene glycol is 5000-80000, preferably 10000-50000, more preferably 10000-30000.

In another preferred example, in the step (4), the cooling temperature is 5-25°C, preferably 10-20°C.

In another preferred embodiment, in the step (4), the separation is centrifugal separation.

In another preferred embodiment, in the step (4), the precipitate obtained after cooling is centrifuged.

In another preferred example, the cyclodextrin-metal organic framework material precipitated in step (4) is washed and dried.

In another preferred embodiment, the solvent used in the washing is C1-C4 alcohol.

In another preferred embodiment, the C1-C4 alcohol is selected from the group consisting of methanol, ethanol, or a combination thereof.

In another preferred embodiment, the washing includes the steps of washing with ethanol and methanol in sequence.

In another preferred embodiment, vacuum drying is performed after washing.

In another preferred example, the cyclodextrin-metal organic framework material obtained in step (4) is neutralized with an acidic substance.

In another preferred example, the neutralization treatment includes the steps of: after the cyclodextrin-metal organic framework material obtained in step (4) is dispersed in an organic solvent, an acidic substance is added, centrifuged to obtain a precipitate and washed to obtain neutrality Chemically processed cyclodextrin-metal organic framework materials.

In another preferred embodiment, the organic solvent is selected from methanol, ethanol, propanol, or a combination thereof.

In another preferred example, the acidic substance is selected from: formic acid, acetic acid, propionic acid, or a combination thereof.

In another preferred example, the washing liquid used in the washing is selected from the group consisting of methanol, ethanol, propanol, or a combination thereof.

In another preferred embodiment, the respiratory tract administration formulation is a dry powder inhaler.

The second aspect of the present invention provides a method for preparing the formulation for respiratory tract administration according to the first aspect of the present invention, the method comprising the steps of: combining the drug-loaded cyclodextrin-metal organic framework with optional The adjuvant that is acceptable for the preparation for respiratory tract administration is mixed to obtain the preparation for respiratory tract administration.

The third aspect of the present invention provides the use of a cyclodextrin-metal organic framework or a drug-loaded cyclodextrin-metal organic framework for preparing a preparation for respiratory administration.

In another preferred embodiment, in the formulation for respiratory administration, the cyclodextrin-metal organic framework is loaded with a drug.

A fourth aspect of the present invention provides a nasal drug delivery device, the device comprising an inhalation device and the respiratory tract drug delivery formulation according to the first aspect of the present invention.

In another preferred embodiment, the inhalation device includes a dry powder inhalation device, a spray device, a powder mist device or an aerosol device.

In another preferred embodiment, the nasal drug delivery device includes a dry powder inhalation device, a capsule (blister) and the respiratory tract drug delivery formulation described in the first aspect of the present invention.

In another preferred embodiment, the capsule or blister contains the formulation for respiratory administration according to the first aspect of the present invention in the form of a reservoir.

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 in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, it is not repeated here.

Description of drawings

Figure 1 is a diagram of the NGI device.

FIG. 2 is a scanning electron microscope image of the cyclodextrin-metal organic framework prepared in Example 1. FIG.

Figure 3 shows the results of cell uptake evaluation.

Figure 4 shows the morphology of CD-MOF-paeonol prepared in Example 2.

5 is a diagram showing the deposition site of paeonol on NGI in the CD-MOF-paeonol prepared in Example 2.

FIG. 6 shows the results of the CD-MOF-paeonol dissolution assay prepared in Example 2. FIG.

Fig. 7 is the cytotoxicity evaluation result, wherein Fig. 7A is the cytotoxicity evaluation result of CD-MOF-paeonol, Fig. 7B is the cytotoxicity evaluation result of CD-MOF,

Figure 8 shows the pharmacokinetic results.

FIG. 9 is the morphology of CD-MOF-Paeonol (PAE-CD-MOF) prepared in Example 6. FIG.

Figure 10A is the in vitro imaging of CD-MOF-RhoB.

Figure 10B is the in vitro imaging of CD-MOF-RhoB-paeonol.

FIG. 11 is the NGI measurement result of cholesterol-CD-MOF-budesonide prepared in Example 18. FIG.

Figure 12 shows the results of crystal form determination of dry powder by X-ray powder diffractometer.

Detailed ways

After extensive and in-depth research, the inventors unexpectedly found that when the drug-loaded cyclodextrin-metal organic framework is used as a preparation for respiratory administration (such as dry powder inhaler), it can avoid the uptake of the drug by macrophages, and improve the The effective absorption of the drug in the lungs, thereby improving the efficacy of the drug through the respiratory route, such as improving the treatment of lung diseases. On this basis, the inventors have completed the present invention.

the term

Unless otherwise defined, 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.

As used herein, the terms "comprising," "including," and "containing" are used interchangeably to include not only closed definitions, but also semi-closed, and open definitions. In other words, the terms include "consisting of", "consisting essentially of".

As used herein, the terms "cyclodextrin" and "CD" are used interchangeably.

As used herein, the terms "cyclodextrin-metal organic framework material" and "CD-MOF" are used interchangeably.

Cyclodextrin-metal organic framework

In the present invention, the cyclodextrin-metal organic framework is abbreviated as "CD-MOF".

In a preferred embodiment, the cyclodextrin-metal organic framework includes one or more features selected from the group consisting of:

The cyclodextrin-metal organic framework is in the form of cubes;

The particle size of the cyclodextrin-metal organic framework is 1-5 μm;

The BET specific surface area of the cyclodextrin-metal organic framework is 200-1200m ² /g, preferably 300-1100m ² /g, more preferably 400-1000m ² /g, and most preferably 400-600m ² / g; and/or

The cyclodextrin-metal-organic framework is selected from the group consisting of surface-unmodified cyclodextrin-metal-organic framework, surface-modified cyclodextrin-metal-organic framework, or a combination thereof.

In another preferred embodiment, the cyclodextrin-metal organic framework is in the form of regular cubes.

In another preferred embodiment, the surface modifier of the surface-modified cyclodextrin-metal organic framework is selected from the group consisting of cholesterol, leucine, poloxamer, pyrene, ferrocene, polypeptide, peroxide compounds, polyisocyanates, glycidyl ethers such as ethylene glycol diglycidyl ether, dibasic or polybasic acids, dibasic or polybasic aldehydes, carbonyl-containing compounds, epoxides, acrylates, succinyl chloride, or a combination thereof.

In another preferred embodiment, the carbonyl-containing compound includes diphenyl carbonate and N,N'-carbonyldiimidazole.

In another preferred embodiment, the cyclodextrin-metal organic framework is prepared by the following method, and the method includes:

(1) providing a first mixed solution, the first mixed solution is a solution containing metal ions and cyclodextrin;

(2) adding the first organic solvent to the first mixed solution to obtain the second mixed solution;

Wherein, the volume ratio of the first organic solvent to the first mixed solution is (0.01-5): 1, preferably (0.1-2): 1, preferably 0.3-1.0: 1, the best The ground is (0.4-0.8):1.

(3) adding a size regulator to the second mixed solution to form a third mixed solution;

(4) The third mixed solution is cooled and separated to obtain the precipitated cyclodextrin-metal organic framework material.

In another preferred example, in the step (1), the metal ions are selected from the following group: Li ⁺ , K ⁺ , Rb ⁺ , Cs ⁺ , Na ⁺ , Mg ²⁺ , Cd ²⁺ , Sn ²⁺ , Ag ⁺ , Yb ⁺ , Ba ²⁺ , Sr ²⁺ , Ca ²⁺ , Pb ²⁺ , La ³⁺ , or a combination thereof.

In another preferred example, in the step (3), the size regulator is selected from the group consisting of polyethylene glycol, povidone, polysorbate, sorbitan monolaurate, poly Oxyethylene lauryl ether, emulsifier OP (nonylphenol polyoxyethylene ether condensate), milk lark A (polyoxyethylene fatty alcohol ether), pluronic (polyoxyethylene polypropylene glycol condensate), dodecane Sodium alkyl sulfate, sodium dodecylbenzenesulfonate, dodecyldimethylbenzylammonium bromide (benzalkonium bromide), or a combination thereof.

In another preferred example, the cyclodextrin-metal organic framework material obtained in step (4) is neutralized with an acidic substance.

In another preferred example, the neutralization treatment includes the steps of: after the cyclodextrin-metal organic framework material obtained in step (4) is dispersed in an organic solvent, an acidic substance is added, centrifuged to obtain a precipitate and washed to obtain neutrality Chemically processed cyclodextrin-metal organic framework materials.

Drug-loaded cyclodextrin-metal organic frameworks

In the present invention, in the drug-loaded cyclodextrin-metal organic framework, the drug is supported on the cyclodextrin-metal organic framework.

Typically, the drug-loaded cyclodextrin-metal organic framework includes:

Cyclodextrin-metal organic framework;

A drug supported on the cyclodextrin-metal organic framework.

In the drug-loaded cyclodextrin-metal organic framework, the loading method of the drug is not particularly limited, and the loading method can be that the drug enters the inner cavity of the cyclodextrin-metal organic framework or the drug is adsorbed on the Dextrin - the surface of the metal organic framework, or a combination of the two.

In another preferred example, the particle size of the drug-loaded cyclodextrin-metal organic framework is 0.2-10 μm, preferably 1-5 μm.

In another preferred embodiment, the drug is loaded on the cyclodextrin-metal organic framework by the following methods: incubation method, co-crystallization method.

In another preferred embodiment, the drugs include anti-inflammatory drugs.

In another preferred example, the molar ratio of the drug to the cyclodextrin-metal organic framework is 0.01-8:1, preferably 0.01-6:1, preferably 0.05-6:1, preferably 0.5-6:1, preferably 1-6:1, most preferably 1.5-6:1.

Respiratory drug formulation and preparation method

The invention provides a preparation for respiratory tract administration, which comprises a drug-loaded cyclodextrin-metal organic framework;

The drug-loaded cyclodextrin-metal organic framework includes:

Cyclodextrin-metal organic framework;

A drug supported on the cyclodextrin-metal organic framework.

In another preferred embodiment, the formulation for respiratory tract administration of the present invention further includes adjuvants acceptable to the formulation for respiratory tract administration.

In the present invention, the components of the term "excipients acceptable for preparations for respiratory tract administration" refer to ingredients that are suitable for use in humans and/or animals without excessive adverse side effects (such as toxicity, irritation and allergic reactions), that is, have reasonable benefits/ hazard ratio substances.

It should be understood that in the present invention, the adjuvants acceptable to the formulation for respiratory administration are not particularly limited, and are commonly used materials in the art, and the types, usage methods, and sources thereof are well known to those skilled in the art.

Examples of acceptable excipients for respiratory preparations include (but are not limited to) carbohydrates, amino acids, propellants, polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween), moisturizing agents Wetting agents (such as sodium lauryl sulfate), buffers, chelating agents, thickeners, pH adjusters, skin penetration enhancers, stabilizers, antioxidants, preservatives, bacteriostatic agents, purified water, pyrogen-free water Wait.

The respiratory tract administration formulations of the present invention can be dry powder inhalers, sprays, powder mists or aerosols.

In another preferred embodiment, the weight ratio of the drug-loaded cyclodextrin-metal organic framework to the adjuvant acceptable for the preparation for respiratory tract administration is 0.2-2:0.2-2, preferably 0.5-1.5:0.5- 1.5, more preferably 0.8-1.2:0.8-1.2.

In another preferred embodiment, the adjuvant acceptable to the formulation for respiratory administration is selected from the group consisting of carbohydrates, amino acids, lecithin and phosphatidylcholine, or a combination thereof.

In another preferred example, the adjuvant acceptable to the formulation for respiratory tract administration is selected from the following group: lactose with a D ₅₀ particle size of 4-11 μm, lactose with a D ₅₀ particle size of 40-70 μm, and a D ₅₀ particle size of 4-11 μm. 70-110 μm of lactose, or a combination thereof.

A typical formulation for respiratory administration is a dry powder inhaler.

Typically, the dry powder inhaler comprises a drug-loaded cyclodextrin-metal organic framework and an adjuvant acceptable to the dry powder inhaler. Acceptable excipients for dry powder inhalers are as described above.

Preferably, the acceptable excipient for dry powder inhalation is lactose.

The preparation method of the described dry powder inhaler is not particularly limited, a preferably the preparation method of the dry powder inhaler, comprising the steps:

1. Mix 28-36% of the amount of adjuvant (such as lactose) acceptable to the dry powder inhaler with 40-60% of the amount of the drug-loaded cyclodextrin-metal organic framework to obtain a first mixture;

2. Add 28-36% of the amount of adjuvant (such as lactose) acceptable to the dry powder inhaler into the first mixture, and mix to obtain the second mixture;

3. Add 40-60% of the drug-loaded cyclodextrin-metal organic framework to the second mixture, and mix to obtain a third mixture;

4. Add 28-36% of the amount of adjuvant (such as lactose) acceptable to the dry powder inhaler into the third mixture, and mix to obtain the dry powder inhaler.

The preparation method of the preparation for respiratory tract administration of the present invention can adopt a suitable conventional preparation method, for example, the method includes the steps of: combining the drug-loaded cyclodextrin-metal organic framework with optional respiratory tract administration The adjuvant acceptable for the preparation is mixed to obtain a preparation for respiratory tract administration.

Use and Mode of Administration

The invention also provides the use of a cyclodextrin-metal organic framework or a drug-loaded cyclodextrin-metal organic framework for preparing a preparation for respiratory administration.

In another preferred embodiment, in the formulation for respiratory administration, the cyclodextrin-metal organic framework is loaded with a drug.

The drug or formulation should be matched with the mode of administration. When using the composition or formulation, an effective amount of the ingredient is administered to the desired subject (such as a human or non-human mammal), wherein the safe and effective daily dose of the ingredient is usually at least about 0.1 mg, and in most cases no more than about 2500 mg. Preferably, the dose is 1 mg-500 mg. Of course, the specific dose should also take into account factors such as the route of administration, health conditions, etc., which are all within the skills of skilled physicians, nutritionists, and health centers. When the blueberry extract and/or the maltose component are administered sequentially, there is no special requirement for the interval of administration. In the present invention, the modes of administration include, but are not limited to, oral administration, transdermal administration, sublingual administration, and the like.

nasal delivery device

The present invention also provides a nasal drug delivery device. The devices include inhalation devices and formulations for respiratory administration of the present invention.

In another preferred embodiment, the inhalation device includes a dry powder inhalation device, a spray device, a powder mist device or an aerosol device.

In another preferred embodiment, the nasal administration device includes a dry powder inhalation device, a capsule (blister) and the respiratory tract administration formulation of the present invention.

In another preferred embodiment, the capsule or blister contains the formulation for respiratory administration of the present invention in the form of a reservoir.

The main advantages of the present invention include:

(1) The cyclodextrin-metal organic framework of the present invention is in the form of a regular cube, which can avoid the uptake of macrophages and improve the effective absorption of the drug in the lungs; wherein, the cyclodextrin-metal organic framework-anti-inflammatory Drugs tend to adhere to the lung endothelial cells and are not easily recognized by macrophages.

(2) The cyclodextrin-metal organic framework can adsorb drugs to form a powder with uniform distribution of drugs at the molecular level, which is suitable for the delivery of very low doses of drugs.

(3) The cyclodextrin-metal organic framework is composed of several unit cells, wherein the unit cell has a cavity of cyclodextrin molecules (pore size is 0.8 nm) and a metal-organic framework hexahedral cavity surrounded by cyclodextrin molecules (pore size of 0.8 nm). 1.7nm). Cyclodextrin-metal organic frameworks have a dual pore structure, which can be loaded with a variety of active substances or drugs with different properties, as well as co-delivery of compound drugs. Specifically, the multiple cage-like structures in the cyclodextrin-metal organic framework can selectively identify drug molecules of different sizes and properties; the cyclodextrin hydrophobic cavity can specifically identify water-insoluble drugs with relatively small molecular sizes. The cavities of metal organic frameworks can accommodate more water-soluble drugs with larger sizes to achieve co-loading and co-delivery of drugs.

(4) The cyclodextrin-metal organic framework is easy to modify and modify. Specifically, the cyclodextrin in the cyclodextrin-metal organic framework can have strong host-guest molecules with cholesterol, pyrene, ferrocene, etc. Recognition; the active hydroxyl group in the cyclodextrin-metal organic framework can chemically react with polypeptides or cross-linking agents containing carboxyl groups, acid anhydrides, acid chlorides, etc. to carry out surface modification and cross-linking.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

计算细粒子分数，绘制体外沉积分布图，以公式

计算射出分数；以公式

计算可吸入分数，按照美国药典规定，计算质量中位数气动粒径MMAD和几何标准偏差GSD。其中，FPD为微细粒子剂量(不得小于药物标示量的10％)，指的是NGI收集盘中收集的空气动力学粒径＜5μm的药量除以测试胶囊数；ED为射出剂量，指的是适配器、人工喉、预分离器和收集盘中收集的总药量除以测试胶囊数；TD为1粒胶囊内药物总量；DD为收集盘沉积剂量。NGI装置图如图1所示。NGI determination method: Weigh an appropriate amount of the sample to be tested, fill it in No. 3 gelatin capsules, and use a new generation of pharmaceutical impactor (NGI) for determination. In order to prevent the particles from being ejected and dusting during the measurement, the collection cup was coated with a 1% (w/v) dimethyl silicone oil n-hexane solution coating solution. Connect the vacuum pump (HCP5) and the two-way magnetic flux valve (TPK2000-R) as required and turn on the switch, set the pumping time and number of pumping times on the two-way flux valve, and put 15 mL of mobile phase (methanol: Water = 45:55, v/v), connect the two-way magnetic flux valve, pre-separator and artificial throat and impactor body, put the capsule into the inhaler (Rotahaler), insert the inhaler into the adapter connected to the artificial throat , Repeat the test for 5 capsules once. After the test, the mobile phase cleaning device, the adapter, the artificial throat, the pre-separator, the 1-7 stages of the impactor body and the collection cup of the microporous collector (MOC) (calculated according to the flow rate) The aerodynamic particle size of the particles falling into each collection cup, when the flow rate is 60L/min, the shear particle size of the first stage is 8.06μm, the second stage is 4.46μm, the third stage is 2.82μm, and the fourth stage 1.66μm, 5th grade is 0.94μm, 6th grade is 0.55μm, 7th grade is 0.34μm), transfer to a 25mL volumetric flask, and make up to volume. The drug content of each deposition site sample was determined by the liquid phase method, and the formula was

Calculate the fine particle fraction and map the in vitro deposition profile with the formula

Calculate shot fraction; with formula

The respirable fraction was calculated, and the mass median aerodynamic particle size MMAD and geometric standard deviation GSD were calculated according to the US Pharmacopeia. Among them, FPD is the dose of fine particles (not less than 10% of the labeled amount of the drug), which refers to the amount of drugs with aerodynamic particle size <5μm collected in the NGI collection tray divided by the number of test capsules; ED is the injected dose, referring to is the total amount of drug collected in the adapter, artificial throat, pre-separator and collection tray divided by the number of test capsules; TD is the total amount of drug in 1 capsule; DD is the dose deposited in the collection tray. The diagram of the NGI device is shown in Figure 1.

Example 1

(1) Preparation of cyclodextrin-metal organic framework (CD-MOF):

Dissolve 649.0 mg of γ-CD and 224.0 mg of KOH mixture (the molar ratio of γ-CD and KOH is 1:8) in 20 mL of water, and sonicate for 10 min to fully dissolve to obtain a first mixed solution, and then add 12 mL of the first mixed solution. Methanol, heated in a 50°C water bath for 20min to obtain a second mixed solution, then add 256mg of PEG20000 to the second mixed solution and shake to dissolve and disperse evenly, continue to react for 10min to obtain a third mixed solution; put the third mixed solution into cold water After standing in a bath (15°C) overnight, centrifuged at 4000 r/min for 5 min, the precipitate was washed twice with ethanol (12 mL) and methanol (12 mL) respectively, and the obtained crystals were vacuum-dried at 40°C for 12 h to obtain CD-MOF crystals. Take the CD-MOF crystals prepared above in a centrifuge cup, add anhydrous ethanol to disperse, add glacial acetic acid, stir well, centrifuge at 4000 r/min for 4 min, wash the precipitate with anhydrous ethanol three times, and place it in a 40°C vacuum drying oven After drying for 12h, CD-MOF crystals were obtained.

The scanning electron micrograph of the CD-MOF crystals is shown in Fig. 2. From Fig. 2, it can be seen that the CD-MOF crystals have a regular cubic shape with a particle size distribution of 1-5 μm. The experimental results of nitrogen gas adsorption show that it has a BET specific surface area of 513 m ² /g.

(2) Evaluation of cellular uptake:

Precisely weigh 1.56g of CD-MOF prepared in Example 1 and place it in a 50mL round-bottomed flask, add 20mL of N,N-dimethylformamide, and after the temperature rises to 80°C, add 1.54g of cross-linking agent diphenyl carbonate Ester and 900 μL catalyst triethylamine, magnetic stirring (500 rpm). After 24 hours of reaction, the reaction solution was placed at room temperature, poured into 100 mL of 95% ethanol to terminate the reaction, centrifuged (4000 rpm, 5 min), and the supernatant was removed. Add 100 mL of pure water to wash once, then add 100 mL of acetone to wash twice, centrifuge separately (4000 rpm, 5 min), remove the supernatant, put the precipitate in a fume hood to dry naturally for about 2 hours, take it out, and vacuum dry it at 40 °C for 12 hours. . Accurately weigh 2.5 mg of RhoB (Rhodamine B), put it in a 10 mL glass bottle, add 5 mL of PBS (pH=5.0) solution, dissolve it by ultrasonic, and then add 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (5.0mg), CD-MOF (230.0mg) treated above, 4-dimethylaminopyridine (6.0mg), mixed well, added catalyst triethylamine 40μL, at 500rpm, 37°C magnetic stirrer Incubate for 24h, wash 5 times with excess pure water after the reaction, then wash with methanol until the supernatant is colorless, and vacuum dry at 40 °C for 12h to obtain the cross-linked CD-MOF-loaded Rhodamine B sample (CL-MOF-RhoB ).

Mice J774A.1 monocyte-macrophages were used to simulate the phagocytosis of macrophages, and were seeded in a glass-bottom culture dish (35mm diameter) at a density of 1×10 ⁴ cells/dish, and the culture medium was discarded after culturing for 24 hours. Take 1 mL of the PBS solution of the cross-linked CD-MOF-loaded Rhodamine B sample with a concentration of 500 μg/mL and add it to the petri dish for incubation. After 4 h, the cells were taken out, and the cells were gently rinsed 3 times with PBS. The cells were fixed with 4% paraformaldehyde for 20 min, and the nucleus and cell membrane were stained with DAPI and DIO respectively, and observed under a laser confocal microscope. During the experiment, blank PBS solution was used as blank control group. According to the staining concentration of RhoB, 20 μg/ mL of RhoB in PBS served as a positive control.

The results of cell uptake evaluation are shown in Figure 3. It can be seen from Figure 3 that the cross-linked CD-MOF-loaded Rhodamine B sample (CL-MOF-RhoB) was added and incubated for 4 h. No fluorescence was found, but more fluorescence was distributed in the periphery, and it was granular, while the positive control group added RhoB PBS solution found fluorescent signals in the cell membrane and cytoplasm in the RhoB channel, indicating that the cross-linked CD-MOF-loaded Rhodamine B sample could not be detected. J774A.1 uptake, cell uptake evaluation results show that the CD-MOF modified with diphenyl carbonate, that is, cross-linked CD-MOF cannot be taken up by J774A.1 cells, which can avoid the phagocytosis of macrophages and help carry drugs in the lungs Department exerts medicinal effect.

Example 2

Preparation of CD-MOF-Paeonol (PAE-CD-MOF):

The drug-carrying paeonol (PAE) is carried by the incubation method, including the steps of: weighing 1.44 g of paeonol into a 5 mL vial, adding 10 mL of absolute ethanol, and ultrasonically dissolving it. Weigh 0.5 g of the CD-MOF prepared in Example 1, add it to a vial, and stir magnetically for 1 h, 300 r/min, and a water bath of 30 °C. Centrifuge at 4000 r/min for 5 min, and precipitate the pellet by vacuum drying at 40° C. overnight to obtain CD-MOF-Paeonol (PAE-CD-MOF). The molar ratio of paeonol to CD-MOF in CD-MOF-paeonol was measured to be 2.51:1. The morphology of CD-MOF and CD-MOF-paeonol was evaluated. The evaluation results are shown in Figure 4. It can be seen from Figure 4 that the CD-MOF-Paeonol has a uniform particle size and a regular cubic crystal shape, with a particle size of about 1-5 μm, which meets the particle size requirements for pulmonary administration of dry powder inhalers.

NGI measurement results of CD-MOF-paeonol prepared in Example 2: CD-MOF-paeonol emptying rate was 103.18±0.86%, indicating that CD-MOF used in inhalation preparations can carry drugs and can be completely removed from the capsules discharge. The deposition site of paeonol in NGI is shown in Figure 5, and the calculated fine particle fraction is 19.98±0.98%, indicating that about 20% of the drug powder can be deposited into the deep lung to exert its efficacy, which is much higher than the Pharmacopoeia regulations of ≥10 %.

CD-MOF-Paeonol Dissolution Determination Method Prepared in Example 2: The dissolution rate of CD-MOF-Paeonol was investigated by the small cup paddle method, and the dissolution rate determination conditions were: the rotation speed was 25r/min, and the temperature was 37.0±0.5 ℃, the medium is 200 mL of PBS solution (pH is 7.4), and samples were taken at different time points, 1 mL each time, passed through a 0.22 μm microporous membrane, centrifuged at 12000 r/min for 3 min, and 20 μL was sampled to determine the content of paeonol. , Paeonol API was selected as the control group. The dissolution test results are shown in Figure 6. It can be seen from Figure 6 that the cumulative dissolution of CD-MOF-Paeonol within 60min is 97.3%; however, the cumulative dissolution of Paeonol API within 60min is 40.4%, indicating that CD-MOF can effectively The effect of promoting the dissolution of paeonol.

Cytotoxicity evaluation of CD-MOF-paeonol prepared in Example 2: Human alveolar basal epithelial cells A549 cells were used to evaluate the pulmonary toxicity of CD-MOF-paeonol. 10 ³ cells/well were inoculated in 96-well plate, the final volume of each well was 200 μL, and cultured overnight. Discard the supernatant, and add 200 μL of CD-MOF paeonol solutions with concentrations of 0.096, 0.48, 2.4, 12, 60 and 300 μg/mL respectively (first prepare CD-MOF-paeonol into 300 μg/mL stock solution with PBS, Dilute with RPMI1640 solution in turn to prepare gradient solution), and 200 μL of CD-MOF solution with concentrations of 10, 20, 50, 100, 200 and 500 μg/mL (first prepare CD-MOF with PBS to a 500 μg/mL stock solution, use in sequence RPMI1640 solution was diluted to prepare gradient solution), blank wells only contained culture medium, and cells and culture medium were added to the control group. After culturing in the incubator for 12 hours, 15 μL of CCK-8 solution was added to each well, and incubated at 37°C for 1 to 2 hours. The culture was terminated, the absorbance (A) value at 450 nm was detected with a microplate reader, the blank well was set to zero, and the cell viability was calculated. Calculated as follows:

Among them, OD _exp is the absorbance of the sample, OD _blank is the absorbance of the blank, and OD _control is the absorbance of the control sample.

The results of cytotoxicity evaluation are shown in Figure 7. It can be seen from Figures 7A-7B that when the concentration of CD-MOF-paeonol is in the range of 0.06-200 μg/mL and the concentration of CD-MOF is in the range of 10-500 μg/mL, the The cell survival was above 90%, and CD-MOF and CD-MOF paeonol had no obvious toxicity to A549 cells.

Example 3

Preparation of CD-MOF-Paeonol Dry Powder Inhaler

251，D₅₀为40-70μm)和2g实施例2制备的CD-MOF-丹皮酚，以一定的顺序(双层三明治法)将各成分加入到V型混合器：乳糖(1/3)—CD-MOF-丹皮酚(1/2)—乳糖(1/3)—CD-MOF-丹皮酚(1/2)—乳糖(1/3)。40r/min先预混合15min，继续以相同的转速混合15min，即得乳糖/CD-MOF-丹皮酚干粉吸入剂。将所得乳糖/CD-MOF-丹皮酚填充于3号明胶胶囊中，与单剂量胶囊型吸入给药装置组成最终的干粉吸入剂。NGI测定及流动性结果：乳糖/CD-MOF-丹皮酚干粉吸入剂的细粒子分数(FPF％)为26.73％，表明超过20％的药物粉体能够沉积到肺深部发挥药效；CD-MOF-丹皮酚的排空率为101.39±1.26％，表明制备的吸入粉体胶囊排空率较好。The CD-MOF-paeonol prepared in Example 2 is mixed with lactose, an acceptable adjuvant for dry powder inhalation: according to the mass ratio of CD-MOF-paeonol and lactose of 1:1, weigh 2g of lactose that has passed through a 100-mesh sieve respectively. (

251, D ₅₀ is 40-70 μm) and 2 g of CD-MOF-paeonol prepared in Example 2, add the ingredients to a V-blender in a certain order (double sandwich method): Lactose (1/3) -CD-MOF-Paeonol (1/2)-Lactose (1/3)-CD-MOF-Paeonol (1/2)-Lactose (1/3). 40r/min pre-mixed for 15min, continued to mix at the same speed for 15min, to obtain lactose/CD-MOF-paeonol dry powder inhaler. The obtained lactose/CD-MOF-paeonol was filled into No. 3 gelatin capsules and combined with a single-dose capsule type inhalation drug delivery device to form the final dry powder inhaler. NGI determination and fluidity results: The fine particle fraction (FPF%) of lactose/CD-MOF-paeonol dry powder inhaler was 26.73%, indicating that more than 20% of the drug powder could be deposited into the deep lung to exert its efficacy; CD- The emptying rate of MOF-paeonol was 101.39±1.26%, indicating that the prepared inhalation powder capsules had better emptying rate.

Example 4

Pharmacokinetic experiments:

30 healthy male rats, weighing 250 ± 30g, were divided into four groups: A, B, C, and D, with 6 rats in each group, group A (intravenous injection of paeonol solution), group B (pulmonary administration Lactose/CD-MOF-Paeonol dry powder inhalation prepared in Example 3), C group (oral gavage of paeonol CMC-Na suspension), D group (oral gavage of CD-MOF- Paeonol CMC-Na suspension), the administration dose was 4 mg/kg (calculated by the content of paeonol), and blood was collected at different times to determine the blood concentration of paeonol.

Determination method of paeonol in biological samples: C18 column Leapsil C18 (50mm×2.1mm, 2.7μm, Dima Technology Co., Ltd.) was used, and the mobile phase was 0.1% formic acid aqueous solution: acetonitrile (55:45, v/v), The flow rate was 0.3 mL/min, the injection volume was 10 μL, and the column temperature was 30 °C. A mass spectrometer was used in positive ion mode with multiple reaction monitoring, the m/z of the parent ion was 167.2, and the m/z of the product ion was 149.2 to collect the paeonol signal.

Pharmacokinetic Results

The average blood concentration-time curves of each group A-D are shown in Figure 8 and Table 1:

Table 1 Pharmacokinetic parameters (n=6, Mean±SD)

As can be seen from Figure 8 and Table 1, for lactose/CD-MOF paeonol dry powder inhalation, the average peak concentration and average AUC of the pulmonary administration group were significantly higher than those of the oral gavage group, and the average peak time was longer short. SPSS17.0 was used to perform t test on the experimental data. The results showed that there was a significant difference in the AUC between the C and D gavage groups and the B dry powder inhalation group (P<0.01), and the AUC of the C and D gavage groups had no significant difference. There was a significant difference in C _max between the C and D gavage groups and the B dry powder inhalation administration group (P<0.01), and there was no significant difference in C and D between the C and D _gavage groups. The results show that paeonol dry powder inhalation can significantly improve the bioavailability compared with oral administration.

Example 5

(1) CD-MOF-Paeonol was prepared according to the procedure of Example 2.

(2) CD-MOF-Paeonol is mixed with lactose, an acceptable excipient for dry powder inhalation:

230，D50为70～110μm)和细粉乳糖(

400，D50为4-11μm)，以一定的顺序(双层三明治法)将乳糖加入到V型不锈钢钢罐：粗乳糖(1/3)—细粉乳糖(1/2)—粗乳糖(1/3)—细粉乳糖(1/2)—粗乳糖(1/3)。混合机转速调至40r/min，混合15min，得到混合乳糖；然后以一定的顺序(双层三明治法)将混合乳糖和中性微米CD-MOF-丹皮酚加入到V型不锈钢钢罐：混合乳糖(1/3)—CD-MOF-丹皮酚(1/2)—混合乳糖(1/3)—CD-MOF-丹皮酚(1/2)—混合乳糖(1/3)，40r/min混合15min，继续40r/min混合15min，即得CD-MOF-丹皮酚，填充于3号明胶胶囊中，与单剂量胶囊型吸入给药装置可组成干粉吸入剂。NGI测定和流动性测定结果如表2，可以看出，当细乳糖比例为10％时细粒子分数(FPF％)最高为29.06％，表明约30％的药物粉体能够沉积到肺深部发挥药效；不同细乳糖含量的处方排空率均约为100％，表明制备的吸入粉体胶囊排空率好。Weigh CD-MOF-paeonol, crude lactose (

230, D50 is 70～110μm) and fine powder lactose (

400, D50 is 4-11μm), add lactose to the V-shaped stainless steel tank in a certain order (double-layer sandwich method): crude lactose (1/3) - fine powder lactose (1/2) - crude lactose (1 /3)—fine powder lactose (1/2)—crude lactose (1/3). The speed of the mixer was adjusted to 40r/min, and mixed for 15min to obtain mixed lactose; then the mixed lactose and neutral micron CD-MOF-paeonol were added to the V-shaped stainless steel tank in a certain order (double-layer sandwich method): mixing Lactose (1/3)—CD-MOF-Paeonol (1/2)—Mixed Lactose (1/3)—CD-MOF-Paeonol (1/2)—Mixed Lactose (1/3), 40r /min mixed for 15min, and continued to mix at 40r/min for 15min to obtain CD-MOF-paeonol, which was filled in No. 3 gelatin capsules and combined with a single-dose capsule inhalation drug delivery device to form a dry powder inhaler. The results of NGI measurement and fluidity measurement are shown in Table 2. It can be seen that when the proportion of fine lactose is 10%, the fine particle fraction (FPF%) is the highest at 29.06%, indicating that about 30% of the drug powder can be deposited in the deep lungs to exert drugs. The emptying rate of prescriptions with different fine lactose contents were all about 100%, indicating that the prepared inhalation powder capsules had good emptying rate.

400加入的丹皮酚干粉吸入剂的制备与评价Table 2 Lactose

Preparation and evaluation of paeonol dry powder inhaler with 400 added

Example 6

(1) Preparation of CD-MOF-Paeonol (PAE-CD-MOF):

The drug-carrying paeonol (PAE) is carried by the incubation method, including the steps of: weighing 3.0 g of paeonol into a 20-mL vial, adding 15 mL of absolute ethanol, and ultrasonically dissolving it. Weigh 0.5 g of the CD-MOF prepared in Example 1, add it to a vial, and stir magnetically for 1 h, 300 r/min, and a water bath of 30 °C. Centrifuge at 4000 r/min for 5 min, and precipitate the pellet by vacuum drying at 40° C. overnight to obtain CD-MOF-Paeonol (PAE-CD-MOF).

The obtained CD-MOF-paeonol is filled in No. 3 gelatin capsules, and can be combined with a single-dose capsule type inhalation drug delivery device to form a dry powder inhaler. The molar ratio of paeonol to CD-MOF was 5.09:1, the particle size was 1-5 μm, and the crystals of CD-MOF-paeonol were regular cubes, as shown in Figure 9.

(2) In vitro imaging experiments

Weigh 1.946g of γ-CD and 0.696g of KOH, add 15mL of pure water, ultrasonicate for 10min, and pass through a 0.45μm microporous membrane (aqueous) to obtain a mother liquor. Take 5 mL of mother liquor, add a certain amount of RhoB and 3 mL of methanol, the solution remains clear; react at 50 °C for 20 min, take it out and let it cool to room temperature. 32 mL of methanol solution (2.8 g/mL) and 64 mg of CTAB were rapidly added, and the solution was allowed to stand at room temperature for 3 h. Centrifuge at 4000 r/min for 5 min, discard the supernatant, use a certain concentration of glacial acetic acid-ethanol solution to wash the precipitate to neutrality, continue to use ethanol to wash the precipitate until the supernatant is no red, and dry the treated precipitate to obtain pellets. CD-MOF-RhoB with a diameter of 1-5 μm. After light anesthesia, DP-4 device was used for pulmonary administration of rats, and CD-MOF-RhoB powder was administered to each rat at 0min, 5min, 15min, 30min, 1h, 2h, 4h, 8h, 12h, and 24h at each time. The rats were euthanized and the lung tissue was completely removed. Fluorescence imaging was performed with an IVIS Spectrum instrument, and data acquisition was performed with Spectrum Living Image 4.0 software. The results are shown in Fig. 10A, and it can be seen from Fig. 10A that the lung fluorescence gradually weakened after administration, indicating that CD-MOF-RhoB was absorbed by the lung tissue. According to the relative quantification of fluorescence intensity, the absorption rate of CD-MOF-RhoB within 4h was about 97%, and the absorption rate within 5-30min was the fastest.

Weigh a certain amount of Paeonol API, place it in a round-bottomed flask, add absolute ethanol to dissolve, add the prepared CD-MOF-RhoB to the above solution, place it on a magnetic stirrer, fix the rotating speed, time and temperature, paeonol-CD-MOF-RhoB was finally obtained. Male SD rats were given CD-MOF-RhoB-paeonol, and the rats were euthanized at 0min, 5min, 15min, 30min, 2h, 6h, and 12h, respectively, and the lung tissue was immediately removed for fluorescence imaging. The results are shown in Figure 10B. It can be seen from Figure 10B that, similar to CD-MOF-RhoB, the fluorescence in the lungs gradually weakened within 0 to 30 minutes after administration, indicating that CD-MOF-RhoB-paeonol was absorbed by the lung tissue. absorb.

230，D₅₀为70～110μm)，以一定的顺序(双层三明治法)将各成分加入到V型混合器：乳糖(1/3)—CD-MOF-丹皮酚(1/2)—乳糖(1/3)—CD-MOF-丹皮酚(1/2)—乳糖(1/3)。40r/min先预混合15min，继续以相同的转速混合15min，即得乳糖/CD-MOF-丹皮酚。将所得乳糖/CD-MOF-丹皮酚填充于3号明胶胶囊中，与单剂量胶囊型吸入给药装置组成最终的干粉吸入剂。结果：乳糖/CD-MOF-丹皮酚干粉吸入剂的细粒子分数(FPF％)为21.25％，证明约20％的药物粉体能够沉积到肺深部发挥药效；排空率为101.58±1.41％，说明所制备的吸入粉体胶囊排空率很好。(3) CD-MOF-paeonol prepared in Example 6 is mixed with lactose, an acceptable adjuvant for dry powder inhalation: according to the mass ratio of CD-MOF-paeonol and lactose of 1:10, weigh 2g of 100 mesh sieved CD-MOF-paeonol and 20 g of lactose through a 100-mesh sieve (

230, _D50 is 70 ~ 110μm), add the ingredients to the V-type mixer in a certain order (double-layer sandwich method): Lactose (1/3)—CD-MOF-Paeonol (1/2)— Lactose (1/3)—CD-MOF-Paeonol (1/2)—Lactose (1/3). 40r/min pre-mixing for 15min, continue to mix at the same speed for 15min, namely lactose/CD-MOF-paeonol. The obtained lactose/CD-MOF-paeonol was filled into No. 3 gelatin capsules and combined with a single-dose capsule type inhalation drug delivery device to form the final dry powder inhaler. Results: The fine particle fraction (FPF%) of the lactose/CD-MOF-paeonol dry powder inhaler was 21.25%, which proved that about 20% of the drug powder could be deposited into the deep lung to exert its efficacy; the emptying rate was 101.58±1.41 %, indicating that the prepared inhalation powder capsule has a good emptying rate.

Example 7

(1) Preparation of CD-MOF: Dissolve a mixture of γ-CD (648.0 mg) and KOH (168.0 mg) (the molar ratio of γ-CD and KOH is 1:6, respectively) in 20 mL of water, and sonicate for 10 min to fully dissolve to obtain mother liquor. Then, 12 mL of methanol was added to the mother liquor, heated in a water bath at 50°C for 20 min, the solution was taken out, and 256 mg of PEG20000 was added and shaken to dissolve and disperse uniformly, and the reaction was continued for 10 min. The reaction solution was sonicated for 5 min respectively, then placed in a cold water bath and left to stand overnight (15°C), the reaction solution was taken out, centrifuged at 4000 r/min for 5 min, and the precipitate was washed twice with ethanol (12 mL) and methanol (12 mL) respectively. The crystals were vacuum-dried at 40°C for 12 h to obtain CD-MOF crystals. Take the CD-MOF crystals prepared above in a centrifuge cup, add anhydrous ethanol to disperse, add glacial acetic acid, stir well, centrifuge at 4000 r/min for 4 min, wash the precipitate three times with anhydrous ethanol, and place it in a 40°C vacuum drying oven to dry After 12 hours, CD-MOF crystals were obtained after drying, and the crystals were in the form of regular cubes with a particle size distribution of 1-5 μm.

(2) CD-MOF-paeonol was prepared according to Example 2, and the molar ratio of paeonol to CD-MOF in CD-MOF-paeonol was measured to be 2.65:1, the particle size was 1-5 μm, and the CD- MOF-paeonol crystals are in regular cubic shape.

230，D₅₀为70～110μm)进行混合，以一定的顺序(双层三明治法)将各成分加入到V型混合器：乳糖(1/3)—CD-MOF-丹皮酚(1/2)—乳糖(1/3)—CD-MOF-丹皮酚(1/2)—乳糖(1/3)。40r/min先预混合15min，继续以相同的转速混合15min，即得乳糖/CD-MOF-丹皮酚。将所得乳糖/CD-MOF-丹皮酚填充于3号明胶胶囊中，与单剂量胶囊型吸入给药装置组成最终的干粉吸入剂。结果：乳糖/CD-MOF-丹皮酚干粉吸入剂的细粒子分数(FPF％)为25.06％，证明约25％的药物粉体能够沉积到肺深部发挥药效，排空率为101.46±0.36％。(3) CD-MOF-paeonol prepared in the above step (2) is mixed with lactose, an acceptable adjuvant for dry powder inhalation: according to the mass ratio of CD-MOF-paeonol and lactose of 1:20, respectively weigh 2g CD -MOF-paeonol and 40g of lactose passed through a 100-mesh sieve (

230, D ₅₀ is 70 ~ 110μm) to mix, in a certain order (double sandwich method), add the ingredients to the V-type mixer: lactose (1/3)-CD-MOF-paeonol (1/2 )—lactose (1/3)—CD-MOF-paeonol (1/2)—lactose (1/3). 40r/min pre-mixing for 15min, continue to mix at the same speed for 15min, namely lactose/CD-MOF-paeonol. The obtained lactose/CD-MOF-paeonol was filled into No. 3 gelatin capsules and combined with a single-dose capsule type inhalation drug delivery device to form the final dry powder inhaler. Results: The fine particle fraction (FPF%) of lactose/CD-MOF-paeonol dry powder inhaler was 25.06%, which proved that about 25% of the drug powder could be deposited into the deep lung to exert its efficacy, and the emptying rate was 101.46±0.36 %.

Example 8

(1) CD-MOF-Paeonol was prepared according to Example 6, and the molar ratio of paeonol to CD-MOF in CD-MOF-Paeonol was measured to be 5.11:1, the particle size was 1-5 μm, and the crystal was Regular cube shape.

230，D50为70～110μm)，以等量递加的方式预混，再将预混粉体加入到V型混合器，40r/min混合15min，继续以相同的转速混合15min，即得乳糖/CD-MOF-丹皮酚。将所得乳糖/CD-MOF-丹皮酚填充于3号明胶胶囊中，与单剂量胶囊型吸入给药装置组成最终的干粉吸入剂。结果：乳糖/CD-MOF-丹皮酚干粉吸入剂的细粒子分数(FPF％)为28.43％，证明增加乳糖量能够使更多的药物粉体能够沉积到肺深部发挥药效，说明乳糖含量增加能够增加粉体的流动性，排空率为101.6±1.41％，说明吸入粉体胶囊排空率较好。(2) The CD-MOF-paeonol prepared in the above step (1) of this embodiment is mixed with lactose, an acceptable adjuvant for dry powder inhalation: according to the mass ratio of CD-MOF-paeonol and lactose of 1:50, respectively called Take 2g CD-MOF-Paeonol and 100g lactose (

230, D50 is 70 ~ 110μm), premix in an equal amount incremental manner, then add the premixed powder to the V-type mixer, mix at 40r/min for 15min, and continue to mix at the same speed for 15min, that is, lactose/ CD-MOF-Paeonol. The obtained lactose/CD-MOF-paeonol was filled into No. 3 gelatin capsules and combined with a single-dose capsule type inhalation drug delivery device to form the final dry powder inhaler. Results: The fine particle fraction (FPF%) of lactose/CD-MOF-paeonol dry powder inhaler was 28.43%, which proved that increasing the amount of lactose could make more drug powders can be deposited into the deep lungs for drug effect, indicating that the content of lactose The increase can increase the fluidity of the powder, and the emptying rate is 101.6±1.41%, indicating that the emptying rate of the inhaled powder capsule is better.

Example 9

(1) CD-MOF-Paeonol was prepared according to Example 6, and the molar ratio of paeonol to CD-MOF in CD-MOF-Paeonol was measured to be 4.98:1, the particle size was 1-5 μm, and the crystal was Regular cube shape.

230，D50为70～110μm)，以等量递加的方式预混，再将预混粉体加入到V型混合器，40r/min混合15min，继续以相同的转速混合15min，即得乳糖/CD-MOF-丹皮酚。将所得乳糖/CD-MOF-丹皮酚填充于3号明胶胶囊中，与单剂量胶囊型吸入给药装置组成最终的干粉吸入剂。结果：乳糖/CD-MOF-丹皮酚干粉吸入剂的细粒子分数(FPF％)为27.41％，说明乳糖含量增加到一定程度，对粉体的整体性质没有明显改善，排空率为102.1±1.41％，说明吸入粉体胶囊排空率较好。(2) The CD-MOF-paeonol prepared in the above step (1) of this embodiment is mixed with lactose, an acceptable adjuvant for dry powder inhalation: according to the mass ratio of CD-MOF-paeonol and lactose is 1:100, respectively called Take 2g CD-MOF-paeonol and 100g lactose (

230, D50 is 70 ~ 110μm), premix in an equal amount incremental manner, then add the premixed powder to the V-type mixer, mix at 40r/min for 15min, and continue to mix at the same speed for 15min, that is, lactose/ CD-MOF-Paeonol. The obtained lactose/CD-MOF-paeonol was filled into No. 3 gelatin capsules and combined with a single-dose capsule type inhalation drug delivery device to form the final dry powder inhaler. Results: The fine particle fraction (FPF%) of lactose/CD-MOF-paeonol dry powder inhaler was 27.41%, indicating that the increase of lactose content to a certain extent did not significantly improve the overall properties of the powder, and the emptying rate was 102.1±102.1± 1.41%, indicating that the emptying rate of inhaled powder capsules is better.

Example 10

(1) CD-MOF was prepared according to Example 1.

(2) Preparation of CD-MOF-budesonide by incubation method: Weigh 300 mg of budesonide into a 50 mL round-bottomed flask, add 20 mL of absolute ethanol to dissolve, then add 3.0 g of CD-MOF, and place the round-bottomed flask on a magnetic stirrer Incubate at 40°C and 500r/min for 3h, filter while hot, and vacuum dry the filter cake at 40°C for 12h. After drying, the powder is passed through a 60-mesh sieve to obtain CD-MOF-budesonide. The crystals are regular The cubic shape, the particle size distribution is 1 ~ 5μm.

Determination method of budesonide: C18 column Diamonsil C18 (4.5×250mm, 5μm), mobile phase is acetonitrile:5mM ammonium acetate aqueous solution (80:20, v/v), flow rate is 0.7mL/min, injection volume 5 μL; mass spectrometry detector, positive ion mode multiple reaction monitoring, parent ion m/z 431.2, product ion m/z 413.2 budesonide signal was collected.

The molar ratio of budesonide to CD-MOF is 0.06:1, CD-MOF-budesonide crystals are filled in No. 3 gelatin capsules, and combined with a single-dose capsule inhalation drug delivery device to form a budesonide dry powder inhaler.

Cytotoxicity evaluation results: When the concentration is less than 17μg/mL, CD-MOF-budesonide has no obvious toxicity to A549 cells.

Example 11

(1) CD-MOF was prepared according to Example 1.

(2) Preparation of CD-MOF-triamcinolone acetonide by incubation method: Weigh 50 mg of triamcinolone acetonide into a 50 mL round-bottomed flask, add 20 mL of absolute ethanol to dissolve, then add 5.0 g of CD-MOF, and place the round-bottomed flask in a magnetic stirrer Incubate at 40°C and 500r/min for 3h, then rotate at 60°C and 100r/min to remove the solvent, place it in a vacuum drying oven at 50°C for 12h and pass through a 60 mesh sieve to obtain CD-MOF- Triamcinolone acetonide crystals are regular cubes with a particle size distribution of 1 to 5 μm, wherein the molar ratio of triamcinolone acetonide to CD-MOF is 0.04:1, and CD-MOF-triamcinolone acetonide crystals are filled in No. 3 gelatin capsules , and a single-dose capsule-type inhalation delivery device to form a triamcinolone acetonide dry powder inhaler. NGI determination and fluidity results: The fine particle fraction (FPF%) of CD-MOF-triamcinolone acetonide dry powder inhalation is 30.02%, which proves that about 30% of the drug powder can be deposited into the deep lung to exert its efficacy; The emptying rate was 100.36±1.65%, which indicated that CD-MOF used in inhalation preparation carrier could carry the drug completely out of the capsule.

Example 12

(1) CD-MOF was prepared according to Example 1.

(2) Preparation of CD-MOF-ciclesonide by incubation method: Weigh 100 mg of ciclesonide into a 50 mL round-bottomed flask, add 20 mL of absolute ethanol to dissolve, then add 2.5 g of CD-MOF, and place the round-bottomed flask in a Incubate on a magnetic stirrer at 40°C and 500r/min for 3h, then rotate to remove the solvent at 60°C and 100r/min, place it in a vacuum drying oven at 50°C for 12h and pass through a 60 mesh sieve to obtain CD- MOF-ciclesonide crystals are in regular cubic shape, with a particle size distribution of 1-5μm, and the molar ratio of ciclesonide to CD-MOF is 0.11:1, which is filled in No. 3 gelatin capsules as the first mixture , and a single-dose capsule-type inhalation drug delivery device to form a dry powder inhaler. NGI determination and fluidity results: The fine particle fraction (FPF%) of CD-MOF-ciclesonide dry powder inhaler is 28.76%, which proves that about 30% of the drug powder can be deposited into the deep lung to exert its efficacy; CD-MOF The emptying rate of CD-MOF was 102.5±2.30%, indicating that the carrier of CD-MOF used for inhalation preparations can carry the drug and expel all the drugs from the capsule.

Example 13

(1) CD-MOF was prepared according to Example 1.

(2) Preparation of CD-MOF-roflumilast by incubation method: Weigh 100 mg of roflumilast into a 50 mL round-bottomed flask, add 20 mL of absolute ethanol to dissolve, then add 2.5 g of CD-MOF, and place the round-bottomed flask on the Incubate on a magnetic stirrer at 40°C and 500r/min for 3h, then rotate to remove the solvent at 60°C and 100r/min, place it in a vacuum drying oven at 50°C for 12h and pass through a 60 mesh sieve to obtain CD- MOF-roflumilast crystals are regular cubes with a particle size distribution of 1 to 5 μm. The molar ratio of roflumilast to CD-MOF is 0.15:1, and the CD-MOF-roflumilast crystals are filled in In No. 3 gelatin capsules, roflumilast dry powder inhalation is formed with a single-dose capsule type inhalation drug delivery device. NGI determination and fluidity results: The fine particle fraction (FPF%) of CD-MOF-roflumilast dry powder inhalation was 31.34%, which proved that about 30% of the drug powder could be deposited into the deep lungs to exert its efficacy; but CD- The emptying rate of MOF was 101.5±1.73%, which indicated that CD-MOF used in inhalation preparation carrier could carry the drug completely out of the capsule.

Example 14

(1) CD-MOF was prepared according to Example 1.

(2) Preparation of CD-MOF-glucocorticoid by incubation method: Weigh 50 mg of beclomethasone, dexamethasone, fluticasone and mometasone into 50 mL round-bottomed flasks, add 20 mL of absolute ethanol to dissolve, and then add 2.5 g of CD- MOF, place the round-bottomed flask on a magnetic stirrer and incubate at a certain temperature and rotation speed, then spin to remove the solvent, place it in a vacuum drying oven at 50 °C for 12 hours, and then pass through a 60-mesh sieve. The obtained sample is in the form of a regular cube. , the particle size distribution is 1~5μm, and the molar ratio of drug to CD-MOF is 0.02:1~0.04:1, filled in No. 3 gelatin capsule, and composed of a single-dose capsule type inhalation drug delivery device to form a drug dry powder inhaler . NGI determination and flowability results: The fine particle fraction (FPF%), Carr index, angle of repose and emptying rate of CD-MOF-glucocorticoid dry powder inhaler are shown in Table 4 below. Due to the cubic structure of CD-MOF, But the FPF% is still around 30%, and almost all the powder can be discharged from the capsule in the NGI test.

Table 4 NGI assay results

FPF% Evacuation rate % beclomethasone 33.78 98.45 Dexamethasone 28.45 102.8 Fluticasone 32.34 101.4 mometasone 25.40 99.83

Example 15

A mixture of 163.0 mg of γ-CD and 56.0 mg of KOH (the molar ratio of γ-CD and KOH is 1:8) was weighed and dissolved in 5 mL of water, fully dissolved by ultrasound for 10 minutes, and filtered with a 0.45 μm filter membrane. Then pre-add 0.5 mL of methanol to the mixed solution of γ-CD and KOH, heat methanol at 50°C in a closed container (the whole closed container is heated), and evaporate the methanol vapor into the mixed system of γ-CD and KOH. After 6 hours of reaction, take out the supernatant, add PEG 20000 at the ratio of 8 mg/mL supernatant, stand for half an hour, centrifuge at 3000 rpm for 5 min, and use ethanol (10 mL×2) and dichloromethane (10 mL×2) respectively. After washing, the obtained crystals were vacuum-dried at 50° C. for 12 h to obtain a micron-scale CD-MOF with a size of 1-10 μm. Take the CD-MOF crystals prepared above in a centrifuge cup, add anhydrous ethanol to disperse, add glacial acetic acid, stir well, centrifuge at 4000 r/min for 4 min, wash the precipitate three times with anhydrous ethanol, and place it in a 40°C vacuum drying oven to dry After 12 hours, CD-MOF crystals were obtained after drying, and the crystals were in the form of regular cubes and the particle size distribution was 1-10 μm. NGI measurement and fluidity results: The fine particle fraction (FPF%) of CD-MOF with a size of 1-10 μm was 10.33%, which proved that the amount of drug powder deposited into the deep lung decreased significantly when the particle size increased; The emptying rate of MOF was 101.5 ± 1.73%, indicating that the increase in size had no significant effect on CD-MOF expulsion from the capsule.

Example 16

Weigh 163.0 mg of γ-CD and 56.0 mg of KOH mixture (the molar ratio of γ-CD and KOH is 1:8) and dissolve it in 5 mL of water, pre-add 3 mL of methanol to the mixed solution, heat it in a water bath at 50 °C for 20 min, take out the solution, add etc. volume of methanol, then add 64 mg of PEG 20000, and after standing for half an hour, centrifuge at 3000 rpm for 5 min, wash with ethanol (10 mL×2) and dichloromethane (10 mL×2) respectively, and dry the obtained crystals in vacuum at 50°C for 12 h to obtain Nano-scale CD-MOF crystal (CD-MOF Nano), size is 200-500nm. Take the CD-MOF crystals prepared above in a centrifuge cup, add anhydrous ethanol to disperse, add glacial acetic acid, stir well, centrifuge at 4000 r/min for 4 min, wash the precipitate three times with anhydrous ethanol, and place it in a 40°C vacuum drying oven to dry After 12 hours, CD-MOF crystals were obtained after drying, and the crystals were in the form of regular cubes and the particle size distribution was 200-500 nm. NGI measurement and flowability results: The fine particle fraction (FPF%) of CD-MOF with a size of 200-500 nm was 4.69%, which proves that the amount of drug powder deposited into the deep lung is significantly reduced when the particle size is less than 1 μm, which may It is because the powder is too small to be excreted with exhalation; due to the reduction of particle size, the fluidity is worse than 1-5μm.

Example 17

(1) CD-MOF was prepared according to Example 1.

(2) Preparation of CD-MOF-Paeonol by Cholesterol Modification: Weigh 1.44g of Paeonol API into a 250mL round-bottom flask, add 100mL of absolute ethanol, ultrasonicate for 10min, and fully dissolve. Then 250 mg of cholesterol was added and dissolved by sonication. Then 5.0 g of CD-MOF crystals were weighed, added to a round-bottomed flask, and stirred for 1 h at 30° C. and 300 r/min in the dark. Then, the solvent was removed by rotary evaporation at 60°C and 100 r/min, dried in a vacuum drying oven at 50°C for 12 hours, and then passed through a 60-mesh sieve to obtain cholesterol CD-MOF-paeonol crystals, which were in the form of regular cubes. The diameter is distributed in the range of 1 to 7 μm. The molar ratio of paeonol to CD-MOF in CD-MOF-paeonol was measured to be 2.63:1.

230，D50为870～110μm)进行混合，以一定的顺序(双层三明治法)将各成分加入到V型混合器：乳糖(1/3)—胆固醇-CD-MOF-丹皮酚(1/2)—乳糖(1/3)—胆固醇-CD-MOF-丹皮酚(1/2)—乳糖(1/3)。40r/min先预混合15min，继续以相同的转速混合15min，即得乳糖/CD-MOF-丹皮酚。将所得乳糖/CD-MOF-丹皮酚填充于3号明胶胶囊中，与单剂量胶囊型吸入给药装置组成丹皮酚干粉吸入剂。结果：乳糖/CD-MOF-丹皮酚干粉吸入剂的细粒子分数(FPF)为25.24％，排空率为101.37±0.24％，说明CD-MOF用于吸入制剂载体能携带药物全部从胶囊中排出。(3) Mix cholesterol-CD-MOF-paeonol with lactose, an acceptable excipient for dry powder inhalation: according to the mass ratio of CD-MOF-paeonol and lactose of 1:5, weigh 2g CD-MOF-paeonol respectively. phenol and 10g lactose (

230, D50 is 870 ~ 110μm) for mixing, and each component is added to the V-type mixer in a certain order (double-layer sandwich method): lactose (1/3)-cholesterol-CD-MOF-paeonol (1/ 2)—Lactose (1/3)—Cholesterol—CD-MOF—Paeonol (1/2)—Lactose (1/3). 40r/min pre-mixing for 15min, continue to mix at the same speed for 15min, namely lactose/CD-MOF-paeonol. The obtained lactose/CD-MOF-paeonol was filled in No. 3 gelatin capsules, and combined with a single-dose capsule type inhalation drug delivery device to form a paeonol dry powder inhaler. Results: The fine particle fraction (FPF) of lactose/CD-MOF-paeonol dry powder inhaler was 25.24%, and the emptying rate was 101.37±0.24%, indicating that CD-MOF used for inhalation preparation carrier can carry all the drugs out of the capsule discharge.

Example 18

(1) CD-MOF was prepared according to Example 1.

(2) Preparation of cholesterol-CD-MOF-budesonide: Weigh 300 mg of budesonide into a 50 mL round-bottomed flask, add 20 mL of absolute ethanol to dissolve, then add 150 mg of cholesterol, and add 150 mg of cholesterol to the round-bottomed flask after the cholesterol is dissolved. 3.0g CD-MOF, put the round-bottomed flask on a magnetic stirrer at 40°C and stirred at 500r/min for 3h, then take it out, filter it while hot, and vacuum dry the filter cake at 40°C for 12h. Mesh sieve to obtain cholesterol-CD-MOF-budesonide, the crystals are in regular cubic shape, the particle size distribution is 1-5 μm, and the molar ratio of budesonide to CD-MOF is 0.1:1. The obtained cholesterol-CD-MOF-budesonide was filled in No. 3 gelatin capsules and combined with a single-dose capsule inhalation drug delivery device to form a budesonide dry powder inhaler.

NGI measurement results: the ejection fraction (EF) was 41.39±1.86%, the fine particle fraction (FPF) was 36.76±0.98%, the respirable fraction (RF) was 75.80±1.00%, the MMAD was 3.86±0.08 μm, and the GSD was 1.99±0.00 μm, it is proved that more than 30% of the drug powder can be deposited into the deep lung to exert the drug effect, as shown in Figure 11.

The crystal form determination of the dry powder by X-ray powder diffractometer showed that the crystal peak of CD-MOF remained unchanged after the cholesterol surface modification and further encapsulation of budesonide, indicating that the preparation process did not affect the crystallization of CD-MOF. degree and structure. However, the characteristic peaks of budesonide and cholesterol disappeared after interacting with CD-MOF, as shown in Figure 12.

(3) Preparation of leucine/poloxamer-CD-MOF-budesonide: the mass ratio of leucine:poloxamer:CD-MOF was 2:2:5 for drug loading, and 225.0 mg were weighed respectively The budesonide was placed in a 100mL round-bottomed flask, and 20mL of absolute ethanol was added to ultrasonically dissolve it completely. , under the condition of 60℃, 600r/min, magnetic stirring for 2h, then rotary-evaporated to remove the solvent at 60℃, 100r/min, placed in a vacuum drying oven at 50℃ for 12h and passed through a 60-mesh sieve to obtain leucine The acid/poloxamer-CD-MOF-budesonide crystal has a regular cubic shape with a particle size distribution of 1-7 μm, wherein the molar ratio of budesonide to CD-MOF is 0.06:1. The obtained leucine/poloxamer-CD-MOF-budesonide was filled into No. 3 gelatin capsules, and combined with a single-dose capsule type inhalation drug delivery device to form a budesonide dry powder inhalation.

The results of leucine/poloxamer-CD-MOF-budesonide dry powder inhalation, bulk density, tap density, compressibility, angle of repose and in vitro lung deposition are shown in Table 5.

Table 5 In vitro deposition data of leucine/poloxamer-CD-MOF-budesonide dry powder inhaler

(4) Take 12 healthy male rats with a body weight of 250 ± 20g and divide them into two groups: A and B. Group A is the administration group of the commercial preparation of budesonide (Pulmicort), and group B is the self-made budesonide. Formulation (cholesterol-CD-MOF-budesonide) administration group, 6 rats in each group. The rats were fasted for 12 hours before the experiment, and lightly anesthetized with isoflurane before the experiment, and the actual dose was calculated by the weight loss method. Each budesonide commercial preparation group was given about 0.18-0.37 mg of budesonide dry powder inhalation, and each self-made preparation group was given about 14-18 mg of cholesterol-CD-MOF-budesonide dry powder inhalation.

The concentration of budesonide in the plasma of the rats in the cholesterol-CD-MOF-budesonide group rose rapidly after pulmonary administration, and the peak concentration could be reached within 30 min, and then quickly eliminated. AUC), statistical analysis showed no significant difference.

Example 19

About 600 mg of CD-MOF prepared in Example 1 was weighed, added to acetonitrile solutions containing AgNO ₃ with concentrations of 2.5, 5 and 10 mM and HAuCl ₄ with concentrations of 0.5 and 1 mM, respectively, and incubated for 72 h. The samples were centrifuged and the precipitate was washed several times with acetonitrile to remove unreacted impurities. The samples were vacuum dried at 40 °C for 12 h to obtain Ag@CD-MOF samples. 500 mg of Ag@CD-MOF crystals were added to a saturated solution of levofloxacin in acetonitrile, and incubated with stirring at 40 °C at 400 r/min. The reaction was stopped after 24 h, centrifuged at 4000 r/min for 5 min, and the supernatant was separated to obtain levofloxacin-Ag@CD-MOF crystals, which were regular cubes with a particle size distribution of 2-3 μm. The morphology of the crystal structure was analyzed by optical microscopy, and the loading of levofloxacin (the drug loading was 10%) was determined by UV-Vis spectrophotometer. The obtained levofloxacin-Ag@CD-MOF crystals were filled in No. 3 gelatin capsules, and combined with a single-dose capsule inhalation drug delivery device to form a levofloxacin-Ag dry powder inhaler.

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content 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 appended claims of the present application.

Claims (10)

1. A preparation for respiratory tract administration, characterized in that, described preparation for respiratory tract administration comprises a drug-loaded cyclodextrin-metal organic framework; The drug-loaded cyclodextrin-metal organic framework includes: Cyclodextrin-metal organic framework; A drug supported on the cyclodextrin-metal organic framework. 2. The preparation for respiratory tract administration according to claim 1, characterized in that, said preparation for respiratory tract administration further comprises an adjuvant acceptable to the preparation for respiratory tract administration. 3. respiratory tract administration preparation as claimed in claim 2 is characterized in that, described respiratory tract administration preparation acceptable adjuvant is selected from the following group: D ₅₀ particle diameter is the lactose of 4-11 μ m, D ₅₀ particle diameter is Lactose of 40-70 μm, lactose with a _D50 particle size of 70-110 μm, or a combination thereof. 4. The formulation for respiratory administration of claim 1, wherein the formulation for administration to the respiratory tract comprises one or more features selected from the group consisting of: The particle size of the drug-loaded cyclodextrin-metal organic framework is 0.2-10 μm, preferably 1-5 μm; The cyclodextrin-metal organic framework is in the form of cubes; The particle size of the cyclodextrin-metal organic framework is 1-5 μm; and/or The BET specific surface area of the cyclodextrin-metal organic framework is 200-1200m ² /g, preferably 300-1100m ² /g, more preferably 400-1000m ² /g, and most preferably 400-600m ² / g; The cyclodextrin-metal-organic framework is selected from the group consisting of surface-unmodified cyclodextrin-metal-organic framework, surface-modified cyclodextrin-metal-organic framework, or a combination thereof. 5. The respiratory tract administration preparation of claim 4, wherein the surface modifier of the surface-modified cyclodextrin-metal organic framework is selected from the group consisting of cholesterol, leucine, poloxamer, Pyrene, ferrocene, polypeptides, peroxides, polyisocyanates, glycidyl ethers such as ethylene glycol diglycidyl ether, dibasic or polybasic acids, dibasic or polybasic aldehydes, carbonyl-containing compounds, epoxy compounds, acrylates, succinyl chloride, or a combination thereof. 6. The respiratory tract administration preparation of claim 1, wherein the cyclodextrin-metal organic framework is prepared by the following method, the method comprising: (1) providing a first mixed solution, the first mixed solution is a solution containing metal ions and cyclodextrin; (2) adding the first organic solvent to the first mixed solution to obtain the second mixed solution; Wherein, the volume ratio of the first organic solvent to the first mixed solution is (0.01-5): 1, preferably (0.1-2): 1, preferably 0.3-1.0: 1, the best Ground is (0.4-0.8): 1; (3) adding a size regulator to the second mixed solution to form a third mixed solution; (4) The third mixed solution is cooled and separated to obtain the precipitated cyclodextrin-metal organic framework material. 7. The formulation for respiratory tract administration of claim 1, wherein the formulation for respiratory tract administration is a dry powder inhaler. 8. A method for preparing a formulation for respiratory tract administration according to claim 1, wherein the method comprises the steps of: combining the drug-loaded cyclodextrin-metal organic framework with optionally respiratory tract administration The adjuvant acceptable for the pharmaceutical preparation is mixed to obtain a preparation for respiratory tract administration. 9. A use of a cyclodextrin-metal organic framework or a drug-loaded cyclodextrin-metal organic framework, characterized in that it is used to prepare a preparation for respiratory administration. 10. A device for nasal administration, characterized in that the device comprises an inhalation device and the formulation for administration to the respiratory tract as claimed in claim 1.

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