CN118787617A - Inhalation powder and preparation method thereof - Google Patents

Abstract

The invention discloses an inhalation powder and a preparation method thereof, and belongs to the technical field of dry powder inhalation. The inhalation powder comprises the following components in parts by weight: 0.06-0.10 parts of _CaCl2 , 0.80-1.50 parts of distearoylphosphatidylcholine, 0.2-2 parts of diketopiperazine fumarate, 0.3-0.5 parts of a drug having an acidic functional group, and a solvent system. The invention uses diketopiperazine fumarate (FDKP) to adsorb fine drug particles to reduce agglomeration, and uses distearoylphosphatidylcholine (DSPC) to produce sponge-like porous structure particles, thereby reducing the aerodynamic particle size. In this structure, the raw material particles are adsorbed onto the flaky structure generated by FDKP, which effectively increases the absorption rate. At the same time, the excellent aerodynamic properties of the porous structure significantly reduce the deposition in the oropharynx, fully reducing the cough and choking sensation, which is beneficial to increase the patient's compliance with drug administration and improve the efficacy.

Description

Inhalation powder and preparation method thereof

Technical Field

The present invention relates to the technical field of dry powder inhalation, in particular to an inhalation powder and a preparation method thereof.

Background Art

Compared with traditional drug delivery methods, pulmonary drug delivery has the advantages of being fast, efficient, and having good patient compliance, and is the most direct and effective route of drug delivery. However, in the process of inhalation drug delivery, certain compounds are salts with carboxyl groups or acids, which can cause coughing and throat choking after inhalation. Coughing can cause the inhaled drug to be exhaled from the body, resulting in low drug delivery efficiency or failure to achieve drug lung deposition.

For example, the marketed semaglutide products are mainly injections and oral tablets, but just like insulin, the oral peptide GLP-1RA molecule is easily destroyed by proteases and gastric acid in the gastrointestinal tract and is difficult to absorb. Pulmonary administration of peptides can avoid the destruction of gastrointestinal enzymes or acidic gastric juice, while improving the efficiency of drug administration.

Vardenafil hydrochloride increases the release of local endogenous nitric oxide in the corpus cavernosum under sexual stimulation by inhibiting phosphodiesterase type 5 (PDE5) that degrades cGMP in the human corpus cavernosum, thereby enhancing the natural response to sexual stimulation. It is widely used in the clinic to treat male erectile dysfunction, and there are also many reports on its therapeutic effects on pulmonary vascular disease and pulmonary hypertension. However, the bioavailability of vardenafil hydrochloride after oral administration is only 20%, and there are also facial flushing, increased blood pressure and gastrointestinal adverse reactions. Inhalation administration can improve the above adverse reactions and increase bioavailability.

However, since semaglutide and vardenafil hydrochloride contain multiple carboxyl groups or hydrochlorides, they cause a significant coughing sensation after inhalation, causing the inhaled drug particles to be exhaled out of the body. Currently, such products are usually administered by liquid inhalation, using buffered salts to alleviate the coughing sensation, and there is no effective solution for dry powder inhalation administration.

Summary of the invention

The purpose of the present invention is to provide an inhalation powder and a preparation method thereof to solve the problems existing in the above-mentioned prior art.

To achieve the above object, the present invention provides the following solutions:

One of the technical solutions of the present invention is an inhalation powder, which is made of the following components in parts by weight: 0.06-0.10 parts of CaCl ₂ , 0.80-1.50 parts of distearoylphosphatidylcholine, 0.2-2 parts of diketopiperazine fumarate, 0.3-0.5 parts of a drug containing an acidic functional group, and 120-150 parts of a solvent system;

The solvent system is a mixed solution of perfluorooctane bromide and distilled water in a volume ratio of 1:6-1:10;

The drug containing an acidic functional group is semaglutide or vardenafil hydrochloride.

The second technical solution of the present invention is a method for preparing the inhalation powder, comprising the following steps:

(1) mixing a drug containing an acidic functional group with diketopiperazine fumarate to undergo a combination reaction to obtain component 1;

(2) After emulsifying DSPC and PFOB, _CaCl2 was added as a stabilizer to obtain component 2;

(3) Component 1 and component 2 are mixed and then spray-dried to collect the powder, which is the inhalation powder.

Based on the above technical solution, the present invention has the following technical effects:

The present invention uses fumaric acid diketopiperazine (FDKP) to adsorb fine drug particles to reduce agglomeration, and uses distearoylphosphatidylcholine (DSPC) to produce sponge-like porous structure particles, thereby reducing the aerodynamic particle size. In this structure, the raw material particles are adsorbed onto the flaky structure generated by FDKP, which effectively increases the absorption rate. At the same time, the excellent aerodynamic properties of the porous structure significantly reduce the deposition in the oropharynx, fully reducing the cough and choking sensation, which is beneficial to increase the patient's compliance with drug administration and improve the efficacy. The present invention uses a pharmaceutical composition to improve the process technology of causing coughing and throat coughing and choking sensations in raw materials containing carboxyl or acidic functional groups during inhalation, which can improve the patient's compliance and drug administration efficiency when the drug is used in a dry powder inhalation preparation, and avoid the problem of low drug administration efficiency caused by the exhalation of inhaled drugs due to coughing behavior.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

FIG1 shows the shape and size of the inhalation powder prepared in Example 1 of the present invention under a scanning electron microscope.

FIG2 shows the shape and size of the inhalation powder prepared in Example 2 of the present invention under a scanning electron microscope.

FIG3 shows the shape and size of the inhalation powder prepared in Example 3 of the present invention under a scanning electron microscope.

FIG4 shows the shape and size of the inhalation powder prepared in Example 4 of the present invention under a scanning electron microscope.

FIG5 shows the shape and size of the inhalation powder prepared in Example 5 of the present invention under a scanning electron microscope.

FIG6 shows the shape and size of the inhalation powder prepared in Example 6 of the present invention under a scanning electron microscope.

7 shows the plasma concentrations of the inhalation powder prepared in Comparative Example 1 of the present invention in mice at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 24, 48, and 72 h after administration.

8 shows the plasma concentrations of the inhalation powder prepared in Comparative Example 2 of the present invention at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 24, 48, and 72 h after administration in mice.

FIG9 shows the plasma concentration of the inhalation powder prepared in Example 2 of the present invention at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 24, 48, and 72 h after administration in mice.

Figure 10 shows the plasma concentrations of the inhalation powder prepared in Comparative Example 3 of the present invention at 0, 0.083, 0.167, 0.33, 0.5, 1, 2, 6, 10, and 24h of administration in mice.

FIG11 shows the plasma concentrations of the inhalation powder prepared in Example 5 of the present invention in mice at 0, 0.083, 0.167, 0.33, 0.5, 1, 2, 6, 10, and 24 h after administration.

DETAILED DESCRIPTION

Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

It should be understood that the terms described in the present invention are only for describing special embodiments and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and/or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to those skilled in the art. The present application description and examples are exemplary only.

The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

The technical solutions described in the present invention, unless otherwise specified, are all conventional solutions in the art, and the reagents or raw materials used, unless otherwise specified, are purchased from commercial channels or have been disclosed.

The embodiment of the present invention provides an inhalation powder, which is prepared from the following components in parts by weight: 0.06-0.10 parts of CaCl ₂ , 0.80-1.50 parts of distearoylphosphatidylcholine, 0.2-2 parts of diketopiperazine fumarate, 0.3-0.5 parts of a drug containing an acidic functional group, and 120-150 parts of a solvent system;

The solvent system is a mixed solution of perfluorooctane bromide and distilled water in a volume ratio of 1:6-1:10;

The drug containing an acidic functional group is semaglutide or vardenafil hydrochloride.

In some specific embodiments, the following components are included in parts by weight: 0.08 parts of CaCl ₂ , 1.1-1.5 parts of distearoylphosphatidylcholine, 1 part of diketopiperazine fumarate, 0.4 parts of a drug containing an acidic functional group, and 140 parts of a solvent system.

The present invention uses fumaric acid diketopiperazine (FDKP) to adsorb fine drug particles to reduce agglomeration, and uses distearoylphosphatidylcholine (DSPC) to produce sponge-like porous structure particles to reduce the aerodynamic particle size. In this structure, the raw material particles are adsorbed onto the scaly structure generated by FDKP, which effectively increases the absorption rate. At the same time, the excellent aerodynamic properties of the porous structure significantly reduce the deposition in the oropharynx, fully reducing the cough and choking sensation, which is conducive to increasing the patient's compliance with medication and improving the efficacy.

The embodiment of the present invention also provides a method for preparing the inhalation powder, comprising the following steps:

(1) mixing a drug containing an acidic functional group with diketopiperazine fumarate to undergo a combination reaction to obtain component 1;

(2) After emulsifying DSPC and PFOB, _CaCl2 was added as a stabilizer to obtain component 2;

(3) Component 1 and component 2 are mixed and then spray-dried to collect the powder, which is the inhalation powder.

In some specific embodiments, the binding reaction conditions are: the binding reaction occurs at pH 2.5-3.5 for 10-20 minutes.

In some specific embodiments, the emulsification method is high pressure homogenization.

Example 1

A semaglutide inhalation powder and a preparation method thereof. The raw materials include: _0.08 parts of CaCl2, 1 part of distearoylphosphatidylcholine, 2 parts of diketopiperazine fumarate, 0.4 parts of a drug containing an acidic functional group, and 140 parts of a solvent system.

The solvent system is a mixed solution of perfluorooctyl bromide and distilled water, and the volume ratio of perfluorooctyl bromide to distilled water is 1:8. The preparation method comprises the following steps:

S01: Combine semaglutide, a drug containing an acidic functional group, with FDKP at pH 2.5-3.5 with a loading of 10%-80% to obtain component 1;

S02: DSPC and PFOB were emulsified by stirring at a constant speed for 20-30 min under a homogenizer, and CaCl ₂ was added as a stabilizer at a molar ratio of DSPC:CaCl ₂ =2:1 to obtain component 2;

S03: Component 1 and component 2 are mixed under stirring conditions and then spray-dried, and the dried powder is collected in a cyclone separator.

Example 2

A semaglutide inhalation powder and a preparation method thereof. The raw materials include: _0.08 parts of CaCl2, 1 part of distearoylphosphatidylcholine, 1 part of diketopiperazine fumarate, 0.4 parts of a drug containing an acidic functional group, and 140 parts of a solvent system.

The solvent system is a mixed solution of perfluorooctyl bromide and distilled water, and the volume ratio of perfluorooctyl bromide to distilled water is 1:8. The preparation method comprises the following steps:

S01: Combine semaglutide, a drug containing an acidic functional group, with FDKP at pH 2.5-3.5 with a loading of 10%-80% to obtain component 1;

S02: DSPC and PFOB were emulsified by stirring at a constant speed for 20-30 min under a homogenizer, and CaCl ₂ was added as a stabilizer at a molar ratio of DSPC:CaCl ₂ =2:1 to obtain component 2;

S03: Component 1 and component 2 are mixed under stirring conditions and then spray-dried, and the dried powder is collected in a cyclone separator.

Example 3

A semaglutide inhalation powder and a preparation method thereof. The raw materials include: _0.08 parts of CaCl2, 1 part of distearoylphosphatidylcholine, 0.2 parts of diketopiperazine fumarate, 0.4 parts of a drug containing an acidic functional group, and 140 parts of a solvent system.

The solvent system is a mixed solution of perfluorooctyl bromide and distilled water in a ratio of 1:8.

The preparation method comprises the following steps:

S01: Combine semaglutide, a drug containing an acidic functional group, with FDKP at pH 2.5-3.5 with a loading of 10%-80% to obtain component 1;

S02: DSPC and PFOB were emulsified by stirring at a constant speed for 20-30 min under a homogenizer, and CaCl ₂ was added as a stabilizer at a molar ratio of DSPC:CaCl ₂ =2:1 to obtain component 2;

S03: Component 1 and component 2 are mixed under stirring conditions and then spray-dried, and the dried powder is collected in a cyclone separator.

Example 4

A vardenafil inhalation powder and a preparation method thereof. The raw materials include: _0.08 parts of CaCl2, 1 part of distearoylphosphatidylcholine, 2 parts of diketopiperazine fumarate, 0.4 parts of a drug containing an acidic functional group, and 140 parts of a solvent system.

The solvent system is a mixed solution of perfluorooctyl bromide and distilled water, and the volume ratio of perfluorooctyl bromide to distilled water is 1:8. The preparation method comprises the following steps:

S01: Combine vardenafil, a drug containing an acidic functional group, with FDKP at pH 2.5-3.5 with a loading of 10%-80% to obtain component 1;

S02: DSPC and PFOB were emulsified by stirring at a constant speed for 20-30 min under a homogenizer, and CaCl ₂ was added as a stabilizer at a molar ratio of DSPC:CaCl ₂ =2:1 to obtain component 2;

S03: Component 1 and component 2 are mixed under stirring conditions and then spray-dried, and the dried powder is collected in a cyclone separator.

Example 5

A vardenafil inhalation powder and a preparation method thereof. The raw materials include: _0.08 parts of CaCl2, 1 part of distearoylphosphatidylcholine, 1 part of diketopiperazine fumarate, 0.4 parts of a drug containing an acidic functional group, and 140 parts of a solvent system.

The solvent system is a mixed solution of perfluorooctyl bromide and distilled water, and the volume ratio of perfluorooctyl bromide to distilled water is 1:8. The preparation method comprises the following steps:

S01: Combine vardenafil, a drug containing an acidic functional group, with FDKP at pH 2.5-3.5 with a loading of 10%-80% to obtain component 1;

S02: DSPC and PFOB were emulsified by stirring at a constant speed for 20-30 min under a homogenizer, and CaCl ₂ was added as a stabilizer at a molar ratio of DSPC:CaCl ₂ =2:1 to obtain component 2;

S03: Component 1 and component 2 are mixed under stirring conditions and then spray-dried, and the dried powder is collected in a cyclone separator.

Example 6

A vardenafil inhalation powder and a preparation method thereof. The raw materials include: _0.08 parts of CaCl2, 1 part of distearoylphosphatidylcholine, 0.2 parts of diketopiperazine fumarate, 0.4 parts of a drug containing an acidic functional group, and 140 parts of a solvent system.

The solvent system is a mixed solution of perfluorooctyl bromide and distilled water, and the volume ratio of perfluorooctyl bromide to distilled water is 1:8. The preparation method comprises the following steps:

S01: Combine vardenafil, a drug containing an acidic functional group, with FDKP at pH 2.5-3.5 with a loading of 10%-80% to obtain component 1;

S02: DSPC and PFOB were emulsified by stirring at a constant speed for 20-30 min under a homogenizer, and CaCl ₂ was added as a stabilizer at a molar ratio of DSPC:CaCl ₂ =2:1 to obtain component 2;

S03: Component 1 and component 2 are mixed under stirring conditions and then spray-dried, and the dried powder is collected in a cyclone separator.

Comparative Example 1

A semaglutide inhalation powder and a preparation method thereof. The raw materials include: _0.08 parts of CaCl2, 1 part of diketopiperazine fumarate, 0.4 parts of a drug containing an acidic functional group, and 140 parts of a solvent system.

The solvent system is a mixed solution of perfluorooctyl bromide and distilled water, and the volume ratio of perfluorooctyl bromide to distilled water is 1:8.

The preparation method comprises the following steps:

S01: Combine semaglutide, a drug containing an acidic functional group, with FDKP at pH 2.5-3.5 with a loading of 10%-80% to obtain component 1;

S02: PFOB was stirred at a constant speed for 10-20 min under a homogenizer, and CaCl ₂ was added as a stabilizer to obtain component 2;

S03: Component 1 and component 2 are mixed under stirring conditions and then spray-dried, and the dried powder is collected in a cyclone separator.

Comparative Example 2

A semaglutide inhalation powder and a preparation method thereof. The raw materials include: _0.08 parts of CaCl2, 1 part of distearoylphosphatidylcholine, 0.4 parts of a drug containing an acidic functional group, and 140 parts of a solvent system.

The solvent system is a mixed solution of perfluorooctyl bromide and distilled water, and the volume ratio of perfluorooctyl bromide to distilled water is 1:8. The preparation method comprises the following steps:

S01: dissolving semaglutide, a drug containing an acidic functional group, in water to obtain component 1;

S02: DSPC and PFOB were emulsified by stirring at a constant speed for 20-30 min under a homogenizer, and CaCl ₂ was added as a stabilizer at a molar ratio of DSPC:CaCl ₂ =2:1 to obtain component 2;

S03: Component 1 and component 2 are mixed under stirring conditions and then spray-dried, and the dried powder is collected in a cyclone separator.

Comparative Example 3

A vardenafil inhalation powder and a preparation method thereof. The raw materials include: _0.08 parts of CaCl2, 1 part of diketopiperazine fumarate, 0.4 parts of a drug containing an acidic functional group, and 140 parts of a solvent system.

The solvent system is a mixed solution of perfluorooctyl bromide and distilled water, and the volume ratio of perfluorooctyl bromide to distilled water is 1:8.

The preparation method comprises the following steps:

S01: Combine vardenafil, a drug containing an acidic functional group, with FDKP at pH 2.5-3.5 with a loading of 10%-80% to obtain component 1;

S02: PFOB was stirred at a constant speed for 10-20 min under a homogenizer, and CaCl ₂ was added as a stabilizer to obtain component 2;

S03: Component 1 and component 2 are mixed under stirring conditions and then spray-dried, and the dried powder is collected in a cyclone separator.

Comparative Example 4

A vardenafil inhalation powder and a preparation method thereof. The raw materials include: _0.08 parts of CaCl2, 1 part of distearoylphosphatidylcholine, 0.4 parts of a drug containing an acidic functional group, and 140 parts of a solvent system.

The solvent system is a mixed solution of perfluorooctyl bromide and distilled water, and the volume ratio of perfluorooctyl bromide to distilled water is 1:8.

The preparation method comprises the following steps:

S01: dissolving vardenafil, a drug containing an acidic functional group, in distilled water to obtain component 1;

S02: DSPC and PFOB were emulsified by stirring at a constant speed for 20-30 min under a homogenizer, and CaCl ₂ was added as a stabilizer at a molar ratio of DSPC:CaCl ₂ =2:1 to obtain component 2;

S03: Component 1 and component 2 are mixed under stirring conditions and then spray-dried, and the dried powder is collected in a cyclone separator.

Effect Example 1

1. Particle distribution test was performed on Examples 1 to 6. The particle distribution test was performed using a new generation impactor (NGI). NGI consists of seven stages and can be calibrated at flow rates of 30, 60, and 90 LPM. The specific test results of the particle distribution are shown in Table 1-2.

Table 1 Test results of particle distribution ^* of semaglutide inhalation powder

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Note: Device represents the amount remaining in the device; Capsule represents the amount remaining inside the capsule without being sucked out; Pre-separator represents the amount remaining in the pre-separator; Stage-1~MOC represents the amount of powder in the receiving tray; SUM represents the amount from the throat to the MOC; ISM represents the amount from stage-2 to the MOC; FPM represents the amount of fine particles; FPF represents the effective lung deposition; MMAD represents the median particle size; GSD represents the geometric standard deviation; R2 represents the model fit.

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Table 1 shows the particle distribution of semaglutide inhalation powder, and Table 2 shows the particle distribution of vardenafil inhalation powder. It can be seen from Tables 1 and 2 that the inhalation powders prepared by the present invention can be well deposited in the lungs, thereby improving the drug administration effect.

2 The particle size of Examples 1 to 6 was measured using a Sympatec laser particle size scanner. The particle size distribution measurement results are shown in Table 3.

Table 3 Particle size distribution measurement results of Examples 1 to 6

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Examples 1-3 show the particle size distribution of semaglutide inhalation powders, and Examples 4-6 show the particle size distribution of vardenafil inhalation powders. As shown in Table 3, the particle size distribution of the inhalation powders is appropriate, which is beneficial to improving the effect of pulmonary administration.

3 The spray-dried Examples 1 to 6 were measured using a scanning electron microscope to observe the morphology and size of the powders. The results are shown in Figures 1 to 6. Figures 1-3 are electron microscope images of semaglutide inhalation powders, and Figures 4-6 are electron microscope images of vardenafil inhalation powders. This experiment used the FDKP flaky structure to adsorb fine drug particles while DSPC produced porous structure particles, reducing the aerodynamic particle size.

4 Thirty healthy volunteers were recruited and used the dry powder inhalers of Examples 1 to 6 and Comparative Examples 1 to 2, respectively. The evaluation levels were divided into no coughing and choking sensation in the throat, slight coughing and choking sensation, and severe coughing and choking sensation. The number of people at each evaluation level was recorded. The results are shown in Table 4.

Table 4

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Examples 1-3 represent semaglutide inhalation powders prepared in combination with FDKP and DSPC, Examples 4-6 represent vardenafil inhalation powders prepared in combination with FDKP and DSPC, and Comparative Examples 1-2 represent semaglutide inhalation powders prepared with only FDKP/DSPC. As can be seen from Table 4, the combination of FDKP and DSPC significantly reduces the deposition of the drug in the oropharynx, can effectively reduce coughing and choking sensations, increase patient compliance with medication, and improve efficacy.

5 In order to investigate the efficacy of semaglutide, 160 patients with T2DM were selected as research subjects and divided into an observation group (Example 2, FDKP: DSPC = 1: 1) and a control group (oral semaglutide) by random number table method, 80 cases in each group. 3-5 mL of venous blood was collected on an empty stomach after administration, and fasting blood glucose (FBG) and 2-hour postprandial blood glucose (2h P-BG) were measured. Glycosylated hemoglobin (Hb A1c) was determined by high pressure liquid ion exchange chromatography separation method. The results are shown in Tables 5-7.

Table 5

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Table 6

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Table 7

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Tables 5 to 7 are data comparisons of inhalation and oral administration of semaglutide. Before treatment, there was no significant difference between the observation group and the control group in terms of fasting blood glucose, 2 h postprandial blood glucose and glycosylated hemoglobin. After administration, the effect of inhalation administration of semaglutide in reducing fasting blood glucose, 2 h postprandial blood glucose and glycosylated hemoglobin was better than that of oral semaglutide, indicating that the present invention can improve the therapeutic effect of semaglutide on blood glucose.

6 In order to investigate the efficacy of vardenafil, 40 volunteers were randomly divided into a control group (oral vardenafil) and an observation group (Example 5, FDKP: DSPC = 1: 1), and the drug was administered half an hour before sexual intercourse every day, 10 mg/time. The evaluation indicators were Traditional Chinese Medicine Symptoms (TCMS) (mainly including dizziness, soreness of waist and knees, chest tightness, sighing, tinnitus, and 5-level scoring (0-4 points) from mild to severe), Erection Quality Scale (EQS) (mainly including erection quality from duration, self-experience of the whole erection process, erection ability, sensitivity of the penis when stimulated, and penis hardness during erection), Erection Hardness (EHS) score, and penile hemodynamic parameters (penile hemodynamic parameters before and after treatment were detected, and the measuring instrument was ES-100V3 Doppler blood flow detector, which detected the peak systolic velocity (PSV), end diastolic velocity (EDV), and resistance index (RI)). The results are shown in Tables 8 to 11.

Table 8 TCMS score

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Table 9 EQS score

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Table 10 EHS score

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Table 11 Penile hemodynamic parameters

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Tables 8 to 11 are data comparisons of vardenafil inhalation and oral administration. Before treatment, there were no significant differences between the observation group and the control group in terms of Traditional Chinese Medicine Symptoms (TCMS), Erection Quality Scale (EQS), Erection Hardness (EHS) scores, and penile hemodynamic parameters. After administration, the scores of the vardenafil inhalation group were better than those of the oral vardenafil group, indicating that the present invention can improve the therapeutic effect of vardenafil on male penile erectile dysfunction.

Effect Example 2

1 The particle size distribution of Comparative Examples 1 to 4 was measured using a Sympatec laser particle size scanner. The results are shown in Table 12.

Table 12 Particle size distribution measurement results of Comparative Examples 1 to 4

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Comparative Example 1 is an inhalation powder prepared by combining semaglutide and FDKP, Comparative Example 2 is an inhalation powder prepared by combining semaglutide and DSPC, Comparative Example 3 is an inhalation powder prepared by combining vardenafil and FDKP, and Comparative Example 4 is an inhalation powder prepared by combining vardenafil and DSPC. The data show that the porous structure of DSPC can effectively reduce the aerodynamic particle size of the inhalation powder.

2 In order to investigate the effects of different compositions on pharmacokinetics, 18 male SD rats were selected and divided into 3 groups, with 6 rats in each group. Example 2 (FDKP: DSPC = 1: 1) and Comparative Examples 1-2 were administered for 7 consecutive days. 0.5 mL of blood was collected from the fundus venous plexus at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 24, 48, and 72 h after administration and placed in a heparinized centrifuge tube. The blood sample was collected in a 1.5 mL EP tube and manually inverted 5-8 times to shake well. The plasma was separated by centrifugation at 3000 g for 5 min (4°C). The plasma was divided into 1.5 mL centrifuge tubes. The sample after aliquoting was placed in a -70±10°C ultra-low temperature refrigerator or dry ice within 30 min.

The results are shown in Figures 7 to 9 and Tables 13 to 16.

Table 13

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Table 14

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Table 15

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Table 16

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As shown in Figures 7 to 9 and Tables 13 to 16, compared with oral administration of semaglutide, inhalation administration can significantly improve bioavailability; compared with injection administration, inhalation administration can achieve higher drug concentrations in the body while prolonging the drug half-life; in inhalation administration, the combination of FDKP and DSPC significantly increases the maximum concentration of the drug in the body, which is beneficial to enhance the drug administration effect.

3 In order to investigate the effect of the composition on pharmacokinetics, 18 male SD rats were selected and divided into 3 groups, with 6 rats in each group. Example 5 (FDKP: DSPC = 1: 1) and Comparative Example 3 were administered for 7 consecutive days. Samples were taken at 0, 0.083, 0.167, 0.33, 0.5, 1, 2, 6, 10, and 24 hours after administration. 0.5 mL of blood was collected from the fundus venous plexus and placed in a heparinized centrifuge tube. After the blood sample was collected in a 1.5 mL EP tube, it was manually inverted 5 to 8 times and shaken well. The plasma was separated by centrifugation at 3000 g for 5 min (4°C). The plasma was divided into 1.5 mL centrifuge tubes, and the sample after the subpackaging was placed in a -70±10°C ultra-low temperature refrigerator or dry ice within 30 min.

The results are shown in Figures 10~11 and Table 17.

Table 17

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As shown in Figures 10-11 and Table 17, compared with oral administration of vardenafil, inhalation administration can reach the highest drug concentration in a shorter time; the combined administration of FDKP and DSPC can significantly increase the drug concentration during the administration period and maintain a higher drug concentration 24 hours after administration, thereby enhancing the drug administration effect.

Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation methods of the present invention. For ordinary technical users in the relevant field, other different forms of changes or modifications can be made on the basis of the above description. It is not necessary and impossible to list all the implementation methods here. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the claims of the present invention.

Claims (5)

1. An inhalation powder, characterized in that it is made of the following components in parts by weight: 0.06-0.10 parts of CaCl ₂ , 0.80-1.50 parts of distearoylphosphatidylcholine, 0.2-2 parts of diketopiperazine fumarate, 0.3-0.5 parts of a drug containing an acidic functional group, and 120-150 parts of a solvent system; The solvent system is a mixed solution of perfluorooctane bromide and distilled water in a volume ratio of 1:6-1:10; The drug containing an acidic functional group is semaglutide or vardenafil hydrochloride. 2. The inhalation powder according to claim 1, characterized in that it comprises the following components in parts by weight: _0.08 parts of CaCl2, 1.1-1.5 parts of distearoylphosphatidylcholine, 1 part of diketopiperazine fumarate, 0.4 parts of a drug containing an acidic functional group, and 140 parts of a solvent system. 3. The method for preparing the inhalation powder according to claim 1 or 2, characterized in that it comprises the following steps: (1) mixing a drug containing an acidic functional group with diketopiperazine fumarate to undergo a combination reaction to obtain component 1; (2) After emulsifying DSPC and PFOB, _CaCl2 was added as a stabilizer to obtain component 2; (3) Component 1 and component 2 are mixed and then spray-dried to collect the powder, which is the inhalation powder. 4. The preparation method according to claim 3, characterized in that the conditions of the binding reaction are: the binding reaction occurs at pH 2.5-3.5 for 10-20 minutes. 5. The preparation method according to claim 4, characterized in that the emulsification method is high-pressure homogenization.