CN104208701A - Compound inhalation preparation containing antifungal drug - Google Patents

Abstract

The invention relates to the components and applications of a compound inhalation preparation containing an antifungal drug. When a trace amount of an antifungal drug is compounded with a drug for treating asthma and chronic obstructive pneumonia, a good curative effect will be generated; and the curative effect is more prominent, when the antifungal drug is compounded with glucocorticoid and an anti-cholinergic agent.

Description

Compound recipe containing antifungal drug sucks preparation

Technical field:

The compound recipe that the present invention relates to containing antifungal drug sucks component and the purposes of preparation.

Background technology:

Antifungal drug is general designation fungus to suppression and killing action material, mainly treats fungus to mammiferous infection.The main route of administration of antifungal medicine is oral or injection, the disease that also can will be caused by atomization inspiration treatment Pulmonary Fungal Infections, but there is comparatively significantly shortcoming in this Neulized inhalation, first be that the fog produced is mainly water vapour, partial pressure of oxygen is made to reduce after diluent air, after continual ultrasonic Neulized inhalation, water vapour occupies whole respiratory tract, oxygen cannot arrive alveolar and cause patient's anoxia, next is that the fog sprayed has certain pressure, oral cavity surrounding air is stoped to enter respiratory tract, make suction gas partial pressure of oxygen lower, 3rd is asthma, Patients with Chronic Obstructive Pulmonary Disease pulmonary function is poor, and the mist low temperature of Ultrasonic atomising taring is low, small airway spasm is easily caused after suction, patient is occurred, and breast is vexed, dyspnea symptom, 4th is diameter of aspirin particle precise control after atomization, high amount of drug is at face, the site deposition such as oral mucosa, in bronchus, the target site depositions such as pulmonary are less, untoward reaction is caused to increase, drug availability is less, easy decomposition, curative effect is poor, 5th is use inconvenience, major part medicine has poor taste, patient's is suitable poor by property, so the less employing of the medicinal atomized suction of antifungal in daily treatment.

Asthma, chronic obstructive pneumonia all belong to the flow limitation disease that respiratory inflammation causes, in recent years along with the impact of smoking, air, anaphylactogen increase etc., sickness rate improves year by year, above-mentioned disease number of patients is many, mortality rate is high, social economical burden weight, has become the important public health problem affecting human health.The treatment of current treatment asthma, chronic obstructive pneumonia is mainly based on inhalant, and compound medicine is then main based on glucocorticoid, epinephrine broxaterol.Also do not find at present antifungal medicine treatment non-microorganism infect cause asthma, use in chronic obstructive pneumonia.

Summary of the invention:

The discovery that we are surprised, produces when micro-antifungal medicine forms compound recipe with the medicine for the treatment of asthma, chronic obstructive pneumonia and acts on preferably, especially more obvious containing curative effect when antifungal medicine, glucocorticoid medicine, anticholinergic agent.

We think it may is because antifungal medicine has carried out certain impact to respiratory tract cell, thus the medicine causing other treatment respiratory tract disease more easily curative effect occurs.

One can suck compound medicament composition, the pharmaceutic adjuvant of inhalation is applicable to by one or more, and as the antifungal medicine of active component, the 2-3 kind composition in the 7 class medicines such as glucocorticoid, anticholinergic agent, LTRA, mastocyte membrane stabilizer, phosphodiesterase inhibitor, epinephrine broxaterol, H1 receptor antagonist.

Described pharmaceutical composition, containing two kinds in the 7 class medicines such as glucocorticoid, anticholinergic agent, LTRA, mastocyte membrane stabilizer, phosphodiesterase inhibitor, epinephrine broxaterol, H1 receptor antagonist.

Described pharmaceutical composition, containing three kinds in glucocorticoid, anticholinergic agent, LTRA, mastocyte membrane stabilizer, phosphodiesterase inhibitor, epinephrine broxaterol, H1 receptor antagonist 7 class medicine.

Described H1 receptor antagonist is one or more in loratadine, Desloratadine, cetirizine, levocetirizine, astemizole, ketotifen, ebastine, fexofenadine, acrivastine, Primalan, mizolastine and salt thereof.Be preferably one or more in loratadine, Desloratadine, cetirizine, levocetirizine, ebastine, mizolastine, acrivastine, Primalan, ketotifen and hydrochlorate thereof, fumarate.Be more preferably one or more in loratadine, Desloratadine, cetirizine hydrochloride, levo-cetirizine hydrochloride.

Described glucocorticoid is one or more in triamcinolone acetonide, beclometasone, fluticasone, mometasone and ester, ciclesonide or budesonide.

Described anticholinergic agent is the one in ipratropium bromide, tiotropium bromide, oxitropium bromide.

Described LTRA is the one in zafirlukast, pranlukast, montelukast, tranilast.

To be set forth in mast cell membrane stabilizing agent be one in sodium cromoglicate, nedocromil.

Described phosphodiesterase inhibitor is the one in Rolipram, roflumilast, Denbufylline.

Described epinephrine broxaterol is one or more in albuterol, terbutaline, fenoterol, procaterol, formoterol, salmaterol, western sieve Bart, bambuterol, zilpaterol, Mabuterol, western Boot sieve, bromine Boot sieve, Afromoterol, QAB-149 and salt thereof.Be preferably the one in salbutamol sulfate, terbutaline sulphate, hydrochloric acid zilpaterol, formoterol fumarate, SALMETEROL XINAFOATE, maleic acid QAB-149.

Described antifungal medicine is one or more in polyenoid class, triazole type or echinocandin antifungal agent thing.

Described polyene antifungal medicine is selected from nystatin, amphotericin B, methylpartricin, hachimycin; Described antifungal drug in triazole class is selected from fluconazol, ketoconazole, miconazole, itraconazole, voriconazole, posaconazole; Described echinocandin antifungal agent thing is selected from Caspofungin, MFG, anidulafungin.

Described pharmaceutical composition, the D90 particle diameter of active component is 1 ~ 10 μm.Be preferably 1-7 μm.Be more preferably 3 ~ 6 μm.

Described pharmaceutical composition is powder spray or aerosol.Be preferably powder spray

Described pharmaceutical composition, is prepared into powder spray, and described pharmaceutic adjuvant comprises one or more in carrier, additives.

The mean diameter of described carrier is 20 ~ 80 μm, is preferably 30 ~ 40 μm.

Described carrier is one or more in saccharide, aminoacid, lecithin, phosphatidylcholine.

Described aminoacid is one or more in glycine, valine, leucine.

Described saccharide is monosaccharide, disaccharide, derived carbohydrate, monosaccharide is mannitol, fructose, glucose, described disaccharide is maltose, trehalose, cellobiose, lactose, sucrose, and described derived carbohydrate is eight acetate fiber two sugar esters, sucrose octa-acetate, eight acetic acid lactose esters, five acetic acid glucose esters, six acetic acid Nitranitols and eight acetic acid Sargassum sugar esters.Preferred lactose.Described lactose is alpha-lactose monohydrate, β-Lactis Anhydrous, one or more in amorphous spray-dried lactose, crystallizing and drying lactose, Lactis Anhydrous.Be preferably Lactis Anhydrous.

Described carrier is preferably one or both the combination in saccharide and lecithin, phosphatidylcholine.

Described additives contain one or more in surfactant, lubricant, antistatic additive.

Described surfactant is poloxamer.

Described lubricant is one or more in magnesium stearate, micropowder silica gel, Pulvis Talci.

Described powder spray, the summation of described active component and the weight ratio of carrier are 1:1 ~ 1000.Be preferably 1:1 ~ 200.

Described powder spray, becomes capsule with the form subpackage of single or multiple dosage.

Described pharmaceutical composition, is prepared into aerosol, and described pharmaceutic adjuvant comprises the pharmaceutically useful propellant and other optional additives that are applicable to aerosol.Described propellant is one or more in hydrofluoroalkane compounds.Be preferably HFA 134a (HFA134a), one or both in 1,1,1.2,3,3,3-heptafluoro-propane (HFA 227).Be more preferably HFA 134a (HFA134a).

Described aerosol, comprises solvent in additives, is selected from glycerol, propylene glycol, Polyethylene Glycol, ethanol or oleic acid.Described solvent is preferably one or more in ethanol, propylene glycol.

Described aerosol formulations is preferably, and the ethanol weight percent content as solvent is 5-20%, and the propellant of surplus.

Described pharmaceutical composition, preparation treatment non-microorganism infect cause asthma, chronic obstructive pulmonary disease medicine in application.

Described pharmaceutical composition, by glucocorticoid, anticholinergic agent, antifungal medicine as active component, and is applicable to the pharmaceutic adjuvant composition of inhalation with one or more.

The preparation method of described aerosol is: the active component micropowder adding recipe quantity in aerosol bottle, opens the valve on bottle, is imported by the mixture of the propellant of premixing and optional additives, valve-off, obtain required aerosol by valve.Optional ultra sonic bath is carried out with solubilising to aerosol bottle

Or following preparation method can be adopted: be distributed in additives by micronized active component, then add in the propellant after pre-cooling and mix, then be dispensed in aerosol bottle.

Should be appreciated that because known reason, as the retention of active component in suction apparatus, the amount of often kind of active component that patient sucks can be different from the amount of metering.Therefore the applicating ratio between active component can be different from the ratio of metering.The ratio preferably used is in the described metered proportions indicated.

Described aerosol bottle and valve system can select disclosed aerosol bottle and valve system in Chinese patent CN98805261.X.

In this patent, the dosage of said medicine is with the weighing scale of medicine itself, does not comprise the weight of its salt or ester, such as MK 100mg, in fact refers to Montelukast 100mg, instead of the sodium salt 100mg of Montelukast.

Particle diameter in the present invention is equivalent volume footpath, is the diameter of the ball identical with actual particle volume.It is generally acknowledged that the diameter that laser method is surveyed is equivalent volume footpath.

Particle diameter corresponding when D90 particle diameter refers to that the cumulative particle sizes distribution number of a sample reaches 90%.Its physical significance be particle diameter be less than it amounts of particles account for 90%, this numerical value can be detected by laser particle instrument.

Mean diameter refers to meso-position radius, can detect with laser particle analyzer.

Detailed description of the invention

Micronization of the present invention can use known mechanical crushing method or spray drying method.Mechanical crushing method refers to and utilizes the method for fluid energy mill (using Nanjing Univ. Instrument Factory QM-3A) respectively medicine and/or carrier powder to be broken into required particle diameter.Spray drying method refers to and medicine and/or carrier is dissolved in organic solvent entirely as in ethanol, through spray dryer (as Buli Minispray, 190 types, Germany or QW-500, Xishan city Lin Zhou drying machine factory), solid material is made required particle diameter.Use during spray drying method and can also add surfactant as poloxamer etc.The process conditions of spray drying method can be: inlet temperature is 105 DEG C, and outlet temperature is 68 DEG C, throughput 90%, and jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.

Powder spray adopts No. 3 plant capsules (sino-america joint-venture Suzhou Capsule Co., Ltd produces, trade name: Vcaps), and each embodiment feeds intake according to 1000 capsules.The capsule loading bubble-cap type of powder spray is aluminum-plastic packaged, takes out, load powder spray inhaler (Shanghai balance pharmaceutical factory) and use during use.

Medicine mist (dripping) the grain abundance measured in embodiment below detects according to the method in 2010 editions pharmacopeia annex XH.

In an embodiment, active component 2 is the combination of following medicine, and wherein μ g/ unit refers to administration unit minimum in medicine, and as Foradil Aerolizer formoterol fumarate refers to that μ g/ grain (capsule-type) or μ g/ inhale (multiple dose), aerosol refers to that μ g/ sprays.D90 particle diameter refers to that all medicines in active component 2 are as a sample, particle diameter corresponding when its cumulative particle sizes distribution number reaches 90%, its physical significance be particle diameter be less than it granule account for 90%.

Embodiment 1

According to following table, active component 1 is mixed with active component 2 with after fluid energy mill micronization, Lactis Anhydrous 10g fluid energy mill is micronized to mean diameter 42 μm, after mixing, be divided in 1000 No. 3 capsules after crossing 3 mixings of 200 mesh sieve, the active component in every capsules sees the following form.

Embodiment 2

According to following table, active component 1 is mixed with active component 2 with after fluid energy mill micronization, Lactis Anhydrous 10g fluid energy mill is micronized to mean diameter 42 μm, after mixing, is divided in 1000 No. 3 capsules after crossing 3 mixings of 200 mesh sieve,, the active component in every capsules sees the following form.

Embodiment number	Active component 1	Dosage (μ g/ grain)	D90 particle diameter (μm)	Active component 2
					2-1	Amphotericin B	50	5.2	M1-2
2-2	Fluconazol	100	4.9	M1-3
					2-3	Ketoconazole	200	5.8	M1-4
2-4	Miconazole nitrate	200	5.3	M1-5
					2-5	Itraconazole	200	4.3	M1-6
2-6	Voriconazole	400	5.1	M1-2
					2-7	Posaconazole	100	4.9	M1-3
2-8	Caspofungin	200	5.2	M1-4
					2-9	MFG	500	4.8	M1-5
2-10	Anidulafungin	100	5.4	M1-6
					2-11	Amphotericin B	50	5.2	M2-2
2-12	Fluconazol	100	4.9	M2-3
					2-13	Ketoconazole	200	5.8	M2-4
2-14	Miconazole nitrate	200	5.3	M2-5
					2-15	Itraconazole	200	4.3	M2-6
2-16	Voriconazole	400	5.1	M2-2
					2-17	Posaconazole	100	4.9	M2-3
2-18	Caspofungin	200	5.2	M2-4
					2-19	MFG	500	4.8	M2-5
2-20	Anidulafungin	100	5.4	M2-6
					2-21	Amphotericin B	50	5.2	M3-2
2-22	Fluconazol	100	4.9	M3-3
					2-23	Ketoconazole	200	5.8	M3-4
2-24	Miconazole nitrate	200	5.3	M3-5
					2-25	Itraconazole	200	4.3	M3-7
2-26	Voriconazole	400	5.1	M3-2
					2-27	Posaconazole	100	4.9	M3-3
2-28	Caspofungin	200	5.2	M3-4
					2-29	MFG	500	4.8	M3-5
2-30	Anidulafungin	100	5.4	M3-6

The preparation of aerosol, active component used is the weight of 1000 administration units, and HFA-134a is HFA 134a, and HFA-227 is HFC-227ea.

Embodiment 3

Active component

Ethanol 10g

HFA-134a?490g

Preparation technology: the ethanol 1000 times of active component in following table 1 and 2 Unit Weight being added recipe quantity, stirs, divided dose fill, sealing-in dose valve system, and HFA-134a is injected in pressurization more respectively, to obtain final product.

Embodiment 4

Active component

Ethanol 10g

HFA-227?490g

Preparation technology: the ethanol 1000 times of active component in following table 1 and 2 Unit Weight being added recipe quantity, stirs, divided dose fill, sealing-in dose valve system, and HFA-227 is injected in pressurization more respectively, to obtain final product.

Embodiment number	Active component 1	Dosage (μ g/ sprays)	D90 particle diameter (μm)	Active component 2
					4-1	Amphotericin B	50	5.2	M1-6
4-2	Fluconazol	100	4.9	M1-5
					4-3	Ketoconazole	200	5.8	M1-4
4-4	Miconazole nitrate	200	5.3	M1-3
					4-5	Itraconazole	200	4.3	M1-2
4-6	Voriconazole	400	5.1	M1-6
					4-7	Posaconazole	100	4.9	M1-5
4-8	Caspofungin	200	5.2	M1-4
					4-9	MFG	500	4.8	M1-3
4-10	Anidulafungin	100	5.4	M1-2
					4-11	Amphotericin B	50	5.2	M2-6
4-12	Fluconazol	100	4.9	M2-5
					4-13	Ketoconazole	200	5.8	M2-4
4-14	Miconazole nitrate	200	5.3	M2-3
					4-15	Itraconazole	200	4.3	M2-2
4-16	Voriconazole	400	5.1	M2-6
					4-17	Posaconazole	100	4.9	M2-5
4-18	Caspofungin	200	5.2	M2-4
					4-19	MFG	500	4.8	M2-3
4-20	Anidulafungin	100	5.4	M2-2
					4-21	Amphotericin B	50	5.2	M3-6
4-22	Fluconazol	100	4.9	M3-5
					4-23	Ketoconazole	200	5.8	M3-4
4-24	Miconazole nitrate	200	5.3	M3-3
					4-25	Itraconazole	200	4.3	M3-2
4-26	Voriconazole	400	5.1	M3-6
					4-27	Posaconazole	100	4.9	M3-5
4-28	Caspofungin	200	5.2	M3-4
					4-29	MFG	500	4.8	M3-3
4-30	Anidulafungin	100	5.4	M3-2

Embodiment 5

Active component 1 is dissolved in ethanol, after filtration, filtrate adopts spraying dry, D90 particle diameter sees the following form, inhalant adjuvant micronization, ratio of adjuvant, mean diameter see the following form, by active component 1,2 and adjuvant mixing, be dispensed in 1000 No. 3 capsules after crossing 3 mixings of 200 mesh sieve, the active component in every capsules sees the following form.

Process conditions are: inlet temperature is 100 DEG C, and outlet temperature is 68 DEG C, throughput 90%, and jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 30mL/h.

The explanation of matched group situation

The medicine composition of matched group 1-1 to 5-6 does not contain active component 1 compared with the Example formulations of corresponding group number, that is the one-tenth of matched group 1-1 to 5-6 is grouped into only containing the active component 2 in the embodiment of corresponding group number and excipient substance, proportioning, preparation technology is identical, such as embodiment 1-3 group is ketoconazole containing active component 1, active component 2 is M1-1 and pharmaceutic adjuvant, corresponding matched group 1-3 is then only containing active component 2(M1-1) and excipient substance, not containing active component 1, active component 2(M1-1) with the amount of excipient substance and the active component 2(M1-1 of embodiment 1-3 group) identical with the amount of excipient substance.

The preparation method of matched group 6-1 to 6-10:

According to following table by active component 1 fluid energy mill micronization, particle diameter is as following table, and Lactis Anhydrous 10g fluid energy mill is micronized to mean diameter 42 μm, after mixing, be divided in 1000 No. 3 capsules after crossing 3 mixings of 200 mesh sieve, the active component in every capsules sees the following form.

Contrast group number	Active component 1	Dosage (μ g/ grain)	D90 particle diameter (μm)
				6-1	Amphotericin B	50	5.2
6-2	Fluconazol	100	4.9
				6-3	Ketoconazole	200	5.8
6-4	Miconazole nitrate	200	5.3
				6-5	Itraconazole	200	4.3
6-6	Voriconazole	400	5.1
				6-7	Posaconazole	100	4.9
6-8	Caspofungin	200	5.2
				6-9	MFG	500	4.8
6-10	Anidulafungin	100	5.4

Pharmacological Examples 1 asthma pharmacological evaluation

1, animal model

Choose healthy male Wistar rat (there is antibacterial to checking out, the rat of fungal infection will not select), body weight is 200 ± 10g, put into the bell glass of about 5 liters, spray into 3% chlorination second phthalein choline and 0.1% histamine phosphate's volume mixed liquor 15 second with the pressure of 400mmHg.After spraying stops, observing the asthmatic latent period (namely asthma occur, breathe be the devil, until twitch time of falling) of rat, draw and breathe heavily the rat that the latent phase is less than 70 seconds or is greater than 120 seconds and will not select,

2, experimental technique

Learn from else's experience and measure the qualified rat of asthmatic latent period, random packet is carried out according to the group in following table, often organize 10, every day carries out administration in the bell glass of about 5 liters, experimental group gives the medicine in embodiment according to the arrangement inhalation route of following table, model group 1 gives according to inhalation route the Lactis Anhydrous that mean diameter is 55 μm, dosage is 5mg/Kg, matched group inhalation route gives corresponding dosage matched group medicine, observe after successive administration asthmatic latent period and tic incidence rate before and after drug change (draw animal when breathing heavily do not occur in 6 minutes the person of falling with draw breathe heavily the volt phase be 360 seconds calculate).

Dosage in experimental group, matched group 6-1 to 6-10 is all as the criterion with antifungal agent dosage, and the dosage of the active component 2 that the drug dose in matched group 1-1 to 5-6 gives according to corresponding experimental group gives.

3, experimentation and result: animal generation asthma until the time of falling of twitching see the following form.

Have multiple form to be the result of this experiment in the present embodiment, problem for convenience of explanation, splits experimental result.

Table 1-1 uses merely antifungal drug experimental result (n=10, mean ± SD)

Difference is not had afterwards before administration by the asthmatic latent period of T testing identity asthmatic model animal by above-mentioned experimental data, basically identical with not administration group, can illustrate that asthmatic model animal only gives antifungal drug, cannot Paroxysmal asthma be extended.

Table 1-2 contains the experimental result (n=10, mean ± SD) of tripartite's compound preparation of antifungal drug

Table 1-3 contains the experimental result (n=10, mean ± SD) of the cubic compound preparation of antifungal drug

Can be illustrated by T inspection by the experimental data showing 1-2,1-3, the curative effect of the tripartite containing antifungal drug or the composition for inhalation in four directions is much better than the composition for inhalation of antifungal drug folk prescription.

The experimental result (n=10, mean ± SD) of the compound preparation of table 1-4 not containing antifungal drug

By table 1-4 with show 1-3 group result of the test and to be checked by T and compare, prove that the curative effect of the tripartite after adding antifungal drug or cubic compound recipe Inhaled pharmaceutical composition exists larger difference with corresponding two sides not containing antifungal drug or tripartite's compound recipe Inhaled pharmaceutical composition, thus the curative effect that proof adds the tripartite after antifungal drug or cubic compound recipe Inhaled pharmaceutical composition is more excellent.

Pharmacological Examples 2 chronic obstructive pulmonary disease pharmacological evaluation

1, chronic obstructive pulmonary disease animal:

Male secondary SD rat, Mus age 8 week age, body weight 150 ~ 170g.Animal is adopted instillation Porcine trypsin method in fumigation (Golden Bridge) gas-adding pipe, namely the 1st, 15 day is tested through trachea instillation Porcine trypsin 0.5mg/kg, start smoked 5% medicated cigarette next day, 1 hour every morning, until the last day of the 10th week.

2, experimental technique

Get healthy male secondary SD rat 10, Mus age 8 week age, body weight 150 ~ 170g, is set to model group 2, and every day gives according to inhalation route the Lactis Anhydrous that mean diameter is 55 μm in the bell glass of about 5 liters, and dosage is 5mg/Kg, successive administration 14 days.

Get the rat of making Chronic obstructive pulmonary disease, random packet is carried out according to the group in following table, often organize 10, every day carries out administration in the bell glass of about 5 liters, experimental group gives the medicine in embodiment according to the arrangement inhalation route in following table, model group 1 gives according to inhalation route the Lactis Anhydrous that mean diameter is 55 μm, and dosage is 5mg/Kg, matched group inhalation route gives corresponding dosage matched group medicine, the equal successive administration of experimental group, model group 1, matched group 14 days.

Dosage in experimental group, matched group 6-1 to 6-10 is all as the criterion with antifungal agent dosage, and the dosage of the active component 2 that the drug dose in matched group 1-1 to 5-6 gives according to corresponding experimental group gives.

3, experimentation and result: experimental group, model group 1,2, rat was put to death in the 11st day after matched group administration, get the right lower lobe lung tissue of every rat, specimens paraffin embedding slices, carry out elastic fibers dyeing, carry out the mensuration of elastic fiber relative amount by HIPS-1000 multi-functional true color pathological picture and text analytical system, concrete data see the following form.

Have multiple form to be the result of this experiment in the present embodiment, problem for convenience of explanation, splits experimental result.

Table 2-1 uses merely antifungal drug experimental result (n=10, mean ± SD)

Group	Medicine	Dosage every day (μ g/kg)	Elastic fiber relative amount (%)
				Matched group 6-1	Amphotericin B	50	11.6±1.5
Matched group 6-2	Fluconazol	100	11.9±1.4
				Matched group 6-3	Ketoconazole	200	11.7±1.6
Matched group 6-4	Miconazole nitrate	200	11.8±1.5
				Matched group 6-5	Itraconazole	200	11.7±1.6
Matched group 6-6	Voriconazole	400	11.9±1.6
				Matched group 6-7	Posaconazole	100	11.6±1.5
Matched group 6-8	Caspofungin	200	11.8±1.6
				Matched group 6-9	MFG	500	11.7±1.5
Matched group 6-10	Anidulafungin	100	11.5±1.4
				Model group 1	Nothing		11.6±1.5
Model group 2	Nothing		22.7±1.9

Difference is not had afterwards before administration by the elastic fiber relative amount of T testing identity Chronic obstructive pulmonary disease animal by above-mentioned experimental data, basically identical with not administration group, can illustrate that Chronic obstructive pulmonary disease animal only gives antifungal drug, the relative scale of lung fiber cannot be improved.

Table 2-2 contains the experimental result (n=10, mean ± SD) of tripartite's compound preparation of antifungal drug

Group	Medicine	Dosage every day (μ g/kg)	Elastic fiber relative amount (%)
				Model group 1	Nothing		11.6±1.5
Embodiment 1-1	Amphotericin B	50	15.8±1.6
				Embodiment 1-11	Amphotericin B	50	15.3±1.5
Embodiment 1-21	Amphotericin B	50	15.4±1.6
				Embodiment 1-2	Fluconazol	100	16.6±1.9
Embodiment 1-12	Fluconazol	100	16.3±1.6
				Embodiment 1-22	Fluconazol	100	16.4±1.8
Embodiment 1-3	Ketoconazole	200	16.4±1.7
				Embodiment 1-13	Ketoconazole	200	16.1±1.7
Embodiment 1-23	Ketoconazole	200	16.2±1.8
				Embodiment 1-5	Itraconazole	200	17.2±1.7
Embodiment 1-15	Itraconazole	200	16.8±1.6
				Embodiment 1-25	Itraconazole	200	17.1±1.8
Embodiment 1-6	Voriconazole	400	17.4±1.8
				Embodiment 1-16	Voriconazole	400	17.1±1.9
Embodiment 1-26	Voriconazole	400	17.3±1.7
				Embodiment 1-7	Posaconazole	100	16.1±2.0
Embodiment 1-17	Posaconazole	100	15.5±1.7
				Embodiment 1-27	Posaconazole	100	16.8±1.8
Embodiment 1-8	Caspofungin	200	16.1±1.8
				Embodiment 1-18	Caspofungin	200	15.4±1.5
Embodiment 1-28	Caspofungin	200	15.9±1.6
				Embodiment 1-10	Anidulafungin	100	15.9±1.6
Embodiment 1-20	Anidulafungin	100	15.3±1.5
				Embodiment 1-30	Anidulafungin	100	15.7±1.7

Can be illustrated by T inspection by the experimental data showing 2-2, the curative effect of the composition for inhalation of the tripartite containing antifungal drug is much better than the composition for inhalation of antifungal drug folk prescription, the composition for inhalation in the same four directions due to antifungal drug adds a kind of medicine compared with all medicines of the composition for inhalation of tripartite, also can prove that the curative effect of the composition for inhalation in the four directions of antifungal drug is much better than the composition for inhalation of antifungal drug folk prescription.

The experimental result (n=10, mean ± SD) of the compound preparation of table 2-3 not containing antifungal drug

Matched group number	Medicine	Elastic fiber relative amount (%)
			2-1	M1-2	14.4±1.9
2-2	M1-3	14.7±1.8
			2-3	M1-4	14.8±1.4
2-4	M1-5	14.6±1.6
			2-5	M1-6	14.8±1.7
2-11	M2-2	14.7±1.5
			2-12	M2-3	14.6±1.4
2-13	M2-4	14.3±1.6
			2-14	M2-5	14.1±1.4
2-15	M2-6	14.8±1.7
			2-21	M3-2	14.5±1.9
2-22	M3-3	14.8±1.8
			2-23	M3-4	14.9±1.6
2-24	M3-5	14.5±1.7
			2-25	M3-7	14.5±1.8
2-30	M3-6	14.1±1.6
			1-1	M1-1	13.7±1.4
1-11	M2-1	13.5±1.3
			1-21	M3-1	13.5±1.4

By table 2-3 with show 2-2 group result of the test and to be checked by T and compare, prove that the curative effect of the tripartite's compound recipe Inhaled pharmaceutical composition after adding antifungal drug and corresponding two side's compound recipe Inhaled pharmaceutical compositions not containing antifungal drug exist larger difference treating in chronic obstructive disease of lung, thus the curative effect that proof adds the tripartite after antifungal drug or cubic compound recipe Inhaled pharmaceutical composition is more excellent.

Claims (10)

1. one kind can suck compound medicament composition, it is characterized in that the pharmaceutic adjuvant being applicable to inhalation by one or more, and as the antifungal medicine of active component, the 2-3 kind composition in the 7 class medicines such as glucocorticoid, anticholinergic agent, LTRA, mastocyte membrane stabilizer, phosphodiesterase inhibitor, epinephrine broxaterol, H1 receptor antagonist.

2. pharmaceutical composition as claimed in claim 1, is characterized in that described antifungal medicine is one or more in polyenoid class, triazole type or echinocandin antifungal agent thing.

3. pharmaceutical composition as claimed in claim 13, it is characterized in that described polyene antifungal medicine is selected from nystatin, amphotericin B, methylpartricin, hachimycin, described antifungal drug in triazole class is selected from fluconazol, ketoconazole, miconazole, itraconazole, voriconazole, posaconazole; Described echinocandin antifungal agent thing is selected from Caspofungin, MFG, anidulafungin.

4. pharmaceutical composition as described in as arbitrary in claim 1-3, is characterized in that described pharmaceutical composition is powder spray or aerosol.

5. pharmaceutical composition as claimed in claim 4, is prepared into powder spray, it is characterized in that described pharmaceutic adjuvant comprises in carrier, additives one or more.

6. pharmaceutical composition as claimed in claim 5, is characterized in that the mean diameter of described carrier is 20 ~ 80 μm.

7. pharmaceutical composition as claimed in claim 5, is characterized in that described carrier is one or more in saccharide, aminoacid, lecithin, phosphatidylcholine.

8. pharmaceutical composition as described in as arbitrary in claim 5-7, it is characterized in that described powder spray, the summation of described active component and the weight ratio of carrier are 1:1 ~ 1000.

9. pharmaceutical composition as claimed in claim 4, is characterized in that described pharmaceutical composition, is prepared into aerosol, and described pharmaceutic adjuvant comprises the pharmaceutically useful propellant and other optional additives that are applicable to aerosol.

10. pharmaceutical composition as described in as arbitrary in claim 1-9 preparation treatment non-microorganism infect cause asthma, chronic obstructive pulmonary disease medicine in application.