CN1471401A - Macrolide formulations for inhalation and methods of treatment of endobronchial infections - Google Patents

Abstract

Macrolide formulations, such as an erythromycylamine formulation, for delivery by aerosolization are described. The concentrated erythromycylamine formulations contain an amount of erythromycylamine effective to treat infections caused by susceptible bacteria. Unit dose devices having a container containing a formulation of the macrolide antibiotic in a physiologically acceptable carrier are also described. Methods for treatment of pulmonary infections by a formulation delivered as an aerosol having mass median aerodynamic diameter predominantly between 1 to 5 mu m are also described.

Description

The method of macrolide formulations that is used to suck and treatment endobronchial infections

Invention field

The present invention relates to be used for by sucking the macrolide formulations that transmission is novel and improve, for example erythromycylamine preparation and treatment susceptibility are acute or the interior modification method that infects of chronic bronchial.Specifically, the present invention relates to preparation, it contains at least a spissated macrolide antibiotic in the acceptable solution of physiology or with dry powder form.Preparation is fit to the macrolide antibiotic medicine to pulmonary branches endotracheal airway space transmit fluid aerosol or dry powder aerosol form, erythromycylamine for example, wherein the major part of aerosol droplets or preparation granules have the quality meta aerodynamic diameter between the 1-5 micron.The effective dose of macrolide preparation and aerosol transmission can effectively treat and/or prevent acute and interior infection of chronic bronchial and pneumonia, and particularly those are because streptococcus pneumoniae (5treptococcus pneumoniae), Haemophilus influenzae (Haemophilus influenzae), staphylococcus aureus (Staphylococcus aureus), morazella catarrhalis (Moraxellacatarrhalis), pneumonia legionella (Legionella pneumophia), Chlamydia pneumoniae (Chlamydiapneumoniae), and mycoplasma pneumoniae (Mycoplasma pneumoniae) causes.The novel formulation volume is little, but the macrolide antibiotic of effective dose can be delivered to sites of infection.In others, the present invention relates to macrolide list agent formulation novel and improvement, transmit to suck by aerosol.

Background of invention

Streptococcus pneumoniae and other typical case and atypical pathogenic infection suffer from the interior space of bronchus [S.Chodosh etc., the Clinical Infectious Diseases1998 of the individual lung of chronic obstructive disease of lung (COPD); 27:730-738].COPD is modal to be chronic bronchitis (CB) and emphysema.

Chronic bronchitis is a kind of pulmonary disease, it is characterized in that lung tissue inflammation and carrying out property destruction.The weakness of lung is assembled relevant with the interior purulent sputum that causes producing that infects of the chronic bronchial that amount of expectoration increases and impaired pulmonary function causes that produces chronic cough, every day among patient CB.The feature of the acute exacerbation of chronic bronchitis (AECB) is generally the increased coughing, produces the clinical decline that purulent sputum and streptococcus pneumoniae, Haemophilus influenzae and morazella catarrhalis cause.Pneumonia also may be because these biologies cause once more or as the syndrome of COPD is infected.Though for CB, particularly whether the antibacterial therapy of CB acute exacerbation treatment suitably has arguement, (JAMA 1995 for Saint etc.; 273:957-960) proof is not when when treating comparison, and the oral cavity antibacterial therapy provides some clinical benefits.In addition, the dosage of antibacterial is important for recurrence time.Therefore, oral cavity antibacterial dosage is high more, does not have interval long more (S.Chodosh etc., the Clinical Infectious Diseases 1998 of medium infection; 27:730-738).

At present, oral administration is for the selected Therapeutic Method of CB for typical case and the activated macrolide of atypia pathogen and fluoroquinolone.Yet the oral administration of macrolide antibiotic has adverse side effect.The modal side effect relevant with oral cavity/parenteral macrolide antibiotic treatment is diarrhoea/forfeiture appetite, feels sick, suffers from abdominal pain and vomiting (R.N.Brogden, D.Peters, Drugs, 1994; 48:599-616 and H.D.Langtry, R.N.Brogden Drugs 1997; 53:973-1004 and the document of wherein quoting).In addition, pseudomembranous colitis is and the oral cavity antibiotic therapy, comprise the relevant serious side effects of oral cavity macrolide treatment (S.H.Anmad etc., Indian J.Pediatr.1993,60:591-594).Macrolide infiltrates lung tissue along with dosage and change of component (R.N.Brogden, D.Peters, Drugs, 1994 behind the oral administration; 48:599-616 and H.D.Langtry, R.N.Brogden Drugs 1997; 53:973-1004 and the document of wherein quoting).In addition, macrolide nothing to do with medicine, for example the change of theophylline systemic concentration is relevant, this be because with the interaction of liver based on the metabolic system of cytochrome.This drug-drug interactions usually needs dosage to regulate or remove a kind of composition from therapeutic scheme.

Erythromycylamine is 14 yuan of ring macrolide, belongs to antibiotic erythromycin family, has similar antibioticogram external to Erythromycin A, and is similar with Erythromycin A, is effective Therapeutic Method of typical and atypical pneumonia.Erythromycylamine has the C-9 amino functional of S-configuration, replaces the C-9 carbonyl of finding in Erythromycin A.A critical limitation of erythromycylamine is that it lacks buccal absorption, therefore in order to realize useful treatment concentration, exploitation prodrug dirithromycin.The prodrug of erythromycylamine is a dirithromycin, it is characterized in that having between C-9 amino and C-11 hydroxyl the acetaldehyde functional group (see figure 1) of bridging.Cyclic acetaldehyde passes through the rapid hydrolysis of non-enzymatic process (about 30 minutes of half-life) in blood plasma.Dirithromycin has shown can successfully treat deterioration (M.Cazzola etc., the Respiratory Medicine that takes place among patient CB; 1998; 92:895-901).(30-44 hour) (R.N.Brogden, D.Peters, Drugs, 1994 long half-lift that the major advantage of erythromycylamine being it; 48:599-616).Unfortunately, the oral cavity usability of dirithromycin 10-14% only in the people most ofly discharges (62-81%) as erythromycylamine at the feces camber.Because erythromycylamine is not absorbed, its prodrug dirithromycin absorbs seldom, and the active drug substance amount that pulmonary infection general typical for treatment and that the atypia antibacterial causes can get seldom.Though this sites of infection has enough erythromycylamine concentration so that curative effect to be provided, drug concentrations is limited.Oral cavity dosage is high more, or the frequent more drug level that improves action site of dirithromycin administration; Yet, easier generation adverse events, and can increase working hard and adaptation of patient.

Reported antibiotic one of the research the earliest of the use solation that is used for the treatment of pulmonary infection among the Lancet 22:1377-9 (1981).Controlled double-blind study for 20 patients CF shows that the aerosol administration of Carbenicillin and glucosamine gentamycin can improve patient's CF health.From then on, dispersive report has detected general aminoglycoside aerosol transmission, particularly tobramycin (seeing for example U.S. Patent number 5,580,269) in the document.Yet the assessment of these researchs and difficult is because antibiotic formulations, breathing technique, aerosol apparatus and compressor are different.In addition, the aerosol transmission is difficult to assessment usually, because differences such as preparation, aerosol transfer device, dosage, granular size, therapies.When for example quality meta aerodynamic diameter (MMAD) is greater than 5 microns, granule is deposited in the upper respiratory tract usually, has reduced the amount that is delivered to the sites of infection in the lower respiratory tract.Arch.Dis.Child., the article of publishing among the 68:788 (1993) has been described the needs of standard method emphatically and to the improvement of patient's CF aerosol-applied medicine.

Because shortage is additive-free and the physiology goes up compatible preparation, particularly granular size homogeneous has been damaged effective aerosol administration at present because some aerosol apparatus can not produce little.With drug delivery space and lung on every side in the bronchus, the particle size range of the aerosol particle that sites of infection is required is about 1-5 micron.Many aerosolized therapeutic agents, the aerosol apparatus that comprises aminoglycoside produce a large amount of particle diameters less than 1 micron or greater than 5 microns aerosol particle.For effective treatment, most of aerosolized particles containing antibotics can not have the MMAD greater than 5 microns.When aerosol contained a large amount of MMAD greater than 5 microns granule, the granule of greater particle size was deposited in the upper respiratory tract, has reduced the antibiotic amount of the sites of infection that is delivered to lower respiratory tract.

The commercially available aerosol apparatus of present three classes, jet nebulizer, vibration porous plate aerosol apparatus and ultrasonic nebulizer can produce and transmit the aerosol particle of diameter between the 1-5 micron, and this particle diameter is preferred for the bacterial infection treatment of lung.Therefore, can in injection, vibration porous plate and ultrasonic nebulizer, effective aerosolized macrolide formulations be very favorable for providing.In addition, newer aerosol generating technique can get at present, comprises that machinery is extruded and passive and energy supply Diskus, is used to transmit the therapeutic agent of dry powder form.

Another requirement of acceptable preparation is suitable storage life.Usually, the antibiotic solution of antibiotic and specific intravenously administrable contains phenol or other antiseptic, to keep drug effect and the generation of catabolite is minimized.Yet phenol and other antiseptic can be induced bronchospasm when aerosolized, and a kind of suffering from pneumonopathy, for example bad incident among the patient of chronic bronchitis.

Use macrolide antibiotic, erythromycylamine for example, be used to suck the aerosol of liquid or dry powder form, have and overcome the weak oral cavity biological utilisation relevant, simultaneously lung is provided the advantage of the antibiotic valid density that can not realize by oral cavity or intravenous route with prodrug.It is its natural high-affinity and persistency in the blood plasma compartment (long blood plasma/organize the half-life) for lung tissue that the erythromycylamine aerosol transmits another advantage.Endobronchial infections can be eliminated or reduce significantly to the transmission of high concentration aerosol, long blood plasma/organize the combination of half-life and high lung affinity will make the macrolide treatment safer after using single agent aerosol.

Therefore, very advantageously provide the macrolide antibiotic preparation, erythromycylamine for example, it does not contain antiseptic, is adjusted to the pH level that slows down or prevent to degrade, and for patient's tolerance, provide be fit to commercially to distribute, storage and suitable half-life of using.

Therefore, an object of the present invention is to provide macrolide antibiotic, the concentrate formulation of erythromycylamine, Erythromycin A, Roxithromycin, Azithromycin and clarithromycin for example, it contains can be by spraying, for example by using injection, vibration porous plate or ultrasonic nebulizer or Diskus effectively aerosolized, become the macrolide antibiotic of valid density of the form of aerosol particle, this aerosol particle particle diameter is mainly between the 1-5 micron.

The invention summary

According to the present invention, find now, the macrolide antibiotic of antimicrobial effective amount that can be by suck being fit to solution that aerosol produces or dry powder form, for example erythromycylamine, Erythromycin A, Roxithromycin, Azithromycin or clarithromycin are administered to the patient, effectively and effectively treatment suffers from or dangerously suffers from endobronchial infections, for example antibacterial streptococcus pneumoniae, Haemophilus influenzae, staphylococcus aureus, morazella catarrhalis and/or atypia pathogen pneumonia legionella, Chlamydia pneumoniae, and/or the people of the infection of mycoplasma pneumoniae and non-human animal.

Therefore, one aspect of the present invention relates to and is fit to the effectively concentrate formulation of transmission, this transmission is by sucking the macrolide antibiotic medicine, for example erythromycylamine, Erythromycin A, Roxithromycin, Azithromycin or clarithromycin, make its enter suffer from or the individual bronchus of the bacillary pulmonary infection of dangerous trouble in the space.

Another aspect of the present invention provides and has been fit to the macrolide antibiotic medicine, for example erythromycylamine, Erythromycin A, Roxithromycin, Azithromycin or clarithromycin, effectively transmit and make spatial preparation in its bronchus that enters the individuality of suffering from bacterial infection, these antibacterials are selected from streptococcus pneumoniae, Haemophilus influenzae, staphylococcus aureus, morazella catarrhalis and/or atypia pathogen pneumonia legionella, Chlamydia pneumoniae and mycoplasma pneumoniae.

Another aspect of the present invention provides and has been fit to the macrolide antibiotic medicine, for example erythromycylamine, Erythromycin A, Roxithromycin, Azithromycin or clarithromycin, effectively transmit and make it enter individual endobronchial space, to prevent or significantly to reduce the preparation of the danger of dangerous patient's pulmonary infection, this pulmonary infection is caused by streptococcus pneumoniae, Haemophilus influenzae, staphylococcus aureus, morazella catarrhalis and/or atypia pathogen pneumonia legionella, Chlamydia pneumoniae and mycoplasma pneumoniae.

Another aspect of the present invention provides liquid preparation, it contains 50-750mg macrolide antibiotic medicine, the equivalent of erythromycylamine, Erythromycin A, Roxithromycin, Azithromycin or clarithromycin for example, this equivalent is included in 0.5-5 milliliter physiology and goes up in the acceptable carrier, for example be diluted to the saline of 1/4 normal saline intensity, wherein said preparation has osmolarity, salinity and the pH of physiology's tolerance, is fit to pass to individuality with conc forms by the aerosol suction.

Another aspect of the present invention provides dry powder formulations, it contains 25-250mg macrolide antibiotic medicine, the equivalent of erythromycylamine, Erythromycin A, Roxithromycin, Azithromycin or clarithromycin for example, this equivalent is included in the physiology and goes up in the acceptable dry powder carrier, be used for passing to individuality with conc forms by the aerosol suction, wherein dry powder formulations contains the macrolide antibiotic medicine of the 50-90% weight of having an appointment.

Another aspect of the present invention provides the method for treatment pulmonary infection, this infection is owing to susceptible bacteria causes, this method is that the individuality of the described treatment of needs is used a kind of aerosol preparations by suction, said preparation contains the macrolide antibiotic medicine of antimicrobial effective amount, for example erythromycylamine, Erythromycin A, Roxithromycin, Azithromycin or clarithromycin, it is mixed with the physiology and goes up compatible solution or dry powder form, wherein in the aerosol preparations particulate quality meta aerodynamic diameter (MMAD) mainly between the 1-5 micron.

In others, the invention provides single agent formulation and device, be applicable to efficient intake system and be connected, single agent device contains the macrolide antibiotic preparation of the present invention that is designed to be equipped with and store relative small size, and give suction apparatus with agent delivery, pass to individual container with aerosol form.In one aspect, single agent device of the present invention comprises sealed container, ampoule for example, it contains the liquid macrolide antibiotic preparation that is less than about 2.0ml, and said preparation contains the about 50-150mg/ml macrolide antibiotic in the acceptable liquid-carrier on the physiology.In addition, the container of single agent device can contain and be less than about 1.5ml, or is less than about 1.0ml liquid macrolide antibiotic preparation, and the macrolide antibiotic preparation can contain the 80-180mg/ml that has an appointment, or about 90-120mg/ml macrolide antibiotic.In yet another aspect, single agent device of the present invention contains sealed container, ampoule for example, and it contains dry powder macrolide antibiotic preparation, and its said preparation contains the about 20-250mg macrolide antibiotic in the acceptable dry powder carrier on the physiology.The single agent container of sealing of the present invention preferably adapts to the macrolide antibiotic agent delivery to efficient suction apparatus, and this device is used for aerosolized and makes individual the suction.

The accompanying drawing summary

Above-mentioned aspect of the present invention and many attendant advantages will be united the easier quilt of accompanying drawing according to as detailed below and be understood, wherein:

Fig. 1 illustrates the chemical constitution of erythromycylamine and dirithromycin;

Fig. 2 representative is with 60,100 and 150mg/mL and pH5.0,6.0 and 7.0, at 4 ℃, as the stability of the erythromycylamine hydrochlorate in the embodiment 4 described aqueous solutions;

Fig. 3 representative is with 60,100 and 150mg/mL and pH5.0,6.0 and 7.0, at 25 ℃, as the stability of the erythromycylamine hydrochlorate in the embodiment 4 described aqueous solutions;

Fig. 4 representative is with 60,100 and 150mg/mL and pH5.0,6.0 and 7.0, at 40 ℃, as the stability of the erythromycylamine hydrochlorate in the embodiment 4 described aqueous solutions;

Fig. 5 representative is with 60,100 and 150mg/mL and pH5.0,6.0 and 7.0, at 60 ℃, as the stability of the erythromycylamine hydrochlorate in the embodiment 4 described aqueous solutions;

Fig. 6 representative is with 60,100 and 150mg/mL and pH5.0,6.0 and 7.0, at 60 ℃, as the stability of the sulphuric acid erythromycylamine in the embodiment 4 described aqueous solutions;

Fig. 7 representative is with 60,100 and 150mg/mL and pH5.0,6.0 and 7.0, at 60 ℃, as the stability of the acetic acid erythromycylamine in the embodiment 4 described aqueous solutions;

Fig. 8 illustrated in the rat (n=3) at potion 25mg/kg intravenously administrable, or potion 30 or 60mg/ml solution sucks after 30 minutes, and the mean plasma concentration of erythromycylamine (0.7 or 1.77mg/kg lung dosage) is as described in embodiment 6.

Fig. 9 illustrated in the rat (n=3) at potion 25mg/kg intravenously administrable, or potion 30 or 60mg/ml solution sucks after 30 minutes, and the average pulmonary concentration of erythromycylamine (0.7 or 1.77mg/kg lung dosage) is as described in embodiment 6.

Figure 10 has illustrated in the rat (n=3) that in 3 days the every day inhalation is after 30 minutes, erythromycylamine in the streptococcus pneumoniae pulmonary infection model is renderd a service, and compares with the 5mg/ml (0.13mg/kg) described in the embodiment 7,25mg/ml (0.27mg/kg) and 50mg/ml (1.3mg/kg) inhalation dose; With

Figure 11 has illustrated that single agent administration is after 30 minutes in the rat (n=3), erythromycylamine in the streptococcus pneumoniae pulmonary infection model is renderd a service, and compares with the 1mg/ml (0.03mg/kg) described in the embodiment 8,5.5mg/ml (0.13mg/kg), 25mg/ml (0.27mg/kg) and 50mg/ml (1.3mg/kg) inhalation dose.

After Figure 12 had illustrated that the 60mg/ml sulfuric acid solution is used in single agent, suction in 30 minutes, average blood plasma in the dog and full lung erythromycylamine concentration were as described in embodiment 9.

After Figure 13 had illustrated that the 60mg/ml sulfuric acid solution is used in single agent, suction in 30 minutes, the average lung erythromycylamine concentration of each lobe of the lung in the dog was as described in embodiment 9.

The detailed description of preference

Erythromycylamine and dirithromycin are the macrolide with the described chemical constitution of Fig. 1.Dirithromycin, the prodrug of erythromycylamine is the wide spectrum macrolide antibiotic that is used for the treatment of AECB and pneumonia.Be used for macrolide antibiotic of the present invention and comprise for example erythromycylamine, dirithromycin (prodrug of erythromycylamine), Erythromycin A, clarithromycin (6-O-erythromycin), Azithromycin or Roxithromycin.The macrolide of other renewal, for example (for example (ABT-773 makes a summary the ketone cyclic lactone F-2133-2141 and HMR-3647 (Drugs of the Future for 39 ICAAC (1999), JIUYUE-29 days on the 26th, 23,591 (1998), 38 ICAAC (1998), JIUYUE-27 days on the 24th, the summary A-49))) and the aldehyde cyclic lactone (see J.Med.Chem., 1998,41,1651-1659 and 1660-1670) also can be used for enforcement of the present invention.In one aspect of the invention, used macrolide antibiotic is erythromycylamine or dirithromycin in the aerosol preparations as herein described.Erythromycylamine and dirithromycin have the described chemical constitution of Fig. 1.

According to the present invention, provide treatment to need the method for the individuality of treatment, for example this individuality suffers from endobronchial infections, comprises individuality by sucking the macrolide antibiotic preparation administration of antimicrobial effective amount.This aspect of the present invention is specially adapted to prepare spissated macrolide, erythromycylamine for example, be applicable to by small size, the high output speed of breathing promotion and efficient suck aerosolized, to produce the macrolide aerosol particle diameter between the 1-5 micron, this is that macrolide effectively is transmitted into space in the bronchus, needs with treatment susceptibility infected by microbes.Preparation preferably contains seldom, but the small size physiology that is formulated in of effective dose goes up macrolide in the acceptable solution.For example, the aqueous solution that a kind of salinity was regulated can produce by patient well tolerable, but prevents accessory adverse side effect, for example the macrolide aerosol particle of bronchospasm and cough generation.For example, 1/4 normal saline solution is used for this purpose.Use macrolide formulations provided by the invention by more effective, in the enough shorter time, use the macrolide littler, thereby reduced administration cost and drug waste, significantly strengthened the probability that patient adapts to than the volume of conventional dosage regimen.

Therefore, according to an aspect of the present invention, provide treatment to need the individuality of treatment, the method of for example suffering from the individuality of susceptibility endobronchial infections, comprise individuality is used the aerosol preparations of potion atomization by suction, said preparation contains acceptable carrier on have an appointment 50-750mg macrolide and the materia medica.In others of the present invention, the aerosol of using in enforcement of the present invention can be a liquid preparation, contain the 50-150mg/ml macrolide antibiotic of having an appointment, preferably about 70-130mg/ml macrolide antibiotic, more preferably from about 90-110mg/ml macrolide antibiotic.Preferably individuality is used the aerosol preparations of small size.Therefore aspect this individuality is being used the atomization liquid aerosol preparation that potion is less than about 2.0ml.In yet another aspect, individuality is used the atomization liquid aerosol preparation that potion is less than about 1.5ml.In yet another aspect, individuality is used the atomization liquid aerosol preparation that potion is less than about 1.0ml.

In others, Macrocyclic lactone compounds of the present invention can be mixed with and be used for the dry powder form that aerosol transmits.Term used herein " powder " means a kind of compositions, and it contains the segmentation solid granulates, and it can free-flow, and can easily be dispersed in the suction apparatus, suck by individuality subsequently, thereby make granule reach pulmonary, permeate and be deposited on every side in the airway.Therefore, powder formulation of the present invention is called as " respirable ".Preferred powder mean diameter has than uniform spherical less than 10 microns.More preferably diameter is less than about 7.5 microns, most preferably less than about 5.0 microns.Usually particle size distribution is between about 0.1-5 micron, particularly about 1-5 micron.Dry powder formulations of the present invention has moisture, makes granule easily to be dispersed in and forms aerosol in the suction apparatus.The water that normally about 10% weight of this moisture (%w) is following is less than the water of about 5%w usually and preferably is less than the water of about 3%w.

Dry powder formulations of the present invention contains acceptable carrier on the Macrocyclic lactone compounds of the present invention for the treatment of effective dose and a kind of materia medica usually.Dry powder formulations of the present invention can contain the macrolide antibiotic of the 25-250mg that has an appointment, preferably the macrolide antibiotic of about 50-200mg, the more preferably from about macrolide antibiotic of 75-150mg.Aspect this, dry powder formulations can contain the macrolide antibiotic of the 50%-90% weight of having an appointment of the present invention, the macrolide antibiotic of preferably about 60%-88% weight and the macrolide antibiotic of 75%-85% weight more preferably from about.

Acceptable carrier comprises and can enter patient pulmonary on the suitable materia medica, and does not have the carrier of remarkable bad toxicology effect to comprise for example stabilizing agent, filler, buffer agent, salt etc. for lung.Acceptable carrier obtains required stability on the materia medica of use capacity, dispersibility, and concordance and bulking feature are to guarantee that the individual evenly pulmonary of needs is transmitted compositions.The actual amount of acceptable carrier can be about 0.05%-99.5%w on the materia medica.More preferably can use acceptable carrier on the materia medica of about 5%-95%w.Most preferred, can use acceptable carrier on the materia medica of about 10%-90%.

The drug excipient that is used as carrier among the present invention comprises stabilizing agent, for example human serum albumin (HAS); Filler, for example saccharide, aminoacid and polypeptide; PH regulator agent or buffer agent; Salt, for example sodium chloride etc.These carriers can be crystal or amorphous form, maybe can be both mixture.Preferred filler comprises compatible saccharide, polypeptide, aminoacid or its combination.Suitable saccharide comprises monosaccharide, for example galactose, D-maltose, sorbose etc.; Disaccharide, for example lactose, trehalose etc.; Cyclodextrin, for example 2-HP-; And polysaccharide, for example Raffinose, maltodextrin, glucosan etc.; Aldehyde alcohol, for example mannitol, xylitol etc.One group of preferred saccharide comprises lactose, trehalose, Raffinose, maltodextrin and mannitol.Suitable polypeptide comprises aspartame.Aminoacid comprises alanine and glycine, preferred glycine.Can add additive, make that in spray-drying process conformation is stable and improve the dispersibility of powder as the small component of dry powder formulations of the present invention.These additives comprise hydrophobic amino acid, for example tryptophan, tyrosine, leucine, phenylalanine etc.Suitable pH regulator agent or buffer agent comprise from the organic salt of organic bronsted lowry acids and bases bronsted lowry preparation, for example sodium citrate, sodium ascorbate etc.; Optimization citric acid sodium.

In others, the present invention relates to spissated macrolide formulations, for example spissated erythromycylamine preparation is fit to by aerosolized macrolide effectively is transmitted into space in the bronchus.The present invention is fit to the spissated erythromycylamine of preparation, be used for by spray, vibration porous plate, ultrasonic or the dry powder aerosol apparatus is aerosolized, the generation particle diameter is the erythromycylamine aerosol particle between the 1-5 micron, it is that erythromycylamine effectively is delivered in the bronchus space is preferred, be used for the treatment of streptococcus pneumoniae, Haemophilus influenzae, staphylococcus aureus, morazella catarrhalis and pneumonia legionella, Chlamydia pneumoniae, and mycoplasma pneumoniae infection.Preparation preferably contains on a small quantity, but the erythromycylamine of effective dose, it is formulated in the acceptable solution of physiology of the relative small size with certain salinity, or as dry powder, be adjusted to and allow to produce the well tolerable erythromycylamine aerosol of patient, but prevent to produce less important adverse side effect, for example bronchospasm and cough.

The primary requirement of any aerosolized preparation is its safety and effectiveness.Other advantage is low treatment cost, the practicality of use, long shelf life, the optimization of storage and aerosol apparatus.

Aerosol preparations is mainly sprayed and is changed into the particle diameter that can be delivered to tip and alveolar bronchiole, wherein streptococcus pneumoniae, Haemophilus influenzae, staphylococcus aureus and morazella catarrhalis, with atypia pathogen pneumonia legionella, Chlamydia pneumoniae and mycoplasma pneumoniae or other susceptibility antibacterial be present in suffer with chronic bronchitis and the patient of pneumonia in.Streptococcus pneumoniae, Haemophilus influenzae, staphylococcus aureus, morazella catarrhalis, pneumonia legionella, Chlamydia pneumoniae and mycoplasma pneumoniae are present in whole airway, comprise in bronchus, bronchioles and the lung parenchyma.Yet they mainly are present in tip and the alveolar bronchiole.When infecting deterioration, antibacterial also may be present in the alveolar.Therefore, in one aspect, the invention provides a kind of preparation, it is delivered to the tip bronchioles by network in the whole bronchus, finally is delivered in the parenchyma.

Prepare aerosolized erythromycylamine preparation, be used for erythromycylamine effectively is delivered to space in the pulmonary branches trachea.Select specific injection, vibration porous plate or ultrasonic nebulizer, form the mainly erythromycylamine aerosol particle between the 1-5 micron of quality meta aerodynamic diameter.The preparation of erythromycylamine and the amount of transmission can effectively treat and/or prevent endobronchial infections, particularly because antibacterial streptococcus pneumoniae, Haemophilus influenzae, staphylococcus aureus and morazella catarrhalis, the infection that causes with atypia pathogen pneumonia legionella, Chlamydia pneumoniae and mycoplasma pneumoniae.Preparation has the permission of being adjusted to and produces the well tolerable aerocolloidal salinity of erythromycylamine of patient.In addition, preparation has suitable osmolarity.Preparation has little volume that can be aerosolized, the erythromycylamine of effective dose can be passed to sites of infection.In addition, aerosolized preparation is not by causing that adverse side effect causes the airway function damage.

Available have relative two-forty aerosol output, high propellant dose-effect power and be limited to patient's injection in actual air-breathing period, administration of antibiotics preparation.Therefore, though conventional air-blast atomizer shows the aerosol output speed of 3 microlitres/second disease, the common demonstration of suction apparatus used in the invention process is not less than about 5 microlitre/seconds, more preferably is not less than about 6.5 microlitre/seconds, most preferably is not less than the aerosol output speed of about 8 microlitre/seconds.In addition, conventional air-jet nebulizer has lower propellant dose-effect power, usually discharge the aerocolloidal nominal standard dose of conduct of about 55% (or following), be used for suction apparatus of the invention process usually discharge at least about 75%, more preferably at least about 80%, most preferably at least about 85% loading dose, the aerosol that sucks as patient.In others, conventional air-jet nebulizer continue to discharge aerosolized medicine usually in the whole transmission phase, no matter therefore patient has wasted the drug dose of the load of considerable part whether in the resting state of air-breathing, expiration or breath cycle.On the contrary, being used for preferred suction apparatus of the present invention is that breathing is activated, is limited to the actual aerosol particle that transmits macrolide formulations air-breathing period patient.Meet above-mentioned condition, and be applicable to that representative suction apparatus of the invention process is Aerodose ^TMAnd go into device, and available from Aerogen, Inc., Sunnyvale, California.Aerodose ^TMInhaler produces aerosol with the perforated membrane that piezoelectric vibrator drives.The aerosol transmission is that breathing is activated, is limited to the intake period of breathing, does not mind that promptly inhaling the circulation expiration phase takes place aerosolized.Compare with the inhaler of holding one's breath, airpath design allows normal suction-expiration to breathe.In addition, Aerodose ^TMInhaler is independence of handing and the inhaler that transports easily.Though piezoelectric vibrator aerosol maker, for example Aerodose ^TMInhaler is preferred in the present the invention process, can use to meet above-mentioned performance condition, and can transmit small dose volumes deposited of the present invention, has efficient relatively sedimentary other inhaler and sprayer unit in the short period relatively.

In others of the present invention, above-mentioned method provides single agent formulation and device according to the present invention, and patient is used the macrolide antibiotic preparation with inhaler.Preferred single agent device contains a container, and it is designed to fill and store the macrolide antibiotic preparation of the present invention of relative small size and gives suction apparatus with agent delivery, is used for patient with the aerosol form transmission.In one aspect, single agent container of the present invention contains a plastic ampoule, and macrolide formulations of the present invention wherein is housed, and in sealed under aseptic conditions.Preferred single agent ampoule is furnished with and turns on joint or other device of opening easily, is used to open ampoule, and gives suction apparatus with the macrolide antibiotic agent delivery.The ampoule that contains pharmaceutical preparation is well known to those skilled in the artly (to see for example U.S. Patent number 5,409,125,5,379,898,5,213,860,5,046,627,4,995,519,4,979,630,4,951,822,4,502,616 and 3,993,223, its disclosure is incorporated herein for your guidance).Single agent container of the present invention can be designed to directly insert suction apparatus of the present invention, is used for giving suction apparatus with contained macrolide antibiotic agent delivery, and finally gives patient.

According to this aspect of the present invention, single agent device is provided, it is the container of a sealing, wherein contain and be less than about 5.0ml, preferably be less than about 3.0ml, most preferably be less than the liquid macrolide antibiotic preparation of about 2.0ml, it contains the 50-150mg/ml macrolide antibiotic of having an appointment in physiologically acceptable carrier, and the container of sealing is fit to the macrolide antibiotic agent delivery to being used for aerosolized suction apparatus.The suitable macrolide antibiotic that the present invention uses this aspect comprises those macrolide antibiotics that describe in detail above.In present preference, the macrolide antibiotic that uses in single agent device of the present invention is an erythromycylamine.In others of the present invention, single agent device of the present invention can contain liquid macrolide antibiotic preparation, and it contains the macrolide antibiotic of the 70-130mg/ml that has an appointment.In others of the present invention, single agent device of the present invention can contain liquid macrolide antibiotic preparation, and it contains the macrolide antibiotic of the 90-110mg/ml that has an appointment.

In the preferred liquid list of the present invention agent formulation, physiologically acceptable carrier can be a normal saline solution, the normal saline solution of 1/4 intensity for example, be adjusted to and produce the well tolerable erythromycylamine aerosol of patient, but prevent the salinity of accessory adverse side effect (for example bronchospasm and cough) substantially.

In another aspect of the present invention, dry powder formulations of the present invention is placed suitable single agent container, its amount enough provides macrolide antibiotic chemical compound of the present invention to patient, is used for sucking single agent treatment by dry powder.The dry powder list agent container that preferably is contained in the suitable suction apparatus can aerosolized dry powder composite based on macrolide, by being dispersed in, it forms aerosol in air-flow, in a chamber, catch the aerosol of generation like this then, this chamber is combined with mouthpiece, and it is used to allow the patient of needs treatment suck subsequently.This dose container comprises the container of any sealing preparation known in the art, and for example gelatin and plastic capsule have removable part, makes air-flow (for example air) enter container, with the dispersion of dry powder preparation.The example of this container is a U.S. Patent number 4,227, in 522,4,192,309 and 4,105,027 known those.Suitable containers also comprises those that are connected with Glaxo ' sVentolin Rotohaler board powder inhalator or Fison ' s Spinhaler board powder inhalator.Another kind provides suitable single agent container of remarkable moisture barrier to form with the aluminium foil plastic sheet.The macrolide powder is packed into according to weight or volume in the depression of the paper tinsel that can be shaped, with the paper tinsel that covers-plastic sheet sealing.This container that is used for powder inhalation device is at U.S. Patent number 4,778, describes to some extent in 054, is used for Glaxo ' sDiskhaler RTM (U.S. Patent number 4,627,432,4,811,731; With 5,035,237).All these documents are incorporated herein for your guidance.

According to this aspect of the present invention, single agent device is provided, it contains a sealed container, wherein contain dry powder formulations, said preparation contains the 25-250mg macrolide antibiotic of having an appointment, preferably about 50-200mg macrolide antibiotic, 75-150mg macrolide antibiotic more preferably from about, in physiologically acceptable dry powder carrier, the container of sealing is applicable to the macrolide antibiotic agent delivery is arrived suction apparatus, is used for aerosolized.Aspect this, dry powder formulations can contain the macrolide antibiotic of the 50%-90% weight of having an appointment of the present invention, the macrolide antibiotic of preferably about 60%-88% weight and the macrolide antibiotic of 75%-85% weight more preferably from about.

Aerosol erythromycylamine preparation

In order to assess the stability of erythromycylamine in aqueous solution, prepared three kinds of antibiotic salt forms, and placed under different temperature, time, concentration and the pH condition.Erythromycylamine concentration is determined by the HPLC method.The data of these stability studies have disclosed several important discoveries shown in Fig. 2-7.At first, as expection, the stability of aminoguanidine hydrochloride erythromycin be directly proportional with the temperature of solution (seeing Fig. 2-5).The second, erythromycylamine solution compares at acid pH 5 and 6 more stable (Fig. 5) at neutral pH7.This result is consistent to the effect of macrolide antibiotic degraded with known pH.One of main degradation pathway is the forfeiture neutral sugar, and cladinose (see J.Chrom.A, 812m, 1998,255-286).The 3rd, acetic acid erythromycylamine solution is at the pH6 hydrochloric acid with sulfate under identical pH more stable (comparison diagram 7 and Fig. 5 and 6) corresponding with 7 ratios.

Liquid of the present invention and dry powder formulations contain the 50-750mg that has an appointment for every dose, preferably about 75-600mg, most preferably from about 100-500mg macrolide antibiotic medicine, for example acetic acid erythromycylamine.This is equivalent to minimum but the erythromycylamine of streptococcus pneumoniae, Haemophilus influenzae, staphylococcus aureus, morazella catarrhalis, pneumonia legionella, Chlamydia pneumoniae and mycoplasma pneumoniae infection in the space in the inhibition bronchus of effective dose.

The at present preferred liquid aerosol erythromycylamine preparation of the present invention contains the 90-110mg sulphuric acid erythromycylamine of having an appointment in every 1mL1/4 normal saline.This is equivalent to suppress the representativeness of AECB bacterial infection and the erythromycylamine of effective dose.

Patient and aerosol generator all are responsive for osmolarity, pH and the ionic strength of preparation.Found now this problem can be easily by at 1/4 normal saline, contain promptly that preparation erythromycylamine solution solves in the saline of 0.225% sodium chloride.1/4 normal saline is that erythromycylamine is delivered to spatial suitable carrier in the bronchus.

Chronic bronchitis people and other suffer from the high incidence that the patient who infects in the chronic bronchial has bronchospasm or asthma airway.These airways are for hypotonic and high permeation colloidal sol, for permeability ionic concentration, particularly halogen, and chlorine and be responsive for example for acid or alkaline aerosol.But stimulate the effect clinical manifestation of airway to be cough or bronchospasm.Both of these case all can stop aerosolized erythromycylamine effectively is delivered to space in the bronchus.

The amino Akne-Mycin of acetic acid, hydrochloric acid and sulphuric acid that every milliliter 1/4 normal saline contains the 60-100mg erythromycylamine has the osmolarity of 130-400mOsm/kg.This is using in the aerocolloidal safety range (table 1) for the chronic bronchitis people.

Table 1

The osmolarity of erythromycylamine solution as salt form,

The function of pH and concentration: experiment and notional result

Salt	????pH	Concentration (mg/ml)	Experiment (mOsm/kg)	Theoretical (mOsm/kg)
					Acetic acid	????5.0	????60	????300	????245
		????100	????518	????408
							????150	????840	????613
Acetic acid	????6.0	????60	????365
							????100	????639
		????150	????701
					Acetic acid	????7.0	????60	????501
		????100	????891
							????150	????746
Hydrochloric acid	????5.0	????60	????227	????245

		????100	????382	????408
							????150	????601	????613
Hydrochloric acid	????6.0	????60	????224
							????100	????382
		????150	????598
					Hydrochloric acid	????7.0	????60	????226
		????100	????386
							????150	????594
Sulphuric acid	????5.0	????60	????130	????163
							????100	????239	????272
		????150	????396	????409
					Sulphuric acid	????6.0	????60	????132
		????100	????238
							????150	????395
Sulphuric acid	????7.0	????60	????132
							????100	????241
		????150	????391

The pH of preparation transmits no less important for aerosol.As before noticing, when aerosol when being acid or alkaline, it can cause bronchospasm and cough.The safety range of pH is relative; Some patients will tolerate the tart aerosol of appropriateness, and will cause bronchospasm in other people.Any aerosol that has in the susceptibility individuality less than 4.5 pH will cause bronchospasm; Aerosol with the pH between the 4.5-5.0 can cause this problem once in a while.The aerosol of pH between 5.0-7.0 is considered to safe.Avoid pH greater than any aerosol of 10.0, because can cause the stimulation of bronchospasm.The best pH of aerosol preparations is pH5.0-7.0.

In one aspect, the preferred main atomization of liquid preparation of the present invention becomes granule, and this granule can be with end and alveolar bronchiole and the lower respiratory tract of drug delivery to the antibacterial place.In order effectively erythromycylamine to be delivered to pulmonary branches endotracheal airway space by aerosol, the essential aerosol particle of quality meta aerodynamic diameter between the 1-5 micron that form.Be used for the treatment of and prevent endobronchial infections, particularly because the preparation and the transmission capacity of the erythromycylamine of the infection that antibacterial streptococcus pneumoniae, Haemophilus influenzae, staphylococcus aureus, morazella catarrhalis, pneumonia legionella, Chlamydia pneumoniae and mycoplasma pneumoniae cause must be effectively at the bronchus inner surfacies.The formulation dosage of transmitting preferably has minimum actual aerosolized volume, the erythromycylamine of effective dose can be delivered to sites of infection.Preferred preparation also provides the condition that does not influence the airway function.Therefore, preferred formulation contains the medicine of capacity, is allowing its effective transmission, avoids simultaneously preparing under the condition of untoward reaction.Novel formulation of the present invention meets these requirements.

According to the present invention, erythromycylamine is mixed with the dosage form that the patient who is used for chronic bronchitis and pneumonia sucks treatment.Because patient is found everywhere through the world, and needs preparation that rational long shelf life can be arranged.Storage condition and preparation stability thereby become important.

As mentioned above, the pH of solution is important.5.0-7.0 preferred about 6.0 pH is best for storage and long shelf life.

Preparation is stored in 1 milliliter of-2 milliliters of low density polyethylene (LDPE) (LDPE) vial usually.With blowing-fill-the aseptic filling vial of seal process.Seal vial with aluminium foil bag.

Preparation is another very important condition for the stability of oxidation.If medicine is degraded before aerosolized, small amount of drug is passed to lung, and therefore infringement is treated and caused the condition that may cause for the generation of erythromycylamine resistance, because the dosage that transmits very little.In addition, the erythromycylamine catabolite can cause bronchospasm and cough.For the oxidative degradation that prevents erythromycylamine with acceptable stability is provided,, produce product with low oxygen content by the LDPE vial being packaged in the oxygen protective package (comprising aluminium foil bag, 6 every bag).Before the vial filling, the solution in the blending tank leads to nitrogen, and the ring bag head is eliminated nitrogen.With this method, prevent the hydrolysis and the oxidation of erythromycylamine.

II. aerosolized device

The aerosolized device that is used for the present invention's practice for example sprays, vibrates porous plate or ultrasonic nebulizer and preparation spraying of the present invention can be formed aerosol particle usually, and it mainly is a 1-5 micron size.In this application, mainly be meant at least 70%, but the aerosol particle of preferred all generations more than 90% is in the 1-5 micrometer range.

Can produce and transmit size particles between the 1-5 micron, aerosol apparatus for treatment streptococcus pneumoniae, Haemophilus influenzae, staphylococcus aureus, morazella catarrhalis, pneumonia legionella, Chlamydia pneumoniae and mycoplasma pneumoniae infection the best, for example spray, ultrasonic, vibration porous plate and fill can the dry powder inhaler, can buy at present, or with known method and material production.The running of jet nebulizer is by air pressure solution to be broken into aerosol droplets.The running of vibration porous plate aerosol apparatus is the ultrasonic vacuum that produces by the porous plate that uses rapid vibration, so that solvent droplets is pushed through porous plate.The running of ultrasonic nebulizer is by piezoquartz, and it becomes little aerosol droplets with liquid shear.Yet only the preparation of some erythromycylamines can be effectively by these three kinds of atomizer spray, because these pH and the ionic strengths of installing for preparation are responsive.

Though can use various devices, only the aerosol apparatus of limited quantity is applicable to the present invention.Be used for preferred aerosol apparatus of the present invention and comprise for example AeroNeb ^TMAnd AeroDose ^TMVibration porous plate aerosol apparatus (AeroGen, Inc., Sunnyvale, California), the Sidestream aerosol apparatus (Medic-Aid Ltd., West Sussex, England), Pari LC Plus ^With Pari LC Star ^Jet nebulizer (Pari RespiratoryEquipment, Inc., Richmond, Virginia) and Aerosonic ^TM(DeVilbiss MedizinischeProdukte (Deutschland) GmbH, Heiden, Germany) and UltraAire ^(OmronHealthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizer.

III. aerosol pharmacokinetics

By IV and inhalation route rat is used erythromycylamine solution, measure the drug level in blood plasma and the lung.The data of these researchs are shown in Fig. 8 and 9.Select two kinds of dosage levels for sucking pipeline, 1.7 and 0.7mg/kg, with single vein dosage (25mg/kg) relatively.

The dosage demarcation AUC of erythromycylamine is respectively 24.21,1067.84 and 848.34 μ gh/g in IV (25mg/kg), suction (1.7mg/kg) and the lung (0.7mg/kg).Therefore, directly lung is transmitted erythromycylamine by inhalation route, the lung levels of drugs that reaches on the microgram level than high about 40 times of intravenous route administration.Therefore, should be more effective by sucking antibiotic therapy than oral cavity or the treatment of IV approach.

IV. aerosol is renderd a service

Erythromycylamine vein and aerosol administration are all very effective.At the lowest dose level (10mg/kg every day) of test intravenous use erythromycylamine and make the lung burden of streptococcus pneumoniae drop to (the every gram lung of 10CFU/) but below the detectable limit, shown in embodiment 7.Aerosol also is very effective (see figure 10), with 5mg/ml (calculating dosage 0.13mg/kg every day) aerosol solution streptococcus pneumoniae detectable recovery is only arranged.In addition, when with the concentration when using 3 days greater than required dosage every day, erythromycylamine is very effective.0.13mg/kg single dose (CFU/ gram reduce be no more than 2 orders of magnitude) poorer slightly than 3 days effects of 0.13mg/kg (declines of 5 orders of magnitude) continuous administration.Yet single agent 0.67mg/kg realizes almost completely removing this microorganism from lung tissue, and is similar to the multi-agent effect, shows that in this concentration second and three dose does not almost have extra value (seeing Figure 11).

The pharmacokinetics assessment prompting of aerosolized erythromycylamine, its valid data show, the lung concentration suitable with multi-agent IV every day, oral cavity or aerosol dose can realize that the about 3-5 of dosage that single agent should be more required than the similar effect of three daily doses doubly by single agent aerosol.

Practicality

An aspect of practicality of the present invention is to use the macrolide antibiotic of small size high concentration, for example erythromycylamine preparation and suitable aerosol apparatus, the erythromycylamine of effective dose passed to suffer with chronic bronchitis, space in the people's of bronchiectasis and pneumonia the bronchus, these diseases cause owing to macrolide susceptibility antibacterial or other infection.Preparation safety and cost are very cheap.In addition, preparation can be deposited in the nitrogen environment, and control pH is with tolerance, so that the commercial suitable shelf life that distributes to be provided.

Embodiment 1

The conventional method of preparation erythromycylamine salt: acetic acid erythromycylamine synthetic

In ice bath, drip 1.56mL (27.2mmol, 2.0 equivalents) glacial acetic acid in the 100mL MeOH solution of refrigerative 10.0g (13.6mmol) erythromycylamine.Solution is warm to ambient temperature through 30 minutes, then removal of solvent under reduced pressure.Add Et ₂O (50ml) concentrated slurry.Repeat to obtain 11.52g (96.9%) white powder acetic acid erythromycylamine monohydrate; IR (KBr, cm ^-1) 1718,1560,1406,1168,1080,1055,1012; 1H NMR (400MHz, CD ₃OD) δ 0.89 (t, 3H, J=7.2Hz), 1.06-1.32 (m, 27H), 1.35-1.47 (m, 4H), and 1.52-1.66 (m, 3H), 1.85-2.02 (m, 8H), 2.03-2.26 (m, 2H), and 2.45-2.49 (m, 1H), 2.66-2.77 (m, 5H), 2.91-3.09 (m, 3H), 3.21-3.40 (m, 6H), 3.58 (d, 1H, J=7.0Hz), 3.67 (s, 1H), 3.78-3.83 (m, 2H), 4.10-4.13 (m, 1H), 4.59 (d, 1H, J=7.0Hz), 4.88-5.0 1 (m, 12H); MS m/z 735.6 (M ^-2AcOH-2H ₂O); KF 2.33%H ₂O.

C ₄₁H ₈₀ON ₂O ₁₇The analytical calculation value: C, 56.40; H, 9.24; N, 3.21.Measured value: C, 56.38; H, 9.21; N, 3.16.

Embodiment 2

Synthesizing of sulphuric acid erythromycylamine

In ice bath, drip 0.73mL (13.6mmol, 1.0 equivalents) concentrated sulphuric acid in the 100mL MeOH solution of refrigerative 10.0g (13.6mmol) erythromycylamine.Solution is warm to ambient temperature through 30 minutes, then removal of solvent under reduced pressure.Add Et ₂O (50ml) concentrated slurry.Repeat to obtain 11.13g (96.1%) white powder sulphuric acid erythromycylamine monohydrate; IR (KBr, cm ^-1) 1718,1384,1168,1122,1078,1012; ¹HMR (400MHz, CD ₃OD) δ 0.89 (t, 3H, J=7.2Hz), 1.08-1.32 (m, 27H), 1.45-1.63 (m, 7H), and 1.89-2.04 (m, 2H), 2.23-2.31 (m, 2H), 2.44-2.47 (m, 1H), and 2.84-2.89 (m, 5H), 2.99-3.07 (m, 3H), 3.30-3.49 (m, 6H), 3.58 (d, 1H, J=7.0Hz), 3.69 (s, 1H), and 3.78-3.86 (m, 2H), 4.09-4.11 (m, 1H), 4.60 (d, 1H, J=6.8Hz), 4.87-4.99 (m, 12H); MS m/z 735.7 (M ⁺-H ₂SO ₄-2H ₂O); KF 2.93%H ₂O.

C ₃₇H ₇₄N ₂O ₁₆The analytical calculation value of S: C, 52.22; H, 8.76; N, 3.29.Measured value: C, 52.55; H, 8.91; N, 3.27.

Embodiment 3

Synthesizing of aminoguanidine hydrochloride erythromycin

In ice bath, drip 2.34mL (27.2mmol, 2.0 equivalents) 37% hydrochloric acid in the 100mL MeOH solution of refrigerative 10.0g (13.6mmol) erythromycylamine.Solution is warm to ambient temperature through 30 minutes, then removal of solvent under reduced pressure.Add Et ₂O (50ml) concentrated slurry.Repeat to obtain 11.24g (97.9%) white powder aminoguanidine hydrochloride erythromycin dihydrate; IR (KBr, cm ^-1) 1718,1466,1383,1170,1078,1055,1011; ¹H NMR (400MHz, CD ₃OD) δ 0.87-0.91 (m, 3H), 1.10-1.31 (m, 27H), 1.43-1.65 (m, 7H), and 1.89-2.01 (m, 2H), 2.25-2.27 (m, 2H), 2.45-2.48 (m, 1H), 2.82-3.10 (m, 8H), 3.34-3.42 (m, 8H), 3.57-3.58 (m, 1H), 3.67 (s, 1H), 3.80-3.82 (m, 2H), 4.08-4.11 (m, 1H), 4.61-5.00 (m, 13H); MS m/z 735.6 (M ⁺-2HCl-2H ₂O); KF4.38%H ₂O.

C ₃₇H ₇₆Cl ₂N ₂O ₁₂The analytical calculation value: C, 52.65; H, 9.08; N, 3.32.Measured value: C, 52.21; H, 9.18; N, 3.20.

Embodiment 4

The water preparation and the stability of erythromycylamine salt

(9.0g, 12.2mM) free alkali adds the 100mL Erlenmeyer flask of taring to formulations prepared from solutions with erythromycylamine.In flask, add deionized water (25mL), stir with magnetic stirrer.Add 1N sulphuric acid (24.5ml, 2 equivalents) and stirring on one side gradually.When solution is clarified, from agitating plate, reclaim also and weigh again.Drip deionized water, obtain final solution weight 62.9g.Solution is divided into 3 20ml parts, by dripping 1N sodium hydroxide or sulphuric acid, on one side with the pH meter monitoring, pH regulator is arrived desirable value (5.0,6.0 or 7.0).Weight (6.0g and 3.6g) by regulating erythromycylamine and the vitriolic volume of 1N (16.3 and 9.8ml) are with the solution of method for preparing 100mg/mL and 60mg/mL.Prepare 150,100 and the acetic acid and the hydrochlorate solution of the erythromycylamine of 60mg/ml as mentioned above, except adding 1N acetic acid and 1N hydrochloric acid (2 equivalent), with preparation salt and regulate pH.

Each salt form equal portions under each concentration and each pH are stored under 4,40 and 60 ℃ and the ambient temperature.

Stability is measured

All solution (t=0) and 24 hours, 48 hours, 8 days, 15 days and analyzed in 22 days immediately after preparation are except basic degradation samples 8 days the time is omitted later experiment.

Sample freezing and heating equilibrated to ambient temperature at least one hour before sample preparation.The final dilution volume of all samples is 10ml.The dilution of all samples comprises the 50mM phosphate buffer of pH6.5 and the mixture of acetonitrile 80: 20 (v/v).

An amount of sample (40 microlitres are for 150mg/ml solution, and 50 microlitres are for 100mg/ml, and 100 microlitres are for 60mg/ml) is transferred in the 20ml flicker vial.In vial, add 10ml diluent and fully mixing.

Standard fabrication

Duplicate preparation standard, and used at most 3 days.The free alkali (30mg) of erythromycylamine is transferred to the flask of the 50ml volume of taring, the record exact weight.Add diluted sample thing and simple ultrasonic dissolution.Cool down criteria also is diluted to certain volume with diluent.

Sample and standard analysis

With RPHPLC (reversed-phase high-performance liquid chromatography) analytic sample and standard.Be used to separate with 250 * 4.6mmPhenomenex Luna CN post (5 micron grain size).All analyses are carried out on Agilent Technologies HP1100 tomographic system, obtain data and use Agilent Technologies ChemStation data system to store.Described in analyte parameter such as the following table 2.

Table 2

Flow velocity	????1.0ml/min
		Column temperature	????30℃
Volume injected	20 microlitres
		Detector	The UV absorbance of 200nm
Running time
		10 minutes
Mobile phase A			50mM phosphate, pH2.1
	Mobile phase B	Acetonitrile
Form			????80/20?A/B

Embodiment 5

The osmolarity of erythromycylamine saline solution

In each 10ml volume flask, take by weighing three parts of aminoguanidine hydrochloride erythromycin (0.6g, 1.0g and 1.5g).In each flask, add Easypure UV water (8ml), and ultrasonic up to dissolving fully, be diluted to certain volume then.Repeat this process with sulphuric acid and acetic acid erythromycylamine.Measure the pH and the osmolarity of each solution, and osmolarity and the theoretical value of measuring compared.

The salt (4 ℃) of preparation equilibrates to room temperature among the embodiment 4, measures osmolarity.Table 3 has shown the result.

The research of table 3 erythromycylamine salt osmolarity

Aminoguanidine hydrochloride erythromycin lot number TEM-702-171 dihydrate, molecular weight=843.91g/m

Target weight (g)

Actual weight (g)

Theoretical osmolarity

Actual osmolarity

????pH

Estimate

		????(mOsm)	????(mOsm)
						????0.600	?0.59957	????279	????213	????7.57	Muddy fully
????1.00	?1.00443	????474	????357	????7.59	Muddy fully
						????1.50	?1.50258	????733	????534	????7.60	Muddy fully

Sulphuric acid erythromycylamine lot number TEM-702-169 monohydrate, molecular weight=883.14g/m

????0.600	?0.60368	????146	????137	????77.62	Muddy fully
						????1.00	?1.00430	????258	????227	????77.63	Muddy fully
????1.50	?1.49941	????408	????340	????77.61	Muddy fully

Acetic acid erythromycylamine lot number TEM-702-167 monohydrate, molecular weight=873.08g/m

????0.600	??0.60189	????195	????207	????6.62	Slight muddy
						????1.00	??1.00713	????345	????346	????6.67	Slight muddy
????1.50	??1.50178	????552	????516	????6.62	Slight muddy

(((weight (g)/molecular weight wt) * material number)/0.01L) * (1000mOsm/10sm)=XmOsm

6 pairs of rat aerosoies of embodiment transmit erythromycylamine: the feature of aerosol pharmacokinetics

The IV pharmacokinetics: erythromycylamine (250mg) is dissolved in the 5ml distilled water, adds the 12ml concentrated sulphuric acid.In solution, add dilute sulfuric acid (1: gradually 10v/v) with complete dissolved substance.Add the sulfuric acid solution of dilution gradually, make pH value of solution reach 6.8-7.2.By adding distilled water, overall solution volume reaches 8ml.The solution (25mg/kg) of 200 microlitre sulphuric acid erythromycylamines by the terminal cava vein administration of tail, is passed to male Sprague-Dawley rat (Gilroy, CA 95020 for Simonsen Laboratories, 1180C Day Road).With 1-4% isoflurane anesthesia animal, and after administration, collected lungs and blood sample from 3 rats in 0.083,0.25,0.5,1,2,4,6,8 and 24 hour.By using heparin, collect blood sample with cardiac puncture as anticoagulant.Lung is taken out in operation after collecting blood sample, removes bronchus and trachea, abandons.The following processing of remaining lung tissue.Lung and blood sample are placed on ice immediately centrifugal immediately blood sample collection blood samples after collection.Lung and plasma sample are stored at-80 ℃ up to test.

With the erythromycylamine concentration in effective LC-MS method mensuration blood plasma and the lung (every gram lung tissue).Before extraction, use oleandomycin (interior mark, 1 mcg/ml) pulse (spike) plasma sample (100 microgram).With the protein in 3.3% trichloroacetic acid (TCA) the removal plasma sample (100 microlitre).Centrifugal sample (10,000rpm, 10 minutes) is transferred to HPLC two-part filter (centrifilter) with supernatant, and the two-part filtration (10,000rpm, 10min).Mobile phase contain 0.1% acetic acid-acetonitrile (70: 30, v/v, pH=3.2) solution, flow velocity are 0.5ml/min3 minute, flow velocity is 0.1% acetic acid-acetonitrile 3 minutes of 0.8ml/min then.Rustless steel analytical column (ZorbaxSB-C18,2.1mm ID * 150.0mm, 5 microns, Phenomenex core formula guard column) is as static phase.Column temperature is 50 ℃.Carry out the quantitative of erythromycylamine with HP 1100 LC/MSD API-electric injection systems.Data obtain to be decided to be the selected ion monitoring pattern.Method is linear (r＞0.9990) in the concentration range of 0.01-50 mcg/ml.The absolute recovery is 95.0 ± 2.19%.

With distilled water homogenize lung sample.In sample, add oleandomycin as interior mark.With the albumen in the 0.9M TCA removal homogenize thing.Sample is 10, and centrifugal 10 minutes of 000rpm transfers to HPLC two-part filter (centrifilter) with supernatant, and the two-part filtration (10,000rpm, 10min).Mobile phase contain 0.1% acetic acid-acetonitrile (70: 30, v/v, pH=3.2) solution, flow velocity are 0.5ml/min3 minute, then flow velocity be 0.8ml/min 0.1% acetic acid-acetonitrile (60: 40, v/v) 3 minutes.Rustless steel analytical column (Zorbax SB-C18,2.1mm ID * 150.0mm, 5 microns, Phenomenex core formula guard column) is as static phase.Column temperature is 50 ℃.Carry out the quantitative of erythromycylamine with HP1100 LC/MSD API-electric injection system.Data obtain to be decided to be the selected ion monitoring pattern.Method is linear (r＞0.9990) in the concentration range of 0.01-200 microgram/gram.Extraction efficiency is 93.8 ± 2.54%.

According to the statistical moment theory, use WinNonlin ^TMProfessional Version 2.0 softwares (Pharsight Corporation) are estimated pharmacokinetic parameter, area under curve and average residence time.Estimate but observe peak concentration (C _Max).

Suck pharmacokinetics:, in the 43ml distilled water of 50 ml volumes flasks and 4.27ml (4.27mmol) 1M sulphuric acid, add 3.191g (4.08mmol) erythromycylamine (94% purity) for 60mg/ml solution.By adding extra 53 microlitres (0.053mmol) 1M sulphuric acid, solution is adjusted to pH6.5 then.Volume is adjusted to 50ml with distilled water.Dilution 60mg/ml solution in 1/2 normal saline, preparation 30mg/ml solution.The osmolarity of the solution that obtains such as Advanced ^TMThat Micro-Osmometer3300 type (AdvancedInstruments, Inc., Norwood Mass.) is measured is 148mOsm.

32-hole Rodents only the nose contact system (Battelle, Richland, WA) in, rat is by sucking contact 30 or 60mg/ml sulphuric acid erythromycylamine solution 30 minutes.The Battle system only nose Rodents contact system based on Cannon Flow-Past nasus system (A.m.Ind Hyg Assoc J 1983 Dec only; 44 (12) 923-8), constitute, always have 32 holes by 4 laminar stackable stainless steel layers.System comprises monitoring of input and output air-flow and control, collects the aerosol data with the NORES1.1.4 version software that Battelle provides.With PARI LC STAR ^TMThe aerosolized erythromycylamine solution of aerosol apparatus.By at the densimetric analysis that begins to contact the filter sample of obtaining in 10 and 20 minutes the back, measure average aerosol concentration.For 30 and 60mg/ml solution, average aerosol concentration is respectively 0.54 ± 0.06 and 1.36 ± 0.30mg/L.

From 3 rats after administration as mentioned above 0.083,0.25,0.5,1,2.4, collected lung and blood sample in 8 and 24 hours.The sample collection that sucks research is identical with intravenous research with processing procedure.

The bioanalytical method that sucks research is identical with intravenous research.The precipitation dosage that calculates in the lung (lung dosage) suck 30 or 60mg/ml erythromycylamine solution be respectively about 0.70 or 1.77mg/kg after 30 minutes.Lung Rapid Dose Calculation in the lung is as follows:

LDD＝MAC×MV×DE×FLD÷MBW

LDD=lung deposit dose wherein,

The average aerosol concentration of MAC==for 30 and 60mg/ml solution is respectively 0.54 and 1.36mg/L.

MV=minute volume=0.1L/min

DE=duration of contact=30 minute

The sedimentary mark of FLD=lung=0.1

MBW=average weight=0.23kg

Intravenous and suck is used behind the erythromycylamine pharmacokinetic parameter in the lung and to sum up as table 4:

The pharmacokinetic parameter (N=3) of erythromycylamine in the lung behind vein or twice inhalation in table 4 rat.

	Medicament administration approach and dosage
				Pharmacokinetic parameter	Intravenous 25mg/kg	Suck 30mg/ml (lung dosage: 0.7mg/kg)	Suck 60mg/ml (lung dosage: 1.77mg/kg)
?C max(microgram/gram)	??68.99	????89.33	????155.24
				AUC (microgram hour/gram) 1	??605.19	????854.27	????1357.35
AUC (microgram hour/gram) 2	??24.21	????1220.39	????766.86
				?MRT(h) 3	??10.8	????10.5	????11.2

1. the area under curve of estimating in 0-24 hour after the administration.

2. dosage is demarcated the area under curve of 1mg/kg.

3. average residence time of estimating in 0-24 hour after the administration.

N.e.: do not estimate.

Embodiment 7

Aerosol and the IV of erythromycylamine in the induced lung model of streptococcus pneumoniae infection renders a service

Method: use 50-100 microlitre streptococcus pneumoniae A66 (bacterial strain #PG04716) in the trachea, infect male Sprague-Dawley rat with the sepharose 4B preparation.Be suspended in by the broth culture with PG04716 in the agarose of thawing, the preparation inoculum is suspended in the agarose suspension in the sterile mineral oil, mix on one side, produce the little sepharose 4B that contains antibacterial.Centrifugal recovery pearl is resuspended in the Sterile Saline, and is injected directly into by incision of trachea and is applied to animal in the lung.

Preparation erythromycylamine solution in Sterile Saline.By injection in tail vein medium-sized vein or by aerosol contact administration of antibiotics.Only passing through with In-Tox Aerosol Exposure System (04-1100 type), the nose contact realizes the aerosol contact.This system is designed to contact the blanket gas colloidal sol transmission system of being closed the Rodents in plastic tube, and it is at one end to open system (nostril), and the other end seals to keep system integrity.Pari LCStar ^TMAir-jet nebulizer produces aerosol with about 6.5 liters/minute air-flow.Vacuum is decided to be 9 liters/minute, and the total air flow that uses rarer air routing system is 7.5 liters/minute.

Treatment is in infection beginning in back 24 hours, and carry out once every day, carried out 3 days.Aerosol was used 30 minutes every day.After the 4th day and last administration after the infection 12 hours, kill animals, operation removes lung down.After removing down, homogenate lung, dilution and quantitative bed board on blood agar sugar.Dull and stereotyped preservation 24 hours is also calculated the streptococcus pneumoniae bacterium colony, to determine bacterial load.The result is as shown in table 5:

Table 5

Erythromycylamine is to the effectiveness of streptococcus pneumoniae in the pneumonia of rats model

Approach	Dosage (mg/kg every day)	The CFU/ gram that reclaims
			????IV	????0	????8.5×10 7
	????10	????BQL *
				????20	????BQL *
	????40	????BQL *
			Aerosol	????0	????4.1×10 7
	????0.13	????3.5×10 2
				????0.67	????BQL *
	????1.33	????BQL *

^*BQL=is below quantitation limit

Embodiment 8

After the potion of erythromycylamine was handled, the aerosol of erythromycylamine was renderd a service in the induced lung model of streptococcus pneumoniae infection

As infection male Sprague-Dawley rat as described in the embodiment 7 and contact the aerosol treatment.Single agent treatment was used aerosol 30 minutes in infection beginning in back 24 hours with specified dosage.Do not carry out other treatment, observe animal up to operation.In the 4th day (after the administration the 3rd day) after the infection, their lung is taken off in kill animals and operation.After taking off, homogenate lung, dilution and quantitative bed board on blood agar sugar.Dull and stereotyped preservation 24 hours is also calculated the streptococcus pneumoniae bacterium colony, to determine bacterial load.Result after single agent administration as shown in figure 11, further the result is as shown in table 6:

Table 6

Erythromycylamine is to the effectiveness of streptococcus pneumoniae in the pneumonia of rats model

The dosage number	Dosage (mg/kg every day)	The CFU/ gram that reclaims
			????3	????0	????4.1×10 7
????3	????0.13	????3.5×10 7
			????3	????0.67	????BQL
????3	????1.33	????BQL

BQL=is below quantitation limit

Embodiment 9

The dog aerosol is transmitted erythromycylamine: the feature of aerosol pharmacokinetics

Suck pharmacokinetics:, in the 43ml distilled water of 50 ml volumes flasks and 4.27ml (4.27mmol) 1M sulphuric acid, add 3.191g (4.08mmol) erythromycylamine (94% purity) for 60mg/ml solution.Then solution is adjusted to pH6.5, adds extra 53 microlitres (0.053mmol) 1M sulphuric acid.Volume is adjusted to 50ml with distilled water.Sucking in the face shield contact system (Inveresk Research, Scotland UK) dog contact 60mg/ml sulphuric acid erythromycylamine solution one time 30 minutes.

Take out Canis familiaris L. in the hurdle from the dog breeders district, it is transferred in the administration laboratory.In the administration process, allow fixedly Canis familiaris L. of zooman or suspender belt/harness system.Mask with the sealing that is connected with the aerosol apparatus of determining suitable characteristics before the beginning administration carries out inhalation.Doser comprises a mask and mouthpiece, and mouthpiece is connected with flexible conduit, and this conduit links to each other with sprayer device.Mouthpiece is positioned at the animal mouth, and at the tongue top, mask is sealed in around the dog snout with rubber sleeve.The dump valve of mask is connected with extraction system.After doser assembles and be fixed on the dog fully, move to dog by aerosol along flexible pipeline and show air-breathing.

After administration, collected the lung samples from two dogs in 2,24,48,72,96 and 120 hours.Lung is taken off in operation, separates each lobe of the lung (right caudal lobe, left caudal lobe, right cranium leaf, left cranium leaf, right middle lobe and auxilliary leaf) and is used for analyzing.Animal from all survivals after 2,24,48,72,96 and 120 hours is collected plasma sample.

With the erythromycylamine concentration in LC-MS method mensuration blood plasma and the lung (every gram lung tissue).Before extraction, use oleandomycin (interior mark, 1 mcg/ml) pulse (spike) plasma sample (100 microgram).With the protein in 3.3% trichloroacetic acid (TCA) the removal plasma sample (100 microlitre).Centrifugal sample (10,000rpm, 10 minutes) is transferred to HPLC two-part filter (centrifilter) with supernatant, and the two-part filtration (10,000rpm, 10min).Mobile phase contain 0.1% acetic acid-acetonitrile (70: 30, v/v, pH=3.2) solution, flow velocity are 0.5ml/min3 minute, then flow velocity be 0.8ml/min 0.1% acetic acid-acetonitrile (60: 40, v/v) 3 minutes.Rustless steel analytical column (Zorbax SB-C18,2.1mm ID * 150.0mm, 5 microns, Phenomenex core formula guard column) is as static phase.Column temperature is 50 ℃.Carry out the quantitative of erythromycylamine with HP 1100 LC/MSD API-electric injection systems.Data obtain to be decided to be the selected ion monitoring pattern.Method is linear (r＞0.9990) in the concentration range of 0.01-50 mcg/ml.Definitely reclaim greater than 90%.

With distilled water homogenize lung sample.In sample, add oleandomycin as interior mark.With the albumen in the 0.9M TCA removal homogenize thing.Sample is 10, and centrifugal 10 minutes of 000rpm transfers to HPLC two-part filter (centrifilter) with supernatant, and the two-part filtration (10,000rpm, 10min).Mobile phase contain 0.1% acetic acid-acetonitrile (70: 30, v/v, pH=3.2) solution, flow velocity are 0.5ml/min3 minute, then flow velocity be 0.8ml/min 0.1% acetic acid-acetonitrile (60: 40, v/v) 3 minutes.Rustless steel analytical column (Zorbax SB-C18,2.1mm ID * 150.0mm, 5 microns, Phenomenex core formula guard column) is as static phase.Column temperature is 50 ℃.Carry out the quantitative of erythromycylamine with HP1100 LC/MSD API-electric injection system.Data obtain to be decided to be the selected ion monitoring pattern.Method is linear (r＞0.99) in the concentration range of 2-100 microgram/gram for lung.Extraction efficiency is greater than 90%.

According to the statistical moment theory, use WinNonlin ^TMProfessional Version 3.1 softwares (Pharsight Corporation) are estimated pharmacokinetic parameter, area under curve (AUC) and average residence time (MRT) and half-life (T1/2).Estimate but observe peak concentration (C _Max).

At the pharmacokinetic parameter in lung and the blood plasma after using erythromycylamine in the dog shown in table 7 and Figure 13 and 14.

Table 7

Sucked in 30 minutes in the dog and use behind the 60mg/ml solution in the lung and in the blood plasma

The pharmacokinetic parameter of erythromycylamine (N=2).

	Pharmacokinetic parameter (unit)
					Substrate	????C max(microgram/gram)	AUC (0-120h) (microgram hour/gram) 1	????t 1/2(hour)	????MRT ????(h) 1
Full lung	????69	????2085	????27	????29
					Blood plasma	????1.0	????29	????n.e.	????37
Right caudal lobe	????77	????2078	????26	????26

Left side caudal lobe	????68	????2000	????26	????28
					Right cranium leaf	????87	????2517	????24	????27
Left side cranium leaf	????54	????1857	????29	????31
					Right middle lobe	????48	????1979	????30	????34
Auxilliary leaf	????68	????2256	????31	????31

1. average retention time

N.e. do not estimate.

Embodiment 10

The liquid aersol transmission of erythromycylamine

According to the conventional method of the foregoing description, the solution of preparation sulphuric acid erythromycylamine (100mg/ml) in 1/4 normal saline (pH7.0).The patient who is less than in 10 minutes the acute exacerbation of suffer with chronic bronchitis (AECB), use AeroGen Aerodose ^TMInhaler sucks the solution of using 1.0ml dosage by aerosol.Observe the alleviating of symptom of the minimizing of the antibacterial relevant and AECB with AECB.

Embodiment 10

The dry powder aerosol transmission of erythromycylamine

The dry powder formulations and the dry powder carrier (moiety of lactose, 2-hydroxy propyl-Beta-ring glucosan, mannitol and aspartame, gross weight 25mg) of preparation sulphuric acid erythromycylamine (100mg).In less than 2 minutes,, use Glaxo Ventolin Rotohale to the patient of the acute exacerbation of suffer with chronic bronchitis (AECB) ^TMInhaler sucks administered formulation by aerosol.Observe the alleviating of symptom of the minimizing of the antibacterial relevant and AECB with AECB.

Though the preference of the present invention that illustrates and describe should be understood herein various changes without prejudice to the spirit and scope of the present invention.

Claims (38)

1. the aerosol preparations of space susceptibility antibacterial in the individual bronchus that is used for suppressing suffering from endobronchial infections, it is characterized in that, described preparation contains acceptable carrier on have an appointment 50-750mg macrolide antibiotic and the materia medica, and said preparation can aerosol form jet nebulizer, ultrasonic nebulizer, vibration porous plate aerosol apparatus or the Diskus administration that can produce the aerosol particle of quality meta aerodynamic diameter between the 1-5 micron.

2. aerosol preparations as claimed in claim 1 is characterized in that described macrolide antibiotic is selected from erythromycylamine, dirithromycin, Erythromycin A, clarithromycin, Azithromycin and Roxithromycin.

3. aerosol preparations as claimed in claim 1 is characterized in that described macrolide antibiotic is an erythromycylamine.

4. aerosol preparations as claimed in claim 1 is characterized in that described preparation has the pH of 5.0-7.0.

5. aerosol preparations as claimed in claim 1 is characterized in that described aerosol apparatus is a jet nebulizer.

6. aerosol preparations as claimed in claim 1 is characterized in that described aerosol apparatus is a ultrasonic nebulizer.

7. aerosol preparations as claimed in claim 1 is characterized in that, described aerosol apparatus is the porous plate aerosol apparatus.

8. aerosol preparations as claimed in claim 1 is characterized in that, described susceptibility antibacterial is selected from streptococcus pneumoniae, Haemophilus influenzae, staphylococcus aureus, morazella catarrhalis, pneumonia legionella, Chlamydia pneumoniae and mycoplasma pneumoniae.

9. aerosol preparations as claimed in claim 8 is characterized in that pH is 6.0.

10. aerosol preparations as claimed in claim 9 is characterized in that described aerosol apparatus is a jet nebulizer.

11. aerosol preparations as claimed in claim 9 is characterized in that, described aerosol apparatus is a ultrasonic nebulizer.

12. aerosol preparations as claimed in claim 9 is characterized in that, described aerosol apparatus is the porous plate aerosol apparatus.

13. method for the treatment of susceptibility antibacterial endobronchial infections, it is characterized in that, this method is the individuality of this treatment of needs to be used the aerosol preparations of suction, described preparation contains acceptable carrier on have an appointment 50-750mg macrolide antibiotic and the materia medica, and said preparation can aerosol form jet nebulizer, ultrasonic nebulizer, vibration porous plate aerosol apparatus or the Diskus administration that can produce the aerosol particle of quality meta aerodynamic diameter between the 1-5 micron.

14. method as claimed in claim 13 is characterized in that, described macrolide antibiotic is selected from erythromycylamine, dirithromycin, Erythromycin A, clarithromycin, Azithromycin and Roxithromycin.

15. method as claimed in claim 13 is characterized in that, described macrolide antibiotic is an erythromycylamine.

16. method as claimed in claim 13 is characterized in that, described preparation has the pH of 5.0-7.0.

17. method as claimed in claim 13 is characterized in that, the described aerosol apparatus that is used for the aerosol preparations administration is a jet nebulizer.

18. method as claimed in claim 13 is characterized in that, the described aerosol apparatus that is used for the aerosol preparations administration is a ultrasonic nebulizer.

19. method as claimed in claim 13 is characterized in that, the described aerosol apparatus that is used for the aerosol preparations administration is a vibration porous plate aerosol apparatus.

20. method as claimed in claim 13 is characterized in that, described susceptibility antibacterial is selected from streptococcus pneumoniae, Haemophilus influenzae, staphylococcus aureus, morazella catarrhalis, pneumonia legionella, Chlamydia pneumoniae and mycoplasma pneumoniae.

21. method as claimed in claim 13 is characterized in that, individuality is being less than the dosage of using the liquid aersol preparation that contains the about 2.0ml atomization of being less than of 50-150mg/ml macrolide antibiotic of having an appointment in about 10 minutes.

22. method as claimed in claim 21 is characterized in that, described dosage contains the aerosol preparations that is less than about 1.5ml atomization.

23. method as claimed in claim 21 is characterized in that, described dosage contains the aerosol preparations that is less than about 1.0ml atomization.

24. method as claimed in claim 20 is characterized in that, aerosol preparations contains the 70-130mg/ml macrolide antibiotic of having an appointment.

25. a single agent device is characterized in that this device comprises a container, described container contains the macrolide antibiotic preparation that is less than about 2.0ml, and described preparation contains the 50-150mg/ml macrolide antibiotic of having an appointment in the physiologically acceptable carrier of liquid state.

26. single agent device as claimed in claim 25 is characterized in that, described single agent device contains and is less than about 1.5ml macrolide antibiotic preparation.

27. single agent device as claimed in claim 25 is characterized in that, described single agent device contains and is less than about 1.0ml macrolide antibiotic preparation.

28. single agent device as claimed in claim 25 is characterized in that described macrolide antibiotic preparation contains the 70-130mg/ml macrolide antibiotic of having an appointment.

29. single agent device as claimed in claim 25 is characterized in that described macrolide antibiotic preparation contains the 90-110mg/ml macrolide antibiotic of having an appointment.

30. single agent formulation as claimed in claim 25 is characterized in that described macrolide antibiotic is selected from erythromycylamine, dirithromycin, Erythromycin A, clarithromycin, Azithromycin and Roxithromycin.

31. method as claimed in claim 25 is characterized in that, described macrolide antibiotic is an erythromycylamine.

32. single agent device as claimed in claim 25 is characterized in that, described device contains and is less than about 2.0ml macrolide antibiotic preparation, and described preparation contains the 20-200mg/ml erythromycylamine of having an appointment.

33. a single agent device is characterized in that this device comprises a container, described container contains the macrolide antibiotic preparation, and described preparation contains the 25-250mg macrolide antibiotic of having an appointment in the acceptable carrier on the dry powder physiology.

34. single agent device as claimed in claim 33 is characterized in that described macrolide antibiotic preparation contains the 50-200mg macrolide antibiotic of having an appointment.

35. single agent device as claimed in claim 33 is characterized in that described macrolide antibiotic preparation contains the 75-150mg macrolide antibiotic of having an appointment.

36. single agent device as claimed in claim 33 is characterized in that described macrolide antibiotic is selected from erythromycylamine, dirithromycin, Erythromycin A, clarithromycin, Azithromycin and Roxithromycin.

37. single agent device as claimed in claim 33 is characterized in that described macrolide antibiotic is an erythromycylamine.

38. single agent device as claimed in claim 33 is characterized in that described macrolide antibiotic preparation contains the macrolide antibiotic of the 50%-90% weight of having an appointment.

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