CN118903435A - Compound pharmaceutical preparation and application thereof in medicine - Google Patents

Abstract

The present disclosure relates to a compound pharmaceutical preparation and its application in medicine, wherein the compound pharmaceutical preparation comprises at least a first active ingredient and a second active ingredient, and one or more pharmaceutically acceptable excipients; wherein the first active ingredient is benvimod or a pharmaceutically acceptable salt thereof, and the second active ingredient is one or more bronchodilators or a pharmaceutically acceptable salt thereof; and in particular, it relates to the use of the compound pharmaceutical preparation in the preparation of a drug for treating and/or preventing a pulmonary airway disease, wherein the pulmonary airway disease is preferably selected from asthma, chronic obstructive pulmonary disease (COPD), emphysema, bronchitis and airway hyperresponsiveness, and more preferably COPD or asthma.

Description

Compound drug preparations and their medical applications

Technical Field

The present disclosure belongs to the field of medicine and relates to a compound pharmaceutical preparation and its application in medicine. The active ingredients of the compound pharmaceutical preparation include at least a first active ingredient, a second active ingredient and one or more pharmaceutically acceptable excipients. The first active ingredient is benvimod or a pharmaceutically acceptable salt thereof, and the second active ingredient is one or more bronchodilators or a pharmaceutically acceptable salt thereof. The present disclosure particularly relates to the use of the compound pharmaceutical preparation in the preparation of a drug for treating and/or preventing a pulmonary airway disease. The pulmonary airway disease is preferably selected from asthma, chronic obstructive pulmonary disease (COPD), emphysema, bronchitis and airway hyperresponsiveness, and more preferably COPD or asthma.

Background Art

Bronchodilators and inhaled corticosteroids (ICS) are currently the first-line drugs for the treatment of lung airway diseases such as asthma and COPD. Bronchodilators can quickly improve symptoms such as dyspnea and cough during acute asthma attacks. Long-term regular inhaled corticosteroids are more suitable for patients with severe (grade III) and very severe (grade IV) COPD (FEV1 <50% predicted value).

Chronic obstructive pulmonary disease (COPD) is a common and frequently occurring disease of the respiratory system, characterized by incompletely reversible and persistent airflow limitation. With the progressive development of airflow limitation, the chronic inflammatory response of the airways and lungs to harmful particles or gases increases, and acute exacerbations and complications often affect the overall severity of the disease. It is reported that the incidence and mortality of COPD have been increasing year by year, and it is currently the fourth leading cause of death from disease worldwide, seriously endangering people's health. Due to its heavy socioeconomic burden, it has become an important public health issue.

Currently, the more effective drugs for treating COPD or asthma mainly include bronchodilators and inhaled corticosteroids (ICS). Although bronchodilators have the advantage of rapid onset of action, they only treat the symptoms and not the root cause; and ICS treatment is a hormone treatment that cannot be inhaled for a long time. Therefore, new drugs for treating COPD or asthma are urgently needed.

Benvimod is a new type of small molecule non-hormonal drug with the following structure:

Studies have shown that Benvimod can specifically bind to and regulate the aryl hydrocarbon receptor (AhR), playing an important role in many inflammatory autoimmune skin diseases. As a therapeutic AhR modulator drug, Benvimod has proven to be effective since its launch in China and the United States, with extremely low systemic absorption, no treatment-related systemic adverse reactions, and high safety.

Based on the above background, the present disclosure provides a novel compound pharmaceutical preparation, which provides a new option for the treatment of pulmonary airway diseases.

Summary of the invention

In view of this, the purpose of the present disclosure is to provide a novel compound pharmaceutical preparation, which comprises at least a first active ingredient and a second active ingredient, and one or more pharmaceutically acceptable excipients suitable for administration by inhalation, wherein the first active ingredient, benvimod, is a non-hormonal small molecule compound. It has been verified that the compound pharmaceutical preparation provided by the present disclosure is suitable for pulmonary inhalation administration and can obtain a higher pulmonary deposition rate. The disclosure provides a new option with better patient compliance for the treatment of pulmonary airway diseases such as asthma and COPD.

Furthermore, the present disclosure provides a compound pharmaceutical preparation, characterized in that the compound pharmaceutical preparation comprises at least a first active ingredient and a second active ingredient, and one or more pharmaceutically acceptable excipients; wherein the first active ingredient is benvimod or a pharmaceutically acceptable salt thereof, and the second active ingredient is one or more bronchodilators or a pharmaceutically acceptable salt thereof.

In some embodiments of the present disclosure, the compound pharmaceutical preparation described in the present disclosure further includes a third active ingredient, and the third active ingredient is one or more glucocorticoids or a pharmaceutically acceptable salt thereof.

Furthermore, the present disclosure provides a compound pharmaceutical preparation suitable for administration by inhalation, wherein the compound pharmaceutical preparation comprises a first active ingredient, at least one of a second active ingredient and a third active ingredient, and one or more pharmaceutically acceptable excipients suitable for administration by inhalation; the first active ingredient is benvimod or a pharmaceutically acceptable salt thereof, the second active ingredient is one or more bronchodilators or a pharmaceutically acceptable salt thereof, and the third active ingredient is one or more glucocorticoids or a pharmaceutically acceptable salt thereof.

In some embodiments of the present disclosure, the compound pharmaceutical preparation described in the present disclosure, wherein the compound pharmaceutical preparation is in an inhalation dosage form, and the inhalation dosage form is selected from one or more of an inhalation aerosol, an inhalation spray, an inhalation liquid preparation and an inhalation powder.

In some embodiments of the present disclosure, the present disclosure also provides a mechanical inhaler comprising the compound pharmaceutical preparation of the present disclosure, and the mechanical inhaler is usually loaded with the compound pharmaceutical preparation. Specifically, the mechanical inhaler is selected from a pressurized aerosol inhaler, a dry powder inhaler, a nebulizer, and a nebulizer; preferably, the pressurized aerosol inhaler, nebulizer, and nebulizer usually contain about 1 mL to about 200 mL of liquid pharmaceutical preparation, and more usually contain about 1 mL to about 20 mL of liquid pharmaceutical preparation.

In some embodiments of the present disclosure, the nebulizer uses compressed air to atomize the liquid compound pharmaceutical composition into an aerosol that is inhaled into the respiratory tract of the subject. Examples of nebulizers include soft mist nebulizers, vibrating mesh nebulizers, jet nebulizers, and ultrasonic nebulizers. Suitable nebulizer devices include specifically made nebulizers, as well as nebulizers that are readily available on the market today.

In some embodiments of the present disclosure, the compound pharmaceutical preparation suitable for administration by inhalation described in the present disclosure, the one or more pharmaceutically acceptable excipients suitable for administration by inhalation are determined according to the dosage form in which the compound pharmaceutical preparation exists. Specifically, when the compound pharmaceutical preparation described in the present disclosure exists in the form of an inhaled liquid preparation, the excipient is selected from one or more of a solubilizer, a buffer, a diluent, a surfactant and a pH regulator, but is not limited thereto; when the compound pharmaceutical preparation suitable for administration by inhalation described in the present disclosure exists in the form of an inhaled aerosol, the excipient is selected from one or more of a propellant, a preservative, a stabilizer, a solvent and a solubilizing agent, but is not limited thereto; when the compound pharmaceutical preparation suitable for administration by inhalation described in the present disclosure exists in the form of an inhaled powder, the excipient is selected from one or more of a monosaccharide, a disaccharide (such as lactose), a polyol and a cyclodextrin, but is not limited thereto.

Furthermore, the present disclosure provides an inhalation device, comprising:

A delivery device for delivering a combination pharmaceutical formulation containing one, two or more therapeutic doses to the pulmonary airways of a subject in need thereof; wherein the delivery device is preferably an inhaler, and the inhaler is preferably a metered dose inhaler;

and the compound pharmaceutical preparation disclosed herein; wherein the compound pharmaceutical preparation has at least one of a first active ingredient, a second active ingredient and a third active ingredient as an active ingredient; wherein the first active ingredient is benvimod or a pharmaceutically acceptable salt thereof, the second active ingredient is one or more bronchodilators or a pharmaceutically acceptable salt thereof, and the third active ingredient is one or more glucocorticoids or a pharmaceutically acceptable salt thereof.

In some embodiments of the present disclosure, the inhalation device described in the present disclosure, wherein the inhaler is selected from a pressurized aerosol inhaler, a powder mist inhaler, a sprayer and a nebulizer.

Further, the present disclosure provides a powder mist inhalation compound pharmaceutical preparation, wherein the active ingredient of the compound pharmaceutical preparation includes at least one of a first active ingredient, a second active ingredient and a third active ingredient, and one or more pharmaceutically acceptable excipients suitable for administration by inhalation;

The first active ingredient is benvimod or a pharmaceutically acceptable salt thereof, the second active ingredient is one or more bronchodilators or a pharmaceutically acceptable salt thereof, and the third active ingredient is one or more glucocorticoids or a pharmaceutically acceptable salt thereof;

The auxiliary material is preferably selected from one or more of monosaccharides, disaccharides (such as lactose), oligosaccharides and polysaccharides, polyols, cyclodextrins, amino acids, and salts, more preferably selected from one or more of glucose, fructose, arabinose, lactose, sucrose, maltose, trehalose, dextran, dextrin, starch, cellulose, maltodextrin, sorbitol, mannitol, and xylitol, and most preferably selected from one or more of glucose, fructose, lactose, and amino acids.

In some embodiments of the present disclosure, the active ingredient in the powder mist inhalation compound pharmaceutical preparation described in the present disclosure is preferably micronized.

In some embodiments of the present disclosure, the content of benvimod or a pharmaceutically acceptable salt thereof in the powder mist inhalation compound pharmaceutical preparation described in the present disclosure is 0.01% to 30%, preferably 0.01% to 20%, more preferably 0.05% to 15%, further preferably 0.05% to 10%, further preferably 0.05% to 5%, and most preferably 0.05% to 1%; specifically, the content of benvimod or a pharmaceutically acceptable salt thereof may be 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, 2%, 5%, 10%, 15%, 20%, 25% or 30%.

In some embodiments of the present disclosure, the content of the second active ingredient and/or the third active ingredient in the powder mist inhalation compound pharmaceutical preparation described in the present disclosure is 0.01% to 15%, preferably 0.01% to 10%, more preferably 0.05% to 5%, further preferably 0.05% to 3%, further preferably 0.05% to 2%, and most preferably 0.05% to 1%; specifically, the content of the second active ingredient and/or the third active ingredient may be 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, 2%, 3%, 5%, 10% or 15%.

In some embodiments of the present disclosure, the powder mist inhalation compound pharmaceutical preparation described in the present disclosure further includes an additive; the additive is preferably selected from one or more of magnesium stearate, calcium stearate, talcum powder, leucine and micro-powder silica gel.

In some embodiments of the present disclosure, the content of the additive in the powder mist inhalation compound pharmaceutical preparation of the present disclosure, calculated on the basis of the content of the powder mist inhalation compound pharmaceutical preparation, is 0% to 0.15%, preferably 0% to 0.1%, more preferably 0% to 0.05%, and most preferably 0% to 0.01%.

In some embodiments of the present disclosure, the carrier of the powder inhalation drug preparation of the present disclosure is preferably a carrier that has been surface-modified, and more preferably a carrier that has been surface-modified by a surface modifier. The surface modifier includes one or more micropowders of magnesium stearate, monosaccharides, disaccharides, polysaccharides or amino acids, but is not limited thereto.

In some embodiments of the present disclosure, in the powder mist inhalation compound pharmaceutical preparation described in the present disclosure, the excipient is one or more of pharmaceutically acceptable sugars, polyols, and amino acids suitable for inhalation, preferably selected from one or more of lactose, sucrose, glucose, fructose, maltose, trehalose, mannitol, xylitol, sorbitol, leucine, alanine, tryptophan, valine, isoleucine, glycine, phenylalanine, proline, serine, tyrosine, cysteine, methionine, glutamic acid, threonine, aspartic acid, glutamine, lysine, arginine, histidine and asparagine, and more preferably selected from one or more of glucose, fructose, lactose and leucine.

In some embodiments of the present disclosure, in the powder mist inhalation compound pharmaceutical preparation described in the present disclosure, the particle size of the excipient material is 0.1 μm to 500 μm; preferably, the particle size of the excipient material is: D ₁₀ particle size is 0.5 μm to 20 μm, D ₅₀ particle size is 5 μm to 95 μm, and D ₉₀ particle size is 50 μm to 180 μm.

In some embodiments of the present disclosure, in the powder mist inhalation pharmaceutical preparation described in the present disclosure, the particle size of the active ingredient is 0.1 μm to 20 μm; preferably, the particle size of the active ingredient is 0.1 μm to 15 μm; more preferably, the particle size of the active ingredient is: D ₁₀ particle size is 0.4 μm to 1.2 μm, D ₅₀ particle size is 1.2 μm to 5 μm, and D ₉₀ particle size is 5 μm to 10.0 μm.

In some embodiments of the present disclosure, the present disclosure also provides an inhalation device containing the powder mist inhalation compound pharmaceutical preparation, and the powder mist inhalation can be suitable for capsule-type, blister-type or reservoir-type inhalation devices. The inhalation device is loaded with one, two or more therapeutic doses of the compound pharmaceutical preparation. The inhalation device can be a device specially made according to the characteristics of the active ingredients described in the present disclosure, or it can be a ( ).

In some embodiments of the present disclosure, the active ingredient in the powder mist inhalation compound pharmaceutical preparation of the present disclosure exists in a specific stable crystal form.

Furthermore, the present disclosure provides a method for preparing the powder mist inhalation compound pharmaceutical preparation, the method comprising the following steps:

(a) mixing at least one of a first active ingredient, a second active ingredient and a third active ingredient, and then micronizing;

(b) mixing the micronized product of step (a) with a pharmaceutical excipient, or mixing the micronized product of step (a) with a pharmaceutical excipient and an additive;

Wherein, the active ingredients or pharmaceutical excipients are all mixed by drugs or pharmaceutical excipients with different particle sizes.

In some embodiments of the present disclosure, the daily dosage of the powder mist inhalation compound pharmaceutical preparation of the present disclosure is a therapeutically effective amount based on the total content of active ingredients.

In some embodiments of the present disclosure, the powder mist inhalation compound pharmaceutical preparation of the present disclosure is a single-dose preparation, wherein the content of the total content of active ingredients in the single-dose preparation is a therapeutically effective amount.

The inhalation powder spray described in the present disclosure, also known as dry powder inhalation (DPI), is a preparation that allows a patient to actively inhale a dry powder of a drug or a mixed dry powder of a drug and an excipient into the lungs through a specific drug delivery device. The drug powder is dispersed by the airflow generated by the patient's active inhalation to form an aerosol, which is inhaled into the respiratory system with the airflow to produce therapeutic effects. The prescription process is reasonably designed so that the prescription composition and the preparation process are controlled within a certain range, so that a higher effective site sedimentation rate, i.e., fine particle fraction (FPF), can be achieved, and the role of the active ingredients can be maximized, which is crucial for inhalation products. For example, the deposition rate of the drug in the lungs is a key factor affecting the efficacy of the drug, and the lung deposition rate is affected by the properties of the drug particles (particle size, particle size distribution, drug dispersion state), carriers, equipment, external environment, etc.

In some embodiments of the present disclosure, the powder mist inhalation compound pharmaceutical preparation described in the present disclosure, wherein the bronchodilator is selected from anticholinergic drugs, β2 receptor agonists and methylxanthines, preferably anticholinergic drugs or β2 receptor agonists; the anticholinergic drugs include but are not limited to ipratropium bromide and tiotropium bromide; the β2 receptor agonist is selected from salbutamol sulfate, terbutaline sulfate, procaterol salmeterol hydrochloride and formoterol.

In some embodiments of the present disclosure, in the powder mist inhalation compound pharmaceutical preparation described in the present disclosure, the glucocorticoid is selected from beclomethasone dipropionate, budesonide and fluticasone propionate.

Furthermore, the present disclosure relates to the use of the above-mentioned compound pharmaceutical preparation (including the compound pharmaceutical preparation recorded in the main text, the compound pharmaceutical preparation suitable for administration by inhalation and the compound pharmaceutical preparation for powder mist inhalation) in the preparation of drugs for treating and/or preventing pulmonary airway diseases, wherein the pulmonary airway diseases are preferably selected from asthma, COPD, emphysema, bronchitis and airway hyperresponsiveness, more preferably asthma or COPD.

The present disclosure also relates to a method for treating and/or preventing pulmonary airway diseases, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound pharmaceutical preparation as described above (including the compound pharmaceutical preparation described in the main text, the compound pharmaceutical preparation suitable for administration by inhalation, and the compound pharmaceutical preparation for powder inhalation); wherein the pulmonary airway disease is preferably selected from asthma, COPD, emphysema, bronchitis and airway hyperresponsiveness, more preferably asthma or COPD.

The present disclosure also relates to a compound pharmaceutical preparation as described above (including the compound pharmaceutical preparation described in the text, the compound pharmaceutical preparation suitable for administration by inhalation, and the compound pharmaceutical preparation for powder mist inhalation) for use as a medicine.

The present disclosure also relates to a compound pharmaceutical preparation as described above (including the compound pharmaceutical preparation recorded in the main text, the compound pharmaceutical preparation suitable for administration by inhalation and the compound pharmaceutical preparation for powder inhalation) used as a drug for treating and/or preventing pulmonary airway diseases; wherein the pulmonary airway diseases are preferably selected from asthma, COPD, emphysema, bronchitis and airway hyperresponsiveness, more preferably asthma or COPD.

Instruction Manual

Figure 1: Effects of the formulation on body weight and lung function in COPD rats

Definitions and Explanations of Terms

Unless otherwise specified, the definitions of terms recorded in the specification and claims of this application, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific components in embodiments, etc., may be arbitrarily combined and coupled with each other. Such combinations and couplings shall fall within the scope of the description of this application.

With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

The term "subject or patient" refers to a patient in need of prevention or treatment of a skin disease or disorder, wherein the patient is a mammal, for example selected from rodents, cows, pigs, dogs, cats and primates, particularly humans.

To avoid ambiguity, the content of a certain type of excipients, such as oily base, mentioned in this article refers to the total content. If the excipient of this type contains more than one ingredient, it refers to the sum of the contents of all ingredients, not the content of each ingredient separately. If the content is clearly stated as "each", it means the content of each ingredient separately.

As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

As used herein, "plurality" means two or more than two.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given only for illustrative purposes and not for limitation.

Beneficial Effects

The compound pharmaceutical preparation provided by the present disclosure is a combination drug and can be made into a compound pharmaceutical preparation for inhalation administration. Its active ingredients include at least a first active ingredient and a second active ingredient, and the first active ingredient is benvimod (an AhR modulator), which is a non-hormonal small molecule compound, suitable for long-term use, safe and effective. It has been verified that it solves the difficult-to-overcome defects that occur in the current single-drug use, such as the drug resistance of bronchodilators and weak anti-inflammatory. On the other hand, the compound pharmaceutical preparation for powder mist inhalation provided by the present disclosure has a uniform drug content, is easy to disperse, has good powder fluidity, has a very high FPF value, is suitable for pulmonary administration, and obtains a higher pulmonary deposition rate. In addition, benvimod, one of the active ingredients of the compound pharmaceutical preparation provided by the present disclosure, has a long remission period on inflammatory response. Therefore, the disclosure provides a new option for the treatment of pulmonary airway diseases such as COPD or asthma, which improves the use compliance of subjects.

DETAILED DESCRIPTION

The following examples are used to further describe the present disclosure, but these examples are not intended to limit the scope of the present disclosure. If no specific conditions are specified for an experimental method, it is usually carried out under conventional conditions.

Example 1

Active ingredients: Benvimod 1.0% to 10.0%; salmeterol xinafoate 0.5% to 1.0%. Benvimod and salmeterol xinafoate are micronized to a particle size of 0.5-10 μm.

Pharmaceutical excipients: lactose 89.0% to 98.0%, wherein the lactose comprises two types of lactose particle sizes, wherein lactose one accounts for 1% to 10%, and the particle size distribution of lactose one is _D10 between 0.5 μm and 5 μm, _D50 between 4 μm and 8 μm, and _D90 between 7 μm and 12 μm, and lactose two accounts for 10% to 90%, and the particle size distribution of lactose two is _D10 between 15 μm and 50 μm, _D50 between 60 μm and 110 μm, and _D90 between 120 μm and 200 μm.

Preparation method:

Benvimod, salmeterol xinafoate, lactose 1 and lactose 2 were mixed with a high-speed shear mixer to prepare an intermediate powder, and the dry powder was filled into No. 3 gelatin capsules in equal parts. The aerodynamic test results showed that the FPF value was 39.7%, and the flowability test results showed that the contact angle was 24.2°, and the flowability was very good.

Example 2

Active ingredients: benvimod 1.0% to 10.0%; formoterol fumarate 0.05% to 0.5%, benvimod and salmeterol xinafoate are micronized to a particle size of 0.5 μm to 10 μm.

Pharmaceutical excipients: lactose 89.5% to 98.95%, wherein the lactose comprises two types of lactose particle sizes, wherein lactose one accounts for 1% to 10%, and the particle size distribution of lactose one is _D10 between 0.5 μm and 5 μm, D50 between 4 μm and 8 μm, and _D90 between 7 μm and 12 μm, and lactose two accounts for 10% to 90%, and the particle size distribution of lactose two is _D10 between 15 μm and 50 μm, _D50 between 60 μm and 110 μm, and _D90 between 120 μm and 200 μm.

Preparation method: Same as Example 1. The aerodynamic test results showed that the FPF value was 38.4%, and the fluidity test results showed that the contact angle was 27.6°, indicating good fluidity.

Example 3

The aerosol is prepared using 95% ethanol, and the active ingredient is micronized to a particle size of 0.5 μm-10 μm.

Active ingredients: Benvimod 1.0% to 5.0%; Salmeterol xinafoate 0.02% to 0.5%

Pharmaceutical excipients: 95% ethanol 0.5% to 20.0%, tetrafluoroethane to 100%

Preparation process: Add the prescribed amount of active ingredients to 95% ethanol, stir, fill in divided doses, close the dosage valve, and then inject tetrafluoroethane under pressure to obtain the product.

Comparative Example 1

The aerosol is prepared using 95% ethanol, and the active ingredient is micronized to a particle size of 0.5 μm-10 μm.

Active ingredients: Indigo 1.0% to 5.0%; Salmeterol xinafoate 0.02% to 0.5%

Pharmaceutical excipients: 95% ethanol 0.5% to 20.0%, tetrafluoroethane to 100%

Preparation process: Add the prescribed amount of active ingredients to 95% ethanol, stir, fill in divided doses, close the dosage valve, and then inject tetrafluoroethane under pressure to obtain the product.

Biological test: efficacy test on chronic obstructive pulmonary disease (COPD) in rats

Experimental methods:

The rat chronic obstructive pulmonary disease (COPD) model was established by smoke fumigation combined with endotoxin lipopolysaccharide (LPS) aerosolization. Male Wistar rats were randomly divided into Sham group, COPD model control group, salmeterol xinafoate group (0.40 mg/kg), indigo + salmeterol xinafoate group (20 + 0.40 mg/kg), benvimod + salmeterol xinafoate group (10 + 0.40 mg/kg), benvimod + salmeterol xinafoate group (20 + 0.40 mg/kg), with 10 rats in each group. Except for the Sham group, the rats in the other five groups were anesthetized with isoflurane on the first and 15th day, and then 100 μL 1 mg/mL LPS ( Nebulizer, IA-1B model). From the 2nd day to the 14th day, except for the Sham group, the other rats were placed in a fumigation box and passively exposed to 5% (v/v) cigarette smoke for 30 minutes each time, with an interval of 6 hours each time. After obtaining the COPD model rats, according to the above method, from the 16th day to the 45th day, the rats were subjected to individual smoking stimulation every day. In addition, from the 30th day to the 45th day, the rats were given the above drug treatment 1 hour before the smoking.

Experimental results:

Effects on body weight and lung function of COPD rats: On the 30th day after model construction, the body weight of rats in the Sham group increased normally, while the body weight of rats in the COPD model group decreased. After treatment with the salmeterol xinafoate group, indigo + salmeterol xinafoate, and benvimod + salmeterol xinafoate, the body weight was significantly restored (p<0.05 or p<0.01). Among them, the body weight recovery of rats in the benvimod + salmeterol xinafoate (20+0.40mg/kg) combined medication group was better than that in the indigo + salmeterol xinafoate (20+0.40mg/kg) combined medication group (as shown in Figure 1a). In addition, FEV0.3/FVC was reversed in the model group after drug treatment, among which the benvimod + salmeterol xinafoate combined medication group had a better effect on improving the lung function of COPD rats than other groups (as shown in Figure 1b).

Effects on inflammatory cells and inflammatory factors:

COPD is usually associated with increased production of inflammatory factors. The levels of inflammatory response cells such as white blood cells, neutrophils and lymphocytes in bronchial lavage fluid were detected. The results showed that these three types of cells were significantly increased in the COPD model and significantly decreased after drug treatment (p<0.05 or p<0.01). At the same time, serum pro-inflammatory factors (IL-6, IL-1β, TNF-α) were detected. The results showed that the increasing trend of the salmeterol xinafoate group, the indigo + salmeterol xinafoate group, and the benvimod + salmeterol xinafoate group was significantly reversed after treatment (p<0.05). Among them, the therapeutic effect of the combination group of benvimod + salmeterol xinafoate (20+0.40mg/kg) was better than that of the combination group of indigo + salmeterol xinafoate (20+0.40mg/kg), and the degree of reducing IL-6, IL-1β and TNF-α was 1.3 times, 1.4 times and 1.2 times that of the combination group of indigo + salmeterol xinafoate (20+0.40mg/kg), respectively.

Pathological results showed that compared with the COPD model control group, the pathological results of the rats in the drug-treated group were significantly improved, including reduced inflammatory cell infiltration, thinning of the bronchial wall, reduced average alveolar number, reduced alveolar expansion and rupture, etc. Among them, the combination of Benvimod + Salmeterol xinafoate (20 + 0.40 mg/kg) group was significantly better than the combination of Indigo + Salmeterol xinafoate (20 + 0.40 mg/kg) group in improving inflammatory cell infiltration and alveolar number, with inflammatory cell infiltration scores of 1.8 and 2.4, and average alveolar volumes of 45 and 32, respectively.

In summary, the combination of indigo + salmeterol xinafoate and benvimod + salmeterol xinafoate both have good synergistic effects, and are superior to salmeterol xinafoate alone in reducing lung inflammation, improving lung function, and restoring body weight in COPD rats. The efficacy of the combination of benvimod + salmeterol xinafoate (20+0.40mg/kg) is better than the combination of indigo + salmeterol xinafoate (20+0.40mg/kg).

Claims (10)

1. A compound pharmaceutical preparation, characterized in that the compound pharmaceutical preparation comprises at least a first active ingredient and a second active ingredient, and one or more pharmaceutically acceptable excipients; wherein the first active ingredient is benvimod or a pharmaceutically acceptable salt thereof, and the second active ingredient is one or more bronchodilators or a pharmaceutically acceptable salt thereof. 2. The compound pharmaceutical preparation according to claim 1, characterized in that the compound pharmaceutical preparation further comprises a third active ingredient, and the third active ingredient is one or more glucocorticoids or a pharmaceutically acceptable salt thereof. 3. A compound pharmaceutical preparation suitable for administration by inhalation, characterized in that the compound pharmaceutical preparation comprises a first active ingredient, at least one of a second active ingredient and a third active ingredient, and one or more pharmaceutically acceptable excipients suitable for administration by inhalation; the first active ingredient is benvimod or a pharmaceutically acceptable salt thereof, the second active ingredient is one or more bronchodilators or a pharmaceutically acceptable salt thereof, and the third active ingredient is one or more glucocorticoids or a pharmaceutically acceptable salt thereof. 4. The compound pharmaceutical preparation according to any one of claims 1 to 3, characterized in that the compound pharmaceutical preparation is in an inhalation dosage form, and the inhalation dosage form is selected from one or more of an inhalation aerosol, an inhalation spray, an inhalation liquid preparation and an inhalation powder. 5. An inhalation device, comprising: A delivery device for delivering a combination pharmaceutical formulation containing one, two or more therapeutic doses to the pulmonary airways of a subject in need thereof; wherein the delivery device is preferably an inhaler, and the inhaler is preferably a metered dose inhaler; And the compound pharmaceutical preparation according to any one of claims 1 to 4. 6. An inhalation device according to claim 5, wherein the inhaler is selected from the group consisting of a pressurized aerosol inhaler, a powder mist inhaler, a nebulizer and a sprayer. 7. A powder mist inhalation compound pharmaceutical preparation, characterized in that the compound pharmaceutical preparation comprises at least one of a first active ingredient, a second active ingredient and a third active ingredient, and one or more pharmaceutically acceptable excipients suitable for administration by inhalation; The first active ingredient is benvimod or a pharmaceutically acceptable salt thereof, the second active ingredient is one or more bronchodilators or a pharmaceutically acceptable salt thereof, and the third active ingredient is one or more glucocorticoids or a pharmaceutically acceptable salt thereof; The auxiliary material is preferably selected from one or more of monosaccharides, disaccharides, oligosaccharides and polysaccharides, polyols, cyclodextrins, amino acids, and salts, more preferably selected from one or more of glucose, fructose, arabinose, lactose, sucrose, maltose, trehalose, dextran, dextrin, starch, cellulose, maltodextrin, sorbitol, mannitol, and xylitol, and most preferably selected from one or more of glucose, fructose, lactose, and amino acids. 8. The powder inhalation compound pharmaceutical preparation according to claim 7, wherein the content of benvimod or its pharmaceutically acceptable salt is 0.01% to 30%, and the content of the second active ingredient and/or the third active ingredient is 0.01% to 15%, based on the content of the powder inhalation compound pharmaceutical preparation. 9. The powder mist inhalation compound pharmaceutical preparation according to claim 7 or 8, wherein the particle size of the active ingredient is 0.1 μm to 20 μm. 10. Use of the compound pharmaceutical preparation according to any one of claims 1 to 9 in the preparation of a medicament for treating and/or preventing a pulmonary airway disease, wherein the pulmonary airway disease is preferably selected from asthma, COPD, emphysema, bronchitis and airway hyperresponsiveness, more preferably asthma or COPD.