CN1939279A - Albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease - Google Patents

Abstract

The present invention relates to a dual bronchodilator inhalation solution, system, kit and method for relieving bronchospasm in patients suffering from chronic obstructive pulmonary disease (COPD). In one alternative embodiment, the solution of the present invention is a prepackaged, sterile, premixed, premeasured single unit dose of albuterol and ipratropium bromide for patients suffering from COPD. The present solution may be free of antimicrobial preservatives, such as benzalkonium chloride. In another alternative embodiment, the solution of the present invention comprises about 2.50 mg albuterol and about 0.50 mg ipratropium bromide.

Description

The albuterol and ipratropium inhalation solution, system, test kit and the method that are used for relieving symptoms of chronic obstructive pulmonary disease

The application divides an application, the international application no of its original application is PCT/US2002/033353, the China national application number is 02826226.3, the applying date is on October 18th, 2002, and denomination of invention is " albuterol and ipratropium inhalation solution, system, test kit and the method that are used for relieving symptoms of chronic obstructive pulmonary disease ".

MULTIPLE-BLADE

The application be calendar year 2001 the part of No. the 10/034th, 657, the U. S. application submitted to of December 28 days continue, the latter has required the priority of No. the 60/346th, 078, the U.S. Provisional Application submitted to October 26 calendar year 2001 according to 35U.S.C. § 119 (e).These whole disclosures in first to file are hereby incorporated by.

Technical field

The present invention relates to be used to alleviate the combination of the bronchiectasis medication of the symptom relevant with chronic obstructive pulmonary disease.

Background technology

Chronic obstructive pulmonary disease (COPD) is a kind of into type airway disorders that delays, and can cause pulmonary function not exclusively reversibly to descend.Airway pressure among the COPD is limited relevant to the unusual inflammatory reaction of harmful particle or gas with lung.

In the U.S., existing according to estimates 1,600 ten thousand Americans are diagnosed as the COPD of some type, and also have other 1,600 ten thousand people to suffer from this disease, but are not diagnosed.According to the report of U.S. CDC, COPD is the fourth-largest cause of the death of the U.S. (coming after heart disease, cancer and the apoplexy), seizes 112,000 American life every year.

From health care, pay a home visit in the period of the 1985-1995 quantity of COPD of American physician is increased to 16,000,000 from 9,300,000.The quantity survey that nineteen ninety-five is in hospital because of COPD is 500,000.Although sickness rate, hospitalization rate and the mortality rate of COPD in the male all is higher than the women, also fast rise of the mortality rate of female patient in recent years.In the U.S. and other country of the world, COPD obviously is the main and growing threat of health care.

In the prior art, be used for the treatment of in the suction solution of COPD and often contain for example benzalkonium chloride (BAC) of antimicrobial.Be present in the BAC in these solution, do not influence the effect of fugitive (single dose) bronchodilator usually.Yet case report shows that the COPD treatment of reusing band BAC may cause unusual bronchoconstriction.When COPD experimenter sucked BAC, BAC may also can cause the bronchoconstriction of dose dependent.Although there are these side effect, many commercially available suction solution still contain BAC.

Simultaneously, the multiple dose unit form is adopted in the COPD treatment usually, must be diluted to the specific concentrations that is suitable for treating the patient.This has produced some problems.For example, COPD treatment need be told single dosage unit and use from multiple dose unit, but lacks suitable mixing or dilution explanation sometimes, or is used to prepare and uses the explanation of COPD treatment may be difficult to follow or lose easily.The more major issue that exists is that careless dilution or mixed C OPD medicine can cause the application dosage mistake.This is unfavorable especially for the low patient of high dose asthmatic medicament toleration for those.Incorrect mixing also may cause the treatment failure, needs extra medical care like this, has therefore increased the time relevant with treatment, expense and personnel's spending.

Therefore, need be provided for alleviating suction solution, system, test kit and the method for the improvement of the symptom relevant with COPD.

Summary of the invention

The suction solution that an object of the present invention is to provide dual (dual) bronchodilator is to alleviate COPD patient's bronchospasm.

Another object of the present invention provides albuterol pre-packing, scheduled volume and the aseptic suction solution of ipratropium premixing, to be used to alleviate COPD patient's bronchospasm.

Another object of the present invention provides albuterol and the ipratropium inhalation solution that does not contain BAC, to be used for the treatment of the bronchospasm relevant with COPD.

Another object of the present invention provides the application process of albuterol and ipratropium suction preparation, and this suction preparation is used to alleviate the bronchospasm relevant with COPD.

Another object of the present invention provides test kit and/or the system that uses dual bronchodilator, to be used to alleviate the bronchospasm relevant with COPD.

Another object of the present invention provides the preparation method of albuterol and ipratropium inhalation solution, and this suction solution is used to alleviate the bronchospasm relevant with COPD.

Another object of the present invention comprises the device that is used to alleviate the COPD symptom.

By following detailed description the in detail and accompanying drawing of the present invention, those of ordinary skills will be readily appreciated that other purpose of the present invention, characteristics and advantage.

Description of drawings

Fig. 1～4 have been described to use the indefiniteness example that the present invention sucks solution with aerosol apparatus.

Fig. 5 has described the indefiniteness example of pre-package kit of integral body of the present invention or system.

Fig. 6 has described to have the indefiniteness example of one or more pre-filled containers of intake system of the present invention.

Fig. 7 has described the indefiniteness example of the used label of the present invention.

The specific embodiment

Albuterol

The bronchiectatic activity that the present invention is based on albuterol provides the effect of alleviating the symptom relevant with COPD.(albuterol) include but not limited to produce any type of albuterol of ideal bronchiectatic activity at this used term " albuterol " to the patient, comprising but be not limited to: all tautomers of albuterol, enantiomer, stereoisomer, anhydride, acid-addition salts class, basic salt class, solvate, analog and derivant.

In the present invention, acceptable albuterol salt includes but not limited to hydrochlorate, sulfate, maleate, tartrate, citrate etc.These salts are described in United States Patent (USP) 3,644,353, and its disclosure all is incorporated herein by reference at this.

In the present invention, preferred albuterol salt is its sulfate.In an alternative embodiment, the present invention sucks the sulphuric acid that solution comprises racemic salbutamol.Salbutamol sulfate is the β-2-adrenergic bronchodilator with relative selectivity, and empirical formula is Cl3H21NO3.The chemical name of salbutamol sulfate is a α uncle 1-[(fourth amino) methyl]-4-hydroxyl-meta-xylene-α, α '-two alcohol sulfate (2: 1) (salt), its chemical constitution is determined as follows:

Ipratropium

Simultaneously, the present invention's bronchiectatic activity of being based on ipratropium provides the effect of alleviating the symptom relevant with COPD.Ipratropium is a kind of anticholinergic bronchodilators.(Ipratropium) include but not limited to produce any type of ipratropium of ideal bronchiectatic activity at this used term " ipratropium " to COPD patient, comprising but be not limited to: all tautomers of ipratropium, enantiomer, stereoisomer, anhydride, acid-addition salts, basic salt class, solvate, analog and derivant.

In the present invention, the acceptable salt class of ipratropium includes but not limited to halogenide salt for example bromide, chloride and iodide.These and other acceptable salt class has been described in United States Patent (USP) the 3rd, 505, and No. 337, its disclosure all is incorporated herein by reference at this.

In one embodiment of the invention, the salt of preferred ipratropium is its bromide, chemistry 8-nitrogen bicyclo-[3.2.1] by name-octane, 3-(3-hydroxyl-1-oxo-2-phenyl propoxyl group)-8-methyl-8-(1-Methylethyl)-bromide, monohydrate, (in, cis)-, (±)-.The molecular weight of ipratropium bromide is 430.4, and empirical formula is C20H30BrNO3H2O.It easily is dissolved in water and the lower alcohol, and is for example insoluble in ether, chloroform and the fluorocarbon (flourocarbon) at lipophilic solvent.The chemical constitution of having determined ipratropium bromide is as follows:

In the present invention, albuterol and ipratropium can be carried in the various pharmaceutical carriers, and described carrier includes but not limited to water or contains other aqueous solution of the penetrating agent of pharmaceutically acceptable amount.

In an alternative embodiment, the present invention sucks solution and comprises the albuterol and the ipratropium for the treatment of effective dose.Be meant according to industry and/or administrative standard in this used word " albuterol and/or the ipratropium of treatment effective dose ", but two kinds of chemical compounds of safety and dosis tolerata.This consumption is enough to induce effectively COPD patient's bronchiectasis and/or alleviates its bronchospasm.

Suck in the solution in the present invention, the albuterol of treatment effective dose comprises the albuterol of about 0.63mg～about 4.2mg.At this, the effectiveness of albuterol is equivalent to the salbutamol sulfate of about 0.75mg～about 5mg.In an alternative embodiment, the albuterol of treatment effective dose can comprise about 2.5mg albuterol.

In another alternative embodiment of the present invention, the albuterol of treatment effective dose can comprise about 0.60mg～about 5.0mg albuterol, comprising the albuterol of following intermediate range: about 0.60mg～about 0.70mg; About 0.71mg～about 0.80mg; About 0.81mg～about 0.90mg; About 0.91mg～about 1.00mg; About 1.01mg～about 1.10mg; About 1.11mg～about 1.20mg; About 1.21mg～about 1.30mg; About 1.31mg～about 1.40mg; About 1.41mg～about 1.50mg; About 1.51mg～about 1.60mg; About 1.61mg～about 1.70mg; About 1.71mg～about 1.80mg; About 1.81mg～about 1.90mg; About 1.91mg～about 2.00mg; About 2.01mg～about 2.10mg; About 2.11mg～about 2.20mg; About 2.21mg～about 2.30mg; About 2.31mg～about 2.40mg; About 2.41mg～about 2.50mg; About 2.51mg～about 2.60mg; About 2.61mg～about 2.70mg; About 2.71mg～about 2.80mg; About 2.81mg～about 2.90mg; About 2.91mg～about 3.00; About 3.01～about 3.10; About 3.11～about 3.20; About 3.21～about 3.30mg; About 3.31mg～about 3.40mg; About 3.41mg～about 3.50mg; About 3.51mg～about 3.60mg; About 3.61～about 3.70mg; About 3.71～about 3.80mg; About 3.81mg～about 3.90mg; About 3.91mg～about 4.0mg; About 4.01mg～about 4.10mg; About 4.11mg～about 4.20mg; About 4.21mg～about 4.30mg; About 4.31mg～about 4.40mg; About 4.41mg～about 4.50mg; About 4.51mg～about 4.60mg; About 4.61mg～about 4.70mg; About 4.71mg～about 4.80mg; About 4.81mg～about 4.90mg; About 4.91mg～about 5.00mg.

In another alternative embodiment of the present invention, the albuterol of treatment effective dose comprises the salbutamol sulfate of about 0.75mg～about 5.0mg, comprising the salbutamol sulfate of following intermediate quantity: about 0.75mg～about 0.80mg; About 0.81～about 0.90mg; About 0.91mg～about 1.00mg; About 1.01mg～about 1.10mg; About 1.11mg～about 1.20mg; About 1.21mg～about 1.30mg; About 1.31mg～about 1.40mg; About 1.41mg～about 1.50mg; About 1.51mg～about 1.60mg; About 1.61mg～about 1.70mg; About 1.71mg～about 1.80mg; About 1.81mg～about 1.90mg; About 1.91mg～about 2.00mg; About 2.01mg～about 2.10mg; About 2.11mg～about 2.20mg; About 2.21mg～about 2.30mg; About 2.31mg～about 2.40mg; About 2.41mg～about 2.50mg; About 2.51mg～about 2.60mg; About 2.61mg～about 2.70mg; About 2.71mg～about 2.80mg; About 2.81mg～about 2.90mg; About 2.91mg～about 3.00; About 3.01～about 3.10; About 3.11～about 3.20; About 3.21～about 3.30mg; About 3.31mg～about 3.40mg; About 3.41mg～about 3.50mg; About 3.51mg～about 3.60mg; About 3.61～about 3.70mg; About 3.71～about 3.80mg; About 3.81mg～about 3.90mg; About 3.91mg～about 4.0mg; About 4.01mg～about 4.10mg; About 4.11mg～about 4.20mg; About 4.21mg～about 4.30mg; About 4.31mg～about 4.40mg; About 4.41mg～about 4.50mg; About 4.51mg～about 4.60mg; About 4.61mg～about 4.70mg; About 4.71mg～about 4.80mg; About 4.81mg～about 4.90mg; About 4.91mg～about 5.00mg.

In another alternative embodiment of the present invention, the albuterol of treatment effective dose comprises the albuterol of about 0.020 weight %～about 0.14 weight %, comprising the albuterol of following intermediate range: about 0.020 weight %～about 0.029 weight %; About 0.030 weight %～about 0.039 weight %; About 0.040 weight %～about 0.049 weight %; About 0.050 weight %～about 0.059 weight %; About 0.060 weight %～about 0.069 weight %; About 0.070 weight %～about 0.079 weight %; About 0.080 weight %～about 0.089 weight %; About 0.090 weight %～about 0.099 weight %; About 0.10 weight %～about 0.14 weight %.

In another alternative embodiment of the present invention, the albuterol of treatment effective dose comprises the salbutamol sulfate of about 0.025 weight %～about 0.17 weight %, comprising the salbutamol sulfate of following intermediate range: about 0.025 weight %～about 0.029 weight %; About 0.030 weight %～about 0.039 weight %; About 0.040 weight %～about 0.049 weight %; About 0.050 weight %～about 0.059 weight %; About 0.060 weight %～about 0.069 weight %; About 0.070 weight %～about 0.079 weight %; About 0.080 weight %～about 0.089 weight %; About 0.090 weight %～about 0.099 weight %; About 0.10 weight %～about 0.17 weight %.

In another alternative embodiment of the present invention, the ipratropium bromide of treatment effective dose comprises about 0.01mg～about 1.0mg ipratropium bromide.This treatment effective dose can comprise the ipratropium bromide of following intermediate range: about 0.01mg～about 0.02mg; About 0.02mg～about 0.04mg; About 0.05mg～about 0.07mg; About 0.08mg～about 0.10mg; About 0.11mg～about 0.13mg; About 0.14mg～about 0.16mg; About 0.17mg～about 0.19mg; About 0.20mg～about 0.22mg; 0.23mg～about 0.25mg; 0.26mg～about 0.28mg; About 0.29mg～about 0.31mg; About 0.32mg～about 0.34mg; About 0.35mg～about 0.37mg; About 0.36mg～about 0.38mg; About 0.39mg～about 0.41mg; About 0.42mg～about 0.44mg; About 0.45mg～about 0.47mg; About 0.48mg～about 0.50mg; About 0.51mg～about 0.53mg; About 0.54mg～about 0.56mg; About 0.57mg～about 0.59mg; About 0.60mg～about 0.62mg; About 0.63mg～about 0.65mg; About 0.66mg～about 0.68mg; About 0.69mg～about 0.71mg; About 0.72mg～about 0.74mg; About 0.75mg～about 0.77mg; About 0.79mg～about 0.81mg; About 0.82mg～about 0.84mg; About 0.85mg～about 0.87mg; About 0.88mg～about 0.91mg; About 0.92mg～about 0.94mg; About 0.95mg～about 0.97mg; About 0.98mg～about 1.00mg.

In another alternative embodiment of the present invention, comprise the ipratropium bromide of about 0.001 weight %～about 0.030 weight %, comprising the ipratropium bromide of following intermediate range: about 0.001 weight %～about 0.005 weight %; About 0.006 weight %～about 0.010 weight %; About 0.011 weight %～about 0.015 weight %; About 0.016 weight %～about 0.020 weight %; About 0.021 weight %～about 0.025 weight %; 0.026 weight %～about 0.030 weight %.

Comprise antimicrobial BAC in most of medicinal suction solution.The problem relevant with these solution be, short at interval in during these solution of repetitive administration, BAC may cause the eccentricity bronchoconstriction.Another problem is that after the patient sucked BAC, BAC can cause the bronchoconstriction of dose dependent.The present invention sucks solution can not contain BAC, therefore is particularly suitable for emergency, uses this suction solution because need under this situation repeatedly in the short time.Simultaneously, use the suction solution that does not contain BAC, reduced the probability that the detrimental effect relevant with BAC followed generation to the patient.The toxicity relevant and other side effect have also been reduced with BAC.

The present invention sucks solution and also can be aseptic unit dose goods, has so just avoided using in solution BAC.In addition, as shown in table 1, sterile form preparation of the present invention (it comprises the salbutamol sulfate and the ipratropium bromide for the treatment of effective dose) provides stable suction solution, therefore makes said preparation can preserve (for example on shelf) long period of time.

Table 1 stability data

		0.083 weight % salbutamol sulfate and 0.017 weight % ipratropium bromide
						Analyze *		pH	Osmolality (mOsm/kg)
		Salbutamol sulfate	Ipratropium bromide
				0 constantly		98	98			3.3	283
25 ℃/35% relative humidity	12 months	105	99					3.4	285
				24 months	102	101	3.5			282
	40 ℃/15% relative humidity	3 months	100					99	3.5		284
6 months				103	102	3.4	283

^*The percent of label value (0.083 weight % salbutamol sulfate and 0.017 weight % ipratropium bromide).MOsm/kg: milli oozes/kilogram

As mentioned above, be stable in this compositions that provides.For example, can be in this compositions that provides in about 15～30 ℃ of storages, and in the long relatively time, keep stable.In one embodiment, compositions is in 25 ℃ of storages.

In another embodiment, under the uniform temperature after long-time the placement, be wherein to contain greater than the active component of 80%, 85%, 90% or 95% primary quantity for example albuterol and ipratropium in the stability of this compositions that provides.For example, stablize 30 days compositions under 25 ℃, after 30 days, should contain active component in the said composition greater than 80%, 85%, 90% or 95% primary quantity in 25 ℃ of storages.

In another embodiment, described compositions is stable during Long-term Storage, and promptly compositions more than 1,2 or 3 year after (being storage period), still is fit to be applied to the experimenter who this is had needs 25 ℃ of storages.In other embodiments, for example, adopt the estimation of Arrhenius (Arrhenius) kinetics equation to draw, experience this storage after, still residue＞80%,＞85%,＞90% or＞95% bronchodilator.

Other index of the stability of the present composition can be the by-product or the catabolite that occur in time shown in following table 2 and 3.

Table 2

	Albuterol catabolite/related compound accounts for the percent (%) of albuterol	25 ℃, the scope in the time of 6-24 month	Scope in medicine
				1	5-2-((1, the 1-dimethyl ethyl) amino-1-ethoxy)-2-hydroxy benzaldehyde	ND～0.012 weight %
2	Two (2-hydroxyl)-5-(2-tert-butyl group amino-1-ethoxy) benzyl ether		0.09～0.174 weight %
				3	2-tert-butyl group amino-1-(4-hydroxyl-3-methoxy phenyl)-ethanol		0.01～0.12 weight %
4	Tert-butyl group amino-3-chloro-4-hydroxyl-5-methylol 1-Phenylethanone.		ND～0.0002 weight %
				5	Tert-butyl group amino-4-hydroxy-5-methylol 1-Phenylethanone.		ND～0.002 weight %
6	1-(4-hydroxy-3-methyl phenyl)-2-(tert-butyl group amino) ethanol		0.0009～0.036 weight %
				7	1-(5-chloro-4-hydroxyl-3-hydroxymethyl phenyl)-2-(tert-butyl group amino) ethanol		ND
8	Unknown material 1	ND～0.07% is by calculated by peak area
				9	Any other unknown material	ND～0.025% is by calculated by peak area
10	Amount to	0.18～0.23％

ND=does not detect

Table 3

	Ipratropium catabolite/related compound accounts for the percent of ipratropium bromide	25 ℃, the scope when reaching 24 months	Scope in medicine
				1	Tropic acid	ND～0.08 weight %
2	The 8S-ipratropium bromide		ND～0.058 weight %
				3	N-isopropyl-noratropine		ND
4	Ipratropium alcohol (Ipratropium alcohol)	ND～0.038 weight %
				5	Any other unknown material	ND
6	Atropic acid	ND
				7	Amount to (not comprising the APO-ipratropium)	ND～0.2％

ND=does not detect

In one embodiment, the development process of stipulating with American Public Health Association (APHA) is a fundamental measurement, and described compositions is clarifying at least basically.In another embodiment of the invention, after 25 ℃ of placements reached 24 months, based on the APHA standard, the APHA color result of compositions was 0～5 unit (great majority is 0 unit).

In one embodiment, the inventive method provides the compositions of the albuterol content that contains the 2.5mg/ bottle of having an appointment～about 2.75mg/ bottle.In another alternative embodiment, the inventive method provides the compositions of ipratropium content for about 0.45mg/ bottle～about 0.55mg/ bottle.In another alternative embodiment, the inventive method provides the about 2.84ml/ bottle of average loading amount～about 3.30ml/ bottle.

In another alternative embodiment, the present composition can comprise minimum impurity, and described impurity includes but not limited to:

Table 4

1. volatile matter
		Acetone	About NMT 0.2 Φ g/ml or lower
Ethyl acetate	About NMT 0.3 Φ g/ml or lower
		Normal heptane	NMT 0.1 Φ g/ml or lower
N-propyl acetate	NMT 0.3 Φ g/ml or lower
		Toluene	NMT 0.3 Φ g/ml or lower
2-butanone	Do not measure (believing/make an uproar NMT 3)
		Unknown material
2. but elimination thing
		Irganox 129	Do not measure (NMT 0.02 Φ g/ml)
Extractable 1	Do not measure (believing/make an uproar NMT 3)
		Extractable 2	Do not measure (believing/make an uproar NMT 3)
Unknown material	Do not measure (believing/make an uproar NMT 3)

(NMT: be not more than)

In another alternative embodiment, the present composition can comprise minimum particulate matter, and described particulate matter includes but not limited to: NMT is about 1000～5000, preferably be about 3800 particle/bottles＞2 Φ m; NMT is about 10～100, preferably be about 80 particle/bottles＞10 Φ m; Or NMT is about 1～5, preferably is about 3 particle/bottles＞25 Φ m.

Another benefit of aseptic suction solution is the probability that when having reduced medication impurity has been imported the patient, has therefore lowered the probability of patient's opportunistic infection.

Considerable problem is not adhere to COPD pharmacotherapy and dispensing error.Albuterol and ipratropium pre-packing, premixed, scheduled volume are provided for COPD patient, can significantly reduce these problems.These chemical compounds are provided in this way, have simplified the COPD therapy, because it has improved convenience and has eliminated confusion when preparing suitable dosage.Treat and must be diluted to the situation (as previously mentioned, can produce some problems like this) of the specific concentration that is suitable for patient treatment with respect to common employing multiple dose unit, these advantages of the present invention are especially obvious.

The present invention has overcome foregoing problems by the albuterol and the ipratropium of treatment effective dose pre-packing, premixed, scheduled volume and/or unit dosage form are provided.An embodiment, the present invention includes a kind of container of or a plurality of prefills.Described one or more container is equipped with the aqueous solution of single dose separately, and this aqueous solution contains the albuterol and the ipratropium of the treatment effective dose that is used for the treatment of COPD.Suction solution is provided by this way, has avoided dilution or mixed C OPD medicine needs with the dosage that obtains being suitable for treating.Simultaneously, do not need to carry out special pharmacy batching yet, thereby lower medication mistake probability.In addition, also reduce the risk of cross-contamination, and adopt and premixedly promptly also reduced the waste in the medication with the suction solution of form.

Other characteristics of the present invention have, and compare with the COPD treatment of routine, and the present invention has improved the compliance and the quality of life of user.Though the compliance horizontal component ground of any COPD treatment depends on the technology of power and individual's allotment medicine of user, however, easiness for the treatment of as enforcement by control example and the factors such as desirability when receiving treatment still can improve compliance.

The present invention shows as the improvement for the COPD treatment of routine clearly for COPD facilitates, treats fast and reliably.Design the present invention is in order to promote the compliance of user by one or more dosed administration containers that the suction solution that premixed, scheduled volume is housed is provided, and wherein sucks solution and comprises the treatment COPD of treatment effective dose of single dose with albuterol and ipratropium.Can in the method for treatment COPD, use described container, or described container is incorporated in the system and/or test kit that is used for the treatment of COPD.

In an alternative embodiment, the present invention be loaded in the single container, aseptic, premixing, scheduled volume and do not contain the suction solution of BAC, described suction solution contains the albuterol and the ipratropium of the treatment effective dose of single dose.Each unit-dose container is equipped with salbutamol sulfate (being equivalent to the 2.5mg albuterol) and the 0.5mg ipratropium bromide of the 3.0mg/3ml in aseptic aqueous solution.Can add sodium chloride this solution etc. is oozed, also can add hydrochloric acid the pH of solution is transferred to about 4.0.The present invention sucks solution can contain or not contain for example EDTA of chelating agen.

In another alternative embodiment, the present invention sucks solution for not containing the aseptic aerosol apparatus solution of 3ml of BAC, wherein contains the ipratropium bromide of the 0.20mg that has an appointment～about 0.5mg and the salbutamol sulfate of about 0.75mg/3ml～about 3.0mg/3ml.Aerosol apparatus solution is loaded in low density polyethylene (LDPE) (LDPE) unit-dose container.The per unit dose container can be positioned in the paper tinsel system capsule, and each paper tinsel system capsule can be adorned 5 or a plurality of unit-dose container.The paper tinsel system capsule that unit-dose container is housed can be positioned in the shelf carton.

The invention provides the albuterol and the ipratropium inhalation solution that are used for the treatment of different phase COPD (including but not limited to the 0-III phase).The correlated characteristic of different phase COPD is as shown in table 2, and the information in this table is only for the example explanation.Its intention does not lie in and limits the scope of the invention.

Table 2

Stage	Severity	Describe
			0	Risky	*The tidal volume measurement method *Chronic sympton (coughing, have expectorant)
I	Slightly	*FEV 1/FVC＜70％ *FEV 1＞80% predictive value *Be with or without chronic sympton
			II	Medium	*FEV 1/FVC＜70％ *30％≥FEV 1＜80% predictive value (IIA:50% 〉=FEV 1＜80％) (IIB：30％≥FEV 1＜50％) *Be with or without chronic sympton
III	Seriously	*FEV 1/FVC＜70％ *FEV 1＜30% predictive value or be lower than 50% predictive value is with the clinical symptom of respiratory failure or right heart failure

(FEV ₁: the respiratory capacity of exerting oneself for the 1st second; FVC: forced vital capacity)

In the present invention, the albuterol of administering therapeutic effective dose and ipratropium are to induce bronchiectasis and/or the alleviation bronchospasm relevant with COPD.Can use the albuterol and the ipratropium of described amount in bronchospasm outbreak back to the patient, to alleviate the caused dyspnea of COPD.In another embodiment, use to preventability albuterol and ipratropium, promptly prevent the COPD development.

The amount of application of albuterol and ipratropium can be determined according to individual instances, the severity of patient's stature size, symptom to be treated and the curative effect that will obtain should be partly considered at least.Actual dose of using every day (at every turn using the amount of albuterol and ipratropium) and number of times depend on administering mode, for example through inhaler, aerosol apparatus or oral administration.For example, if needed every day allow additionally use the dosage of maximum 2 3mls through the albuterol of the about 2.5mg of spray application and the ipratropium bromide of about 0.5mg every day again, and this dosage is enough to most patient is produced the bronchodilator effect of expection.

Further, albuterol of the present invention and ipratropium inhalation solution can with one or more other medicines couplings.For example, antiasthmatics is theophylline or terbutaline for example, or hydryllin or analgesic for example aspirin, acetaminophen or ibuprofen, can or use in the approaching time with the albuterol of treatment effective dose.Can use medicine of the present invention and above-mentioned one or more medicines by a kind of preparation or two entities that separate.According to the present invention, depend on the needs that reduce the COPD symptom, albuterol and the ipratropium that periodically will treat effective dose separately are applied to individuality, or co-administered in individuality with other medicines.

In another alternative embodiment, can adopt aerosol apparatus to use the present invention and suck solution, described aerosol apparatus includes but not limited to that jet nebulizer, ultrasonic sprayer and breathing actuate (breathactuated) aerosol apparatus.Preferably, aerosol apparatus is the jet nebulizer that is connected on the competent air compressor of air-flow.Aerosol apparatus is equipped with seaming (mouthpiece) or suitable face shield.Specifically, can adopt and be connected to PRONEB ^TMPari-LC-Plus on the compressor ^TMAerosol apparatus (being furnished with face shield or seaming) sucks solution with the present invention and passes to the patient.

In an alternative embodiment, system of the present invention and/or test kit are equipped with the suction solution of pre-packing, scheduled volume, premixed and/or single unit dosage form, and wherein said suction solution contains the albuterol and the ipratropium of the treatment effective dose that is used for the treatment of COPD.Sucking solution can be aseptic and/or not contain BAC.

In another embodiment, the invention provides the system and/or the test kit of the dosed administration container that is used to assemble and preserve one or more prefills, that each container is equipped with is premixed, the suction solution of scheduled volume.This suction solution comprises the albuterol and the ipratropium of the treatment effective dose of single unit dose.This system and/or test kit can provide the container of this prepacked form.Described one or more containers can be made of plastics, and these plastics include but not limited to semi permeability plastics, for example LDPE.Described container also can have Twist-Flex ^TMTop cover (top), this top cover have clothes hook shape (tab-like) handle that is easy to hold, and like this, for example turn on handle-bar grip and can open container.Twist-Flex ^TMThe favourable part of top cover is that it can make using of solution easier, prevents to run off, and need not to cut top cover and can open container etc., thereby reduced cross-contamination.One or more so semipermeable single unit-dose containers can be packaged in the aluminium foil capsule in advance, and like this, aluminium foil just can provide the protective barrier of catch ring environment pollution and light.This barrier has improved storage life and the stability that sucks solution.

In another alternative embodiment, the present invention includes the intake system and/or the test kit of the pre-packing that COPD patient is suitable for.The system and/or the test kit of this pre-packing comprise: (a) albuterol and the ipratropium of the treatment effective dose of one or more single unit dose; (b) described unit dose is used for the treatment of the directions for use of COPD; (c) prefill has the albuterol of described one or more unit dose and the dosed administration container of ipratropium.

In another alternative embodiment, the intake system of the pre-packing of the present invention and/or test kit provide the single unit dose medicine bottle of one or more premixed, scheduled volumes and using method thereof explanation, comprise the albuterol and the ipratropium of the treatment effective dose that is used for the treatment of the bronchospasm relevant with COPD in this medicine bottle.

In another alternative embodiment, the present invention relates to be used to induce the pre-packing therapy system and/or the medicine box of patients with chronic obstructive pulmonary diseases bronchiectasis and alleviation bronchospasm, described pre-packing therapy system comprises:

(a) one or more dosed administration containers; The equal prefill of described one or more containers do not contain premixed, the scheduled volume of benzalkonium chloride (BAC) about 3ml sterile aqueous suck solution, described solution comprises the albuterol and the ipratropium bromide of the treatment effective dose of unit dose; Wherein the amount of albuterol is about 2.5mg, and the amount of ipratropium bromide is about 0.5mg; Described suction solution in described one or more container is suitable for atomizer spray; Suction solution in described one or more container all has long storage life;

(b) have one or more labels of labelling on it, described labelling comprise with described one or more containers in respectively suck the relevant effect of solution, dosage, usage, contraindication and untoward reaction information;

(c) wherein said contraindication information comprises that expression avoids information with the suction solution in described one or more containers to atropine and derivant people hypersensitive thereof; With

(e) wherein said untoward reaction information comprises and informs following information: after using the suction solution in described one or more container, may promote or aggravate angle-closure glaucoma, acute ophthalmalgia, blurred vision, eccentricity bronchospasm, stridulate, the increasing the weight of of symptoms of chronic obstructive pulmonary disease, sleepy, pain, flushing, upper respiratory tract infection, cardiopalmus, sense of taste abnormality, heart rate quickening, sinusitis, backache and throat pain.

Described dosage and administration information can comprise the recommended dose of the suction solution in the described one or more containers of expression, this recommended dose is, about 2.5mg albuterol in the 3ml aqueous solution and about 0.5mg ipratropium bromide, this aqueous solution every day is through spray delivery 4 times, if needed, can use extra maximum 2 recommended dose every day again.In addition, after described untoward reaction information also can comprise the suction solution of representing to use in described one or more container, may be to the information of described suction solution generation type, described anaphylaxis comprises urticaria (urticaris), angioedema, rash, Pruritus, oropharynx (oropharyngeal), edema, bronchospasm and anaphylaxis.This untoward reaction information can comprise that also expression uses the information of contingent allergic effect type reaction behind the suction solution of described one or more containers, and this allergic effect type reaction comprises erythra, pruritus and urticaria.This untoward reaction information can comprise further that also expression uses the tabulation of contingent one or more adverse events behind the described suction solution, and described adverse events comprises chest pain, diarrhoea, gastricism, feels sick, leg cramps, bronchitis, lung disease, pharyngitis, pneumonia and urinary tract infection.

In another alternative embodiment, intake system and/or the test kit that is used for the treatment of the pre-packing of patients with chronic obstructive pulmonary diseases bronchospasm provided by the invention can comprise:

(a) one or more dosed administration containers; Described one or more container all is equipped with premixed, scheduled volume, the stable sterile aqueous that does not contain benzalkonium chloride in advance and sucks solution, and described suction solution is made up of following material: sodium chloride, water, disodium edetate, the pH that will suck solution transfer to the albuterol and the ipratropium bromide of the treatment effective dose of about 4 acid, unit dose; Wherein the amount of albuterol is about 2.50mg, and the amount of ipratropium bromide is about 0.5mg; The solution that respectively sucks in described one or more container all is applicable to atomizer spray; Described suction solution has long storage life;

(b) have one or more labels of labelling, described labelling comprise with described one or more containers in respectively suck the relevant effect of solution, dosage, usage, contraindication and untoward reaction information;

(c) wherein said dosage and administration information comprises the recommended dose of the suction solution in the described one or more containers of expression, described recommended dose is, about 2.5mg albuterol in the 3ml aqueous solution and about 0.5mg ipratropium bromide, this aqueous solution every day is through spray delivery 4 times, if needed, can use extra maximum 2 recommended dose every day again;

(d) wherein said contraindication information comprises that expression avoids information with the suction solution in described one or more containers to atropine and derivant people hypersensitive thereof;

(e) wherein said untoward reaction information comprises and informs following information: after using the suction solution in described one or more container, type may take place, and described anaphylaxis comprises urticaria, angioedema, rash, Pruritus, oropharynx, edema, bronchospasm and anaphylaxis.

(f) after wherein said untoward reaction information comprised the suction solution of using described one or more containers, the information of allergic effect type reaction may take place; Described allergic effect type reaction comprises erythra, pruritus and urticaria.

(g) wherein said untoward reaction information comprises and informs following information: after using the suction solution in described one or more container, may promote or aggravate angle-closure glaucoma, acute ophthalmalgia, blurred vision, eccentricity bronchospasm, stridulate, the increasing the weight of of symptoms of chronic obstructive pulmonary disease, sleepy, pain, flushing, upper respiratory tract infection, cardiopalmus, sense of taste abnormality, heart rate quickening, sinusitis, backache and throat pain; With

(h) wherein said untoward reaction information comprises the tabulation of contingent one or more adverse events behind the suction solution of using in described one or more container; Described adverse events comprises chest pain, diarrhoea, gastricism, feels sick, leg cramps, bronchitis, lung disease, pharyngitis, pneumonia and urinary tract infection.

The intake system of described pre-packing and/or test kit can be a kind of in the various ways, it includes but not limited to: the box of the unit dose medicine bottle of one or more pre-packings is housed, the independent packaging that contains one or more unit dose medicine bottles or the box of capsule perhaps are housed.For example, be used for the treatment of COPD patient's the pre-packaging system of unified standard and/or test kit as shown in Figure 5.Specifically, Fig. 5 has described supportive packing 10.Described supportive packing 10 can include but not limited to box, carton or other any overall containment.In the described supportive packing dosed administration container 21～25 one or more pre-packings, prefill is housed.That each container is equipped with is premixed, the suction solution of scheduled volume.Described suction solution contains the albuterol and the ipratropium bromide of the treatment effective dose that is used for the treatment of COPD of unit dose.Described suction solution can be aseptic and/or not contain the form of BAC.

Also can have one or more labels 13 in the carrier package 10.Described one or more label can have the labelling 14 that this solution of expression is used to alleviate the symptom relevant with COPD (for example bronchospasm).Described label also can have provides the labelling 15 that uses this suction solution to alleviate the directions for use of above-mentioned symptom.Include but not limited to literal, photo, figure, symbol and/or style at this used " labelling ".The indefiniteness example that can appear at the described labelling on one or more labels 13 as shown in Figure 7.Described one or more label is attachable to one or more surfaces of supportive packing 10, or the sheet-fed form, or its any combination.Supportive packing 10 also can comprise and be used for packaging material are encapsulated in interior lid 16.

System of the present invention and/or test kit also can comprise label and/or the directions for use that is designed for promotion user compliance.For example, in one embodiment, system of the present invention and/or test kit comprise the packaging material that or multiple prefill medicine bottle are housed, described medicine bottle comprises, and unit dose sterile aqueous premixed, scheduled volume sucks solution, and described solution comprises the albuterol and the ipratropium bromide for the treatment of effective dose.These packaging material can further have label, and this label is used for illustrating that each medicine bottle can use with aerosol apparatus, to be used to alleviate the symptom relevant with COPD, for example bronchospasm.This directions for use also can comprise the dosage explanation and the usage of each spraying treatment, the explanation of for example adopting aerosol apparatus to use.Described directions for use is attachable to one or more surfaces of these packaging material, and perhaps described explanation also can be sheet-fed or its any combination.

The present invention also relates to treat the symptom relevant method of (comprising bronchospasm) with COPD, wherein can be with the albuterol and the ipratropium bromide of unit dose administering therapeutic effective dose.Described unit dose can be aerosol apparatus solution form.

In another embodiment, the method that the present invention relates to induce the patients with chronic obstructive pulmonary diseases bronchiectasis or alleviate bronchospasm said method comprising the steps of:

(a) provide pre-packing therapy system to the patient, described system comprises: one or more dosed administration containers; The about 3ml of the equal prefill of described one or more container is premixed, scheduled volume and the aqueous that do not contain benzalkonium chloride suck solution, and described suction solution contains the albuterol and the ipratropium bromide of the treatment effective dose of unit dose; Wherein the content of albuterol is about 2.5mg, and the content of ipratropium bromide is about 0.5mg; Suction solution in described one or more container all is applicable to aerosol apparatus sprays; Suction solution in described one or more container has long storage life;

(b) to patient or prescription doctor provide with described one or more containers in the relevant following information of suction solution, promptly pack dosage, usage, contraindication and the untoward reaction information of therapy system in advance;

(c) wherein said contraindication information comprises that expression avoids information with the suction solution in described one or more containers to atropine and derivant people hypersensitive thereof; With

(d) wherein said untoward reaction information comprises and informs following information: after using the suction solution in described one or more container, may promote or aggravate angle-closure glaucoma, acute ophthalmalgia, blurred vision, eccentricity bronchospasm, stridulate, the increasing the weight of of symptoms of chronic obstructive pulmonary disease, sleepy, pain, flushing, upper respiratory tract infection, cardiopalmus, sense of taste abnormality, heart rate quickening, sinusitis, backache and throat pain.

In the method, described dosage and use information and can represent the recommended dose that respectively sucks solution in described one or more container to patient or prescription doctor, this recommended dose is, about 2.5mg albuterol in the 3ml aqueous solution and about 0.5mg ipratropium bromide, this aqueous solution is through spraying administration every day 4 times, if needed, can use extra maximum 2 recommended dose every day again.Described untoward reaction information also can be informed patient or prescription doctor, after using the suction solution in described one or more container, contingent type, described anaphylaxis comprises urticaria, angioedema, rash, Pruritus, oropharynx, edema, bronchospasm and anaphylaxis.Described untoward reaction information also can further be informed patient or prescription doctor, use the suction solution in described one or more container after, the reaction of contingent allergic effect type is comprising erythra, pruritus and urticaria.In addition, this untoward reaction information also comprises the prefabricated tabulation of using contingent one or more adverse events behind the described suction solution, and described adverse events comprises chest pain, diarrhoea, gastricism, feels sick, leg cramps, bronchitis, lung disease, pharyngitis, pneumonia and urinary tract infection.

In another alternative embodiment, the method that the present invention relates to induce the bronchiectasis of patients with chronic obstructive pulmonary diseases or alleviate its bronchospasm, described method comprises the steps:

(a) provide pre-packing therapy system to the patient, described system comprises: one or more dosed administration containers; Premixed, scheduled volume, the stable sterile aqueous of the about 3ml of the equal prefill of described container sucks solution, and described solution does not contain benzalkonium chloride; Described suction solution by water, disodium edetate, sodium chloride, will suck albuterol and ipratropium bromide that the solution pH value transfers to the treatment effective dose of about 4 acid, unit dose, wherein the amount of albuterol is about 2.50mg/3ml, and the amount of ipratropium bromide is about 0.5mg/3ml; Suction solution in described one or more container all is applicable to atomizer spray;

(b) to patient or prescription doctor provide with described one or more containers in the relevant following information of suction solution, promptly pack effect, dosage, usage, contraindication and the untoward reaction information of therapy system in advance;

(c) wherein, the described dosage and the information of using are informed the recommended dose of the suction solution in described one or more container to patient or prescription doctor, this recommended dose is, about 2.5mg albuterol in the 3ml aqueous solution and about 0.5mg ipratropium bromide, this aqueous solution every day is through spray delivery 4 times, if needed, can use extra maximum 2 recommended dose every day again;

(d) wherein said contraindication information comprises that expression avoids information with the suction solution in described one or more containers to atropine and derivant people hypersensitive thereof;

(e) wherein said untoward reaction information comprises and informs patient or prescription doctor following information: after using the suction solution in described one or more container, type may take place, and described anaphylaxis comprises urticaria, angioedema, rash, Pruritus, oropharynx, edema, bronchospasm and anaphylaxis;

The reaction of allergic effect type may take place after using the suction solution of described one or more containers in (f) wherein said untoward reaction information notification patient or prescription doctor; Described allergic effect type reaction comprises erythra, pruritus and urticaria;

(g) wherein said untoward reaction information notification patient or prescription doctor following information: after using the suction solution in described one or more container, may promote or aggravate angle-closure glaucoma, acute ophthalmalgia, blurred vision, eccentricity bronchospasm, stridulate, the increasing the weight of of symptoms of chronic obstructive pulmonary disease, sleepy, pain, flushing, upper respiratory tract infection, cardiopalmus, sense of taste abnormality, heart rate quickening, sinusitis, backache and throat pain; With

(h) described untoward reaction information comprises the prefabricated tabulation of using contingent one or more adverse events behind the described suction solution, and described adverse events comprises chest pain, diarrhoea, gastricism, feels sick, leg cramps, bronchitis, lung disease, pharyngitis, pneumonia and urinary tract infection.

In an alternative embodiment, the inventive method comprises the albuterol of treatment effective dose and the step that ipratropium is applied to the patient.This solution also pre-packing, premixed, scheduled volume, do not contain BAC and/or aseptic.This solution also can be loaded in the single unit dose medicine bottle.

In another alternative embodiment, the inventive method comprises and is applied to the step that this is had the patient of needs with containing the albuterol for the treatment of effective dose and the suction solution of ipratropium.Can adopt aerosol apparatus to use described suction solution, more preferably adopt the jet nebulizer that is connected to the competent air compressor of air-flow to use described suction solution.

In another alternative embodiment, referring to Fig. 1～4, the inventive method comprises the steps: that suction solution that (i) will contain the albuterol for the treatment of effective dose and ipratropium 1 packs in the aerosol apparatus cup 2, can be that this aerosol apparatus transmits power by linking to each other with compressed gas cylinder or electronic compressor; (ii) adopt "T"-shaped joint 3 that aerosol apparatus bowl cover 4 is assemblied on seaming 5 or the face shield 6; (iii) the speed sucking-off of spraying by gas sucks solution 1, and makes it be broken into aerosol; This aerosol is entered in the bronchospasm patient 7 through seaming 5 or face shield 6; (v) this patient continues to breathe, in spray chamber 8, no longer form mist till.This operation can be finished in about 5～15 minutes.

In an alternative embodiment, the common predose that gives the patient is about 2.50mg albuterol and 0.5mg ipratropium, uses every day as required 3 or 4 times through spraying.For albuterol and the ipratropium of using above-mentioned amount, can use whole inclusions of a unit dose medicine bottle (for example about 3.0mg/3ml salbutamol sulfate and 0.5mg/3ml ipratropium bromide).Preferably, regulating the aerosol apparatus flow velocity makes it to use described albuterol and ipratropium in 5～15 minutes.

In an alternative embodiment, the inventive method comprises the steps: that also (i) contains one or more solution of ipratropium or albuterol by dilution, and preparation contains the albuterol for the treatment of effective dose and the suction solution of ipratropium; (ii) described suction solution is applied to the patient who this is had needs.

It is pre-packing, aseptic, scheduled volume, premixed and/or do not contain the preparation method of the suction solution of BAC that the present invention also provides, and described suction solution comprises the husky butylamine and the ipratropium of the treatment effective dose of single unit dose.In this embodiment, the inventive method comprises one or more following steps: (i) for example add the albuterol and the ipratropium for the treatment of effective dose at least in the water to carrier; (ii) with solution sterilization and sealed container.Can add the isotonicity that osmotic pressure regulator comes regulator solution.Preferably, solution of the present invention is isoosmotic, and can add osmotic pressure regulator the isotonicity of solution is transferred to about 280～320mOsm/kg.In addition, can add acid (for example hydrochloride) pH value of solution is transferred to about 3.0～about 5.0, preferably be about 4.0 level.

In another embodiment, the present invention's preparation method of sucking solution comprises one or more following steps: (i) for example add the albuterol and the ipratropium for the treatment of effective dose at least in the water to carrier; (ii) the gained mixture is packed in the container, and mixture is sterilized through steam sterilization or any other sterilizing methods known in the art.Each albuterol and ipratropium mixture are packed in the medicine bottle, pack then, preserve and/or directly use.Mixture at this gained is stable, and it can be divided into many parts of mixture after sterilization if necessary, and each mixture all comprises the albuterol and the ipratropium of the treatment effective dose of unit dose.

Spendable osmotic pressure regulator includes but not limited to sodium chloride, potassium chloride, zinc chloride, calcium chloride and composition thereof.Also other osmotic pressure regulator be can adopt, mannitol, glycerol, glucose and composition thereof included but not limited to.In an alternative embodiment, the present invention can comprise the ion salt of about 0.4 weight %～about 1.0 weight %.Preferably, the present invention comprises the osmotic pressure regulator of 0.9 weight %.

In an alternative embodiment, can prepare the present invention according to the following steps and suck solution: the SANYE agitator (tri-blender) of bottom row's mouth (i) being installed on rustless steel preparation jar and being used to stir; (ii) stir down, in this jar, drop into 18 ℃～25 ℃ the USP that purifies waste water (American Pharmacopeia level) of about 95% aequum; (iii) in this jar, add EDTA USP, hydrochloric acid and treat the salbutamol sulfate USP and the ipratropium bromide of effective dose at least; (iv) continue to be stirred to all chemical constituent dissolvings; (v) if necessary, add the USP that purifies waste water and regulate final volume, thereby make the mixture of albuterol and ipratropium bromide.

From the preparation jar, albuterol and the pumping of ipratropium mixture are sealed in (FFS) machine by the direct injection moulding filling of clean feed-line.Make albuterol and ipratropium mixture pass through 0.2 micron sterilization filter cartridge, enter in the hold-up tank then, enter the perfusion ozzle of filtrated air shower cabinet again by second 0.2 micron sterilization filter cartridge, enter subsequently in the medicine bottle by low density polyethylene (LDPE) (LDPE) molding.Sterilized albuterol and ipratropium mixture are packed in the medicine bottle, make each medicine bottle comprise the albuterol of the treatment effective dose of single unit dose.Medicine bottle sealing after will filling then.Under aseptic condition, adopt the FFS machine with successive operation molding, filling and sealed vial, thereby produce sterile product.For example, can adopt automatic packaging machine, five medicine bottles that loaded of row (Fig. 6) are packaged in the protective layer blocking system capsule.6～12 these seed capsules are packaged in the shelf carton, have formed the pre-packing therapy system that is used for the treatment of COPD patient.Suitable label and directions for use can be added in the shelf carton.

The invention still further relates to the method that forms unit dose aerosol apparatus solution, comprise the steps: that (i) is formulated in the albuterol that containing in pharmaceutically suitable carrier treat effective dose and the mixture of ipratropium bromide.Described mixture is suitable for atomizer spray.

In an alternative embodiment, the present invention also comprises and is used to alleviate the symptom relevant with the COPD device of (comprising bronchospasm).This device is taked label, written explanation or any other form of attach mark on it.This device can have labelling, described labelling is used to illustrate that the patient with symptom relevant with COPD can adopt suction solution at least a pre-packing, aseptic, premixed, scheduled volume and/or that do not contain BAC to treat, and described suction solution is included in the albuterol and the ipratropium of the treatment effective dose of the unit dose in the single medicine bottle.Described suction solution is suitable for atomizer spray.This device also can have guidance and use described suction solution to have the patient's of described symptom labelling with treatment.

Embodiment

In order to estimate effectiveness and the safety that the present invention sucks solution, carried out double blinding, at random, positive control test.About design, result and the conclusion of this research, face describes in detail as follows.

The patient

Always having 863 patients at first registers at random and enters this test.Meet the just qualified adding of patient of table 3 standard.

Table 3. is selected in/exclusion standard

Design considerations	Describe
		Choice criteria	*The diagnosis suffering from copd, its FEV1 is 25～65% of a normal predictive value *Age＞40 year old *Regularly used one or more bronchodilators at least 3 months before this *Smoking history more than at least 10 years *Can not use theophylline, salmaterol and oral β 2 agonists (judging) in duration of test control by researcher. *Can finish 6 minutes walking safely *Informed consent is provided voluntarily
Exclusion standard	*Diagnosis has anthracosis, pneumosilicosis, any organic disease, erythrocytosis that is not attributable to COPD, or pneumonopathy (pulmonale), anoxia, or first visit is and allergic effect rhinitis, atopy or COPD diseases associated *Significant clinically obstructive uropathy, angle-closure glaucoma, unstable angina pectoris or myocardial infarction was arranged in 6 months in the past, the known drug abuse is arranged in nearest 12 months, or 2 months in the past endogenous cause of ill pneumonopathy feelings increase the weight of and are in hospital *Known any composition for the treatment of the reagent thing has anaphylaxis *Treat to use in preceding 30 days of the reagent thing overtesting medicine taking first dosage *Pregnancy or suckling

Treatment

The unitized dose of each independent medicine and ipratropium and albuterol is as shown in table 4 below.Adopt Pari LC Plus ^TMAerosol apparatus and Pari Proneb ^TMCompressor sucks and uses the reagent thing that remains, every day 4 times (per ideally 6 hours 1 time).Duration of test should limit and use bronchodilator simultaneously.In the process of the test, allow oral and suction to use steroid, it is constant that condition is that dosage keeps.

Table 4

Treat the reagent thing	Albuterol (main component)	Ipratropium bromide
			Singly use albuterol	2.5mg
Singly use ipratropium		0.5mg
			Albuterol and ipratropium coupling	2.5mg	0.5mg

Efficacy results

In 863 patients of random assortment and begin treatment, 289 are withdrawed from from test in advance, and this comprises 28 patients that do not meet selected/exclusion standard and should not add.663 patients accept that the present invention sucks solution and at least a other are treated the reagent thing altogether, and measure at least 1 FEV after administration ₁Because Most patients has been finished all 3 kinds of treatments for the treatment of the reagent thing, so contributed 647 can supply the comparing data of evaluation these experimenters of each several part of preliminary analysis.

During cross matching, main efficacy variable is the peak FEV that records in 3 hours behind the dosed administration from before the dosed administration ₁Variation.As shown in table 5, the FEV when albuterol and ipratropium coupling ₁The average numerical value that increases when being significantly higher than any medicine of independent use.Wherein coupling group is higher by 23.6% with albuterol than single, and is higher by 37.2% with ipratropium than single.FEV ₁Responding in time, the variation of process sees Table 6.

The efficacy results of table 5. intersection phase

Parameter	Combination is compared with albuterol				Combination is compared with ipratropium
										n	The combination average	The albuterol average	The p value	n	The combination average	The ipratropium average	The p value
Peak F EV 1(liter)	647	0.387	0.313	＜0.001	647	0.387	0.282	＜0.001

The FEV1 that records during table 6.14 day changes

During parallel test, in last 6 weeks of test, independently patient's group is used 3 kinds of only a kind of medicines for the treatment of in the reagent thing voluntarily.The result of parallel phase is basically with to intersect the phase identical.With intersect observed peak F EV of phase ₁Respond identically, the combination of albuterol and ipratropium has kept being higher than the numerical value of using arbitrary drug component separately equally.

Safety/toleration

According to above-mentioned clinical trial, albuterol and the relevant untoward reaction of ipratropium combination have been estimated.It was reported 1% or more patient adverse events has appearred in treatment, the results are shown in Table 6 by the different pharmaceutical statistics.As can be seen from the table, with regard to patient's the incidence rate that adverse events appears in whole body system, there is not difference between albuterol and ipratropium combination and the independent drug administration.

The report of table 6. adverse events

(1% of adverse events incidence rate 〉=treatment group, wherein combination treatment presents high percent)

Body system COSTART term	Albuterol n (%)	Ipratropium n (%)	Albuterol and ipratropium combination n (%)
				Patient's quantity	761	754	765
The patient n (%) that untoward reaction is arranged	327(43.0)	329(43.6)	367(48.0)
				Whole body
Bitterly	8(1.1)	4(0.5)	10(1.3)
				Chest pain	11(1.4)	14(1.9)	20(2.6)
Digestive system
				Diarrhoea	5(0.7)	9(1.2)	14(1.8)
Dyspepsia	7(0.9)	8(1.1)	10(1.3)
				Feel sick	7(0.9)	6(0.8)	11(1.4)
Musculoskeletal system
				Leg cramps	8(1.1)	6(0.8)	11(1.4)
Respiratory system
				Bronchitis	11(1.4)	13(1.7)	13(1.7)
Lung disease	36(4.7)	34(4.5)	49(6.4)
				Pharyngitis	27(3.5)	27(3.6)	34(4.4)
Pneumonia	7(0.9)	8(1.1)	10(1.3)
				Genitourinary system
Urinary tract infection	3(0.4)	9(1.2)	12(1.6)

Behind albuterol and ipratropium combined therapy, also have patient's report untoward reaction to occur above 1%, comprise constipation and sound variation.

Accompanying drawing at this only supplies the example explanation.They act on without limits to the scope of the invention.Next should be appreciated that and it will be apparent for a person skilled in the art that and can carry out changes and improvements at optimal case of the present invention described here.Can not depart from the scope of the invention and main idea and not reduce under the prerequisite of institute's attendant advantages the present invention is carried out this changes and improvements.Therefore claims comprise these changes and improvements.

Simultaneously, the present invention also can suitably be included in the key element that this further describes, perhaps the present invention is formed or is made up of these key elements basically by these key elements, and can compatibly implement the present invention described here under the situation in this specific disclosed any key element not containing.

Claims (95)

1. suction solution, it comprises: the aqueous formulation of premixed, scheduled volume, contain in the said preparation single unit dose the treatment effective dose be used to the albuterol and the ipratropium bromide of inducing the patients with chronic obstructive pulmonary diseases bronchiectasis or alleviating its bronchospasm, the amount of albuterol is about 0.60mg～about 5.0mg in the wherein said suction solution, and the amount of ipratropium bromide is about 0.01mg～about 1.0mg; Described solution is loaded in the single container.

2. suction solution according to claim 1, wherein, described suction solution is aseptic.

3. suction solution according to claim 1, wherein, described suction solution does not contain benzalkonium chloride.

4. suction solution according to claim 1, wherein, the pH value of described suction solution is about 3.0～about 4.0.

5. suction solution according to claim 1, wherein, the pH of described suction solution is about 4.0.

6. suction solution according to claim 1, wherein, described albuterol exists with the form of its acid-addition salts.

7. suction solution according to claim 6, wherein, the acid-addition salts of described albuterol is a salbutamol sulfate.

8. suction solution according to claim 1, wherein, described albuterol exists with the form of racemic mixture.

9. suction solution according to claim 1, wherein, the amount of albuterol is about 2.00mg～about 3.00mg in the described suction solution.

10. suction solution according to claim 1, wherein, the amount of albuterol is about 2.5mg in the described solution.

11. suction solution according to claim 1, wherein, described suction solution is applicable to aerosol apparatus sprays.

12. suction solution according to claim 11, wherein, described aerosol apparatus is selected from jet nebulizer, ultrasonic sprayer or breathing and actuates aerosol apparatus.

13. suction solution, it comprises: do not contain sterile aqueous preparation benzalkonium chloride, premixed, scheduled volume, said preparation contain single unit dose the treatment effective dose be used to the albuterol and the ipratropium bromide of inducing the patients with chronic obstructive pulmonary diseases bronchiectasis or alleviating its bronchospasm, wherein, the amount of albuterol is about 2.50mg in the described suction solution, and the amount of ipratropium bromide is about 0.5mg; Described solution is loaded in the single container, and wherein said suction solution is applicable to aerosol apparatus and sprays.

14. induce the patients with chronic obstructive pulmonary diseases bronchiectasis or alleviate the method for its bronchospasm, described method comprises the steps: that (a) is applied to described patient with the described suction solution of claim 1.

15. method according to claim 14, wherein, described suction solution is aseptic when being applied to described patient.

16. method according to claim 14, wherein, described suction solution does not contain benzalkonium chloride.

17. suction solution according to claim 14, wherein, described albuterol exists with the form of its acid-addition salts.

18. solution according to claim 17, wherein, the acid-addition salts of described albuterol is a salbutamol sulfate.

19. suction solution according to claim 14, wherein, described albuterol exists with the form of racemic mixture.

20. suction solution according to claim 14, wherein, the amount of albuterol is about 2.0mg～about 3.0mg in the described suction solution.

21. suction solution according to claim 14, wherein, the amount of albuterol is about 2.5mg in the described suction solution.

22. method according to claim 14, wherein, described suction solution through spray application in described patient.

23. induce the patients with chronic obstructive pulmonary diseases bronchiectasis or alleviate the method for its bronchospasm, described method comprises the steps: that (a) is applied to described patient through spraying with the described suction solution of claim 13.

24. induce the patients with chronic obstructive pulmonary diseases bronchiectasis or alleviate the method for its bronchospasm, described method comprises the steps:

(a) will suck the chamber that solution places aerosol apparatus, described aerosol apparatus has seaming or the face shield that links to each other with the chamber of this aerosol apparatus;

(b) described seaming or face shield are close to described patient's mouth or face;

(c) when described patient sees through seaming or face shield and breathes, the described suction solution of mist form is passed to the patient through described seaming or face shield from described aerosol apparatus chamber; With

(d) described patient sees through described seaming or face shield breathing, up to removing all mists at least basically from described aerosol apparatus chamber.

25. induce the patients with chronic obstructive pulmonary diseases bronchiectasis or alleviate the method for its bronchospasm, said method comprising the steps of: the directions for use that the described suction solution of claim 1 is applied to described patient (a) is provided.

26. be used for the treatment of the test kit of the bronchospasm of patients with chronic obstructive pulmonary diseases, described test kit has:

(a) one or more containers; Described one or more container all comprises, and aqueous premixed, scheduled volume sucks solution, and described suction solution contains the albuterol and the ipratropium bromide of the treatment effective dose of single unit dose; Wherein, the amount of albuterol is about 0.60mg～about 5.00mg in the described solution, and the amount of ipratropium bromide is about 0.01mg～about 1.00mg; And described solution is applicable to aerosol apparatus and sprays.

27. test kit according to claim 26, wherein, described suction solution is aseptic.

28. test kit according to claim 26, wherein, described suction solution does not contain benzalkonium chloride.

29. test kit according to claim 26, wherein, the amount of albuterol is about 2.0mg～3.0mg in the described suction solution.

30. test kit according to claim 26, wherein, the amount of albuterol is about 2.50mg in the described suction solution.

31. test kit according to claim 26, it also has the label that is used to represent the bronchospasm that described suction solution can relieve chronic obstructive pulmonary patient.

32. test kit according to claim 26, it also has the directions for use that the described suction solution of use is alleviated the bronchospasm relevant with chronic obstructive pulmonary disease.

33. test kit according to claim 26, wherein, described one or more container packages are in same capsule or box.

34. test kit according to claim 33, wherein, described one or more containers comprise the semi permeability plastics, and are packaged in the aluminium foil capsule.

35. test kit, it is used for the treatment of the bronchospasm of patients with chronic obstructive pulmonary diseases, and described test kit has:

(a) one or more containers; Described one or more container includes the sterile aqueous premixed, scheduled volume that does not contain benzalkonium chloride that can use and sucks solution in aerosol apparatus; Described suction solution comprises the albuterol and the ipratropium bromide of the treatment effective dose of single unit dose, and wherein, the amount of described albuterol is about 2.50mg, and the amount of described ipratropium bromide is about 0.5mg;

(b) label, it is used to represent that described suction solution can be used for relieve chronic obstructive pulmonary patient's bronchospasm; With

(c) directions for use promptly, uses described solution to alleviate the directions for use of described bronchospasm.

36. pack therapy system in advance, it is used for the treatment of the bronchospasm of patients with chronic obstructive pulmonary diseases, described pre-packing therapy system has packaging material, and wherein, described packaging material comprise:

(e) one or more containers; Described one or more container all contains, and aqueous premixed, scheduled volume sucks solution, and described suction solution comprises the albuterol and the ipratropium bromide of the treatment effective dose of single unit dose; The amount of described albuterol is about 0.60mg～about 5.0mg, and the dosage of described ipratropium bromide is about 0.01mg～about 1.0mg; And described solution is applicable to aerosol apparatus and sprays.

37. pre-packing therapy system according to claim 36, wherein, the amount of described albuterol is about 2.00mg～about 3.00mg.

38. pre-packing therapy system according to claim 36, wherein, the amount of described albuterol is about 2.5mg.

39. pre-packing therapy system according to claim 36, wherein, the solution that respectively sucks in described one or more containers all is aseptic.

40. pre-packing therapy system according to claim 36, wherein, the solution that respectively sucks in described one or more containers does not all contain benzalkonium chloride.

41. pre-packing therapy system according to claim 36, wherein, described packaging material also comprise and are used to represent that described suction solution can be used for the label of relieve chronic obstructive pulmonary patient's bronchospasm.

42. pre-packing therapy system according to claim 36, wherein, described packaging material comprise the directions for use that uses described solution to alleviate described bronchospasm.

43. pack therapy system in advance, it is used for the treatment of the bronchospasm of patients with chronic obstructive pulmonary diseases, described pre-packing therapy system has packaging material, and wherein, described packaging material comprise:

(b) one or more containers; Described one or more container all comprises, and sterile aqueous that can use in aerosol apparatus, that do not contain benzalkonium chloride, premixed, scheduled volume sucks solution; Described suction solution comprises the albuterol and the ipratropium bromide of the treatment effective dose of single unit dose, and wherein, the amount of described albuterol is about 2.50mg, and the amount of described ipratropium bromide is about 0.5mg;

(c) label, it is used to represent that described suction solution can be used for alleviating described bronchospasm; With

(d) directions for use promptly, uses described suction solution to alleviate the directions for use of described bronchospasm.

44. the preparation method of the suction solution of premixed, scheduled volume, this suction solution is used for the treatment of the bronchospasm of patients with chronic obstructive pulmonary diseases, and described method comprises the steps:

(a) albuterol and the ipratropium bromide of the treatment effective dose of unit dose are put into carrier, wherein, the concentration of the albuterol in the described carrier is about 0.60mg～about 5.0mg, and the concentration of the ipratropium bromide in the described carrier is 0.01mg～1.00mg; With

(b) provide the described suction solution that is contained in the single container.

45. according to the described method of claim 44, it comprises that also adding hydrochloric acid transfers to about step of 3.0～about 4.0 with the pH value with described suction solution.

46. according to the described method of claim 44, it also comprises and adds the step of osmotic pressure regulator with the isotonicity of regulating described suction solution; Wherein, described osmotic pressure regulator is selected from the group of being made up of sodium chloride, potassium chloride, zinc chloride, calcium chloride and their mixture.

47. according to the described method of claim 44, it is further comprising the steps of:

(a) make described suction solution come it is sterilized by filter or employing steam sterilization.

48. according to the described method of claim 44, it comprises that also adding hydrochloric acid transfers to about 3.5 step with the pH value with described suction solution.

49. be used for the device of relieve chronic obstructive pulmonary patient's bronchospasm, described device has labelling; This labelling provides the suction solution that uses premixed, scheduled volume to treat the directions for use of described bronchospasm, and described solution contains the albuterol and the ipratropium bromide of the treatment effective dose of single unit dose; The amount of wherein said albuterol is about 2.00mg～about 3.00mg, and the amount of described ipratropium bromide is about 0.20mg～about 0.60mg; Described solution is applicable to aerosol apparatus sprays.

50. prepare the method for the aqueous aerosol apparatus solution of stable, scheduled volume, premixed, pre-packing, described solution is used to induce the bronchiectasis of patients with chronic obstructive pulmonary diseases or alleviates its bronchospasm; Said method comprising the steps of:

A) at 18 ℃～25 ℃, mixing water, EDTA, hydrochloric acid, osmotic pressure regulator, salbutamol sulfate and ipratropium bromide in stainless steel storage tank are to form aerosol apparatus solution;

I) ultimate density of albuterol and ipratropium bromide described in the described aerosol apparatus solution is respectively about 0.06 weight %～about 0.1 weight % albuterol and about 0.03 weight %～about 0.1 weight % ipratropium;

Ii) enough hydrochloric acid is added in the described aerosol apparatus solution, the pH value that makes described solution is about 3.0～about 4.0;

Iii) enough osmotic pressure regulators are added in the described aerosol apparatus solution, make the isotonicity of described solution be about 280mOsm/kg～about 320mOsm/kg; With

B) make described aerosol apparatus solution by at least one sterilization filter;

C) with in the aseptic dosed administration container that is loaded into described one or more low density polyethylene (LDPE) systems of described aerosol apparatus solution, that each container all is equipped with is premixed, about 3ml sterile aqueous aerosol apparatus solution of scheduled volume, this solution comprises the albuterol and the ipratropium bromide of the treatment effective dose of unit dose, wherein the dosage of albuterol is about 2.00mg～about 3.00mg, and the dosage of ipratropium bromide is about 0.1mg～about 1.0mg;

D) the described one or more dosed administration containers that this aerosol apparatus solution is housed of sterile sealing; And the stability of the aerosol apparatus solution in wherein said one or more dosed administration containers is that the storage life of described solution is greater than 12 months; Wherein, described aerosol apparatus solution does not contain benzalkonium chloride.

51. according to the described method of claim 50, wherein, described albuterol exists with the form of its acid-addition salts.

52. according to the described method of claim 50, wherein, the acid-addition salts of described albuterol is a salbutamol sulfate.

53. according to the described method of claim 50, wherein, described albuterol exists with the form of racemic mixture.

54. according to the described method of claim 50, wherein, described aerosol apparatus solution is applicable to that actuating aerosol apparatus with jet nebulizer, ultrasonic sprayer and breathing sprays.

55. according to the described method of claim 50, wherein, described osmotic pressure regulator is selected from the group of being made up of sodium chloride, potassium chloride, zinc chloride, calcium chloride and their mixture.

56. according to the described method of claim 50, wherein, described osmotic pressure regulator is a sodium chloride.

57. method according to claim 1, wherein, described osmotic pressure regulator is selected from mannitol, glycerol, glucose and composition thereof.

58. according to the described method of claim 50, wherein, the aerosol apparatus solution in described one or more dosed administration containers comprises the ion salt of about 0.4 weight %～about 1.0 weight %.

59. according to the described method of claim 50, wherein, the aerosol apparatus solution in described one or more dosed administration containers comprises about 0.9% osmotic pressure regulator.

60. according to the described method of claim 50, it is further comprising the steps of: (a) with described one or more dosed administration container packages in the aluminium foil capsule.

61. according to the described method of claim 50, wherein, described sterilization filter is 0.2 micron a sterilization filter cartridge.

62. according to the described method of claim 50, it also comprises makes the step of described aerosol apparatus solution by second sterilization filter.

63. according to the described method of claim 62, wherein, described second sterilization filter is 0.2 micron sterilization cylinder.

64. according to the described method of claim 50, wherein, the concentration of described albuterol is about 0.083 weight %, the concentration of described ipratropium bromide is about 0.017 weight %.

65. according to the described method of claim 50, wherein, the osmolality of described aerosol apparatus solution is about 282mOsm/kg～about 285mOsm/kg.

66. make stable, scheduled volume, premixed, pack the method for aqueous aerosol apparatus solution in advance, described solution is used to induce the bronchiectasis of patients with chronic obstructive pulmonary diseases or alleviates its bronchospasm; Said method comprising the steps of:

A), in stainless storage tank, add and purify waste water at 18 ℃～25 ℃; Described storage tank is furnished with bottom row's mouth and stirs the SANYE agitator of usefulness;

B) under stirring condition, in this storage tank, add EDTA, hydrochloric acid and treat the salbutamol sulfate of effective dose at least and ipratropium bromide until dissolving;

C) add the adjusting final volume of purifying waste water to aequum, thereby form described aerosol apparatus solution;

I) ultimate density of albuterol in the described aerosol apparatus solution and ipratropium bromide is respectively about 0.06 weight %～about 0.1 weight % albuterol and about 0.03 weight %～about 0.1 weight % ipratropium;

Ii) add the hydrochloric acid of capacity in described aerosol apparatus solution, the pH value that makes described solution is about 3.0～about 4.0;

The osmotic pressure regulator that iii) adds capacity in described aerosol apparatus solution makes the isotonicity of described solution be about 280mOsm/kg～about 320mOsm/kg;

B) described aerosol apparatus solution directly being entered molding filling sealer by the feed-line that cleans is the FFS machine;

C) described aerosol apparatus solution is passed through first sterilization filter cartridge of 0.2 micron, this aerosol apparatus solution is flowed in reservoir; Make this aerosol apparatus solution pass through second 0.2 micron sterilization filter cartridge again;

D) described second filter cartridge is connected with at least one filling nozzle that is arranged in the filtrated air shower room; Make described aerosol apparatus solution enter in the dosed administration container of one or more preformed low density polyethylene (LDPE)s by this filling nozzle;

E) in described one or more dosed administration containers, be respectively charged into the aerosol apparatus solution of about 3ml, so that comprise the albuterol and the ipratropium bromide of aseptic unit dose in each container, its dosage is respectively about 2.00mg～about 3.00mg albuterol and 0.1mg～1.0mg ipratropium;

F) sterile sealing comprises described one or more dosed administration containers of aerosol apparatus solution; With

G) wherein, the stability of described aerosol apparatus solution is that the storage life of the described solution in one or more dosed administration containers was greater than 12 months; Wherein, described aerosol apparatus solution does not contain benzalkonium chloride.

67. according to the described method of claim 66, wherein, described albuterol exists with the form of its acid-addition salts.

68. according to the described method of claim 66, wherein, the acid-addition salts of described albuterol is a salbutamol sulfate.

69. according to the described method of claim 66, wherein, described albuterol exists with the form of racemic mixture.

70. according to the described method of claim 66, wherein, described aerosol apparatus solution is applicable to that actuating aerosol apparatus with jet nebulizer, ultrasonic sprayer and breathing sprays.

71. according to the described method of claim 66, wherein, described osmotic pressure regulator is selected from the group of being made up of sodium chloride, potassium chloride, zinc chloride, calcium chloride and their mixture.

72. according to the described method of claim 66, wherein, described osmotic pressure regulator is a sodium chloride.

73. according to the described method of claim 66, wherein, described osmotic pressure regulator is selected from the group of being made up of mannitol, glycerol, glucose and their mixture.

74. according to the described method of claim 66, wherein, the aerosol apparatus solution in described one or more dosed administration containers comprises the ion salt of about 0.4 weight %～about 1.0 weight %.

75. according to the described method of claim 66, wherein, the aerosol apparatus solution in described one or more dosed administration containers comprises the osmotic pressure regulator of about 0.9 weight %.

76. according to the described method of claim 66, wherein, the molding in a continued operation of described one or more dosed administration containers, filling and sealing.

77. according to the described method of claim 66, it is further comprising the steps of: (a) with described one or more dosed administration container packages in the aluminium foil capsule.

78. according to the described method of claim 66, wherein the concentration of albuterol the concentration that is about 0.083 weight % and ipratropium bromide is about 0.017 weight %.

79. according to the described method of claim 66, the osmolality of wherein said aerosol apparatus solution is about 282mOsm/kg～about 285mOsm/kg.

80. pack therapy system in advance, it is used to induce the bronchiectasis of patients with chronic obstructive pulmonary diseases or alleviates its bronchospasm, this is packed therapy system in advance and has:

(f) one or more dosed administration containers; Described one or more container all is equipped with in advance and does not contain about 3ml sterile aqueous benzalkonium chloride, premixed, scheduled volume and suck solution, and described solution comprises the albuterol and the ipratropium bromide of the treatment effective dose of unit dose; Wherein the dosage of albuterol the dosage that is about 2.5mg and ipratropium bromide is about 0.5mg; The solution that respectively sucks in described one or more container all is applicable to aerosol apparatus and sprays; Suction solution in described one or more containers has long storage life;

(g) have one or more labels of labelling on it, described labelling comprise with described one or more containers in respectively suck the relevant effect of solution, dosage, usage, contraindication and untoward reaction information;

(h) wherein, described contraindication information comprises that expression avoids information with the suction solution in described one or more containers to atropine and derivant people hypersensitive thereof; With

(i) wherein, described untoward reaction information comprises informs following information: after using the suction solution in described one or more container, may promote or aggravate angle-closure glaucoma, acute ophthalmalgia, blurred vision, eccentricity bronchospasm, stridulate, the increasing the weight of of symptoms of chronic obstructive pulmonary disease, sleepy, pain, flushing, upper respiratory tract infection, cardiopalmus, sense of taste abnormality, heart rate quickening, sinusitis, backache and throat pain.

81. according to the described pre-packing therapy system of claim 50, wherein, described albuterol exists with the form of its acid-addition salts.

82. according to claims 51 described pre-packing therapy system, wherein, the acid-addition salts of described albuterol is a salbutamol sulfate.

83. according to the described pre-packing therapy system of claim 50, wherein, described dosage and administration information comprises the information of the recommended dose of the suction solution in the described one or more containers of expression, described recommended dose is, about 2.5mg albuterol in the 3ml aqueous solution and about 0.5mg ipratropium bromide, this aqueous solution is used 4 times through spraying every day, if needed, allows to use extra maximum 2 recommended dose every day again.

84. according to the described pre-packing therapy system of claim 50, wherein, described untoward reaction information comprises that expression uses contingent type behind the suction solution in one or more containers, and described anaphylaxis comprises urticaria, angioedema, rash, Pruritus, oropharynx, edema, bronchospasm and anaphylaxis.

85. according to the described pre-packing therapy system of claim 50, wherein, described untoward reaction information comprises that expression uses the contingent allergic effect type reaction in back in the suction solution of one or more containers, this allergic effect type reaction comprises erythra, pruritus and urticaria.

86. according to the described pre-packing therapy system of claim 50, wherein, described untoward reaction information comprises that expression uses the tabulation of contingent one or more adverse events behind the described suction solution, and described adverse events comprises chest pain, diarrhoea, gastricism, feels sick, leg cramps, bronchitis, lung disease, pharyngitis, pneumonia and urinary tract infection.

87. pack therapy system in advance, it is used for the treatment of the chronic obstructive pulmonary disease bronchospasm, described pre-packing therapy system comprises:

(e) one or more dosed administration containers; Described container is all pre-installed to be filled with and is not contained 3ml sterile aqueous suction solution benzalkonium chloride, stable, premixed, scheduled volume; Described suction solution is made up of albuterol and ipratropium bromide that sodium chloride, water, disodium edetate, the pH that will suck solution transfer to the treatment effective dose of about 4 acid and unit dose, wherein, the amount of described albuterol is about 2.50mg, and the amount of described ipratropium bromide is about 0.5mg; Suction solution in described one or more container is suitable for spraying with aerosol apparatus; Described suction solution has long storage life;

(b) have one or more labels of labelling on it, described labelling comprise with described one or more containers in respectively suck the relevant effect of solution, dosage, usage, contraindication and untoward reaction information;

(c) wherein, described dosage and administration information comprises the information of the recommended dose of the suction solution in the described one or more containers of expression, described recommended dose is, about 2.5mg albuterol in the 3ml aqueous solution and about 0.5mg ipratropium bromide, this aqueous solution every day is through spray application 4 times, if needed, allow to use again extra maximum 2 recommended dose every day;

(d) wherein, described contraindication information comprises that expression avoids information with the suction solution in described one or more containers to atropine and derivant people hypersensitive thereof;

(e) wherein, described untoward reaction information comprises informs following information: after using the suction solution in described one or more container, type may take place, and described anaphylaxis comprises urticaria, angioedema, rash, Pruritus, oropharynx, edema, bronchospasm and anaphylaxis;

(f) wherein, described untoward reaction information comprises informs following information: after using the suction solution in described one or more container, the reaction of allergic effect type may take place; Described allergic effect type reaction comprises erythra, pruritus and urticaria;

(g) wherein, described untoward reaction information comprises informs following information: after using the suction solution in described one or more container, may promote or aggravate angle-closure glaucoma, acute ophthalmalgia, blurred vision, eccentricity bronchospasm, stridulate, the increasing the weight of of symptoms of chronic obstructive pulmonary disease, sleepy, pain, flushing, upper respiratory tract infection, cardiopalmus, sense of taste abnormality, heart rate quickening, sinusitis, backache and throat pain; With

(h) described untoward reaction information comprises the tabulation of contingent one or more adverse events behind the suction solution of using in described one or more container; Described adverse events comprises chest pain, diarrhoea, gastricism, feels sick, leg cramps, bronchitis, lung disease, pharyngitis, pneumonia and urinary tract infection.

88. the method that is used to induce the bronchiectasis of patients with chronic obstructive pulmonary diseases or alleviates its bronchospasm said method comprising the steps of:

(a) provide pre-packing therapy system to the patient, described system comprises: one or more dosed administration containers; These one or more containers are all pre-installed to be filled with and are not contained sterile aqueous benzalkonium chloride, premixed, scheduled volume, about 3ml and suck solution, and described solution comprises the albuterol and the ipratropium bromide of the treatment effective dose of unit dose; Wherein, the amount of described albuterol is about 2.5mg, and the amount of described ipratropium bromide is about 0.5mg; Suction solution in described one or more container is suitable for spraying with aerosol apparatus; Suction solution in described one or more container has long storage life;

(b) provide dosage, usage, contraindication and the untoward reaction information of the pre-packing therapy system relevant to patient or prescription doctor with the suction solution in described one or more containers;

(c) wherein, described contraindication information comprises that expression avoids information with the suction solution in described one or more containers to atropine and derivant people hypersensitive thereof; With

(d) wherein, described untoward reaction information comprises informs following information: after using the suction solution in described one or more container, may promote or aggravate angle-closure glaucoma, acute ophthalmalgia, blurred vision, eccentricity bronchospasm, stridulate, the increasing the weight of of symptoms of chronic obstructive pulmonary disease, sleepy, pain, flushing, upper respiratory tract infection, cardiopalmus, sense of taste abnormality, heart rate quickening, sinusitis, backache and throat pain.

89. according to the described method of claim 58, wherein, described albuterol exists with the form of its acid-addition salts.

90. according to the described method of claim 59, wherein, the acid-addition salts of described albuterol is a salbutamol sulfate.

91. according to the described method of claim 58, wherein, the recommended dose of the suction solution in described dosage and administration information notification patient or the described one or more containers of prescription doctor, described recommended dose is, about 2.5mg albuterol in the 3ml aqueous solution and about 0.5mg ipratropium bromide, this aqueous solution every day if needed, allows to use extra maximum 2 recommended dose every day through spray application 4 times again.

92. according to the described method of claim 58, wherein, described untoward reaction information notification patient or prescription doctor, after using the suction solution in described one or more container, type may take place, and described anaphylaxis comprises urticaria, angioedema, rash, Pruritus, oropharynx, edema, bronchospasm and anaphylaxis.

93. according to the described method of claim 58, wherein, described untoward reaction information notification patient or prescription doctor, use in the suction solution of described one or more containers after, the reaction of allergic effect type may take place, and described atopic reaction comprises erythra, pruritus and urticaria.

94. according to the described method of claim 58, wherein, described untoward reaction information comprises uses the prefabricated tabulation that sucks contingent one or more adverse events behind the solution, and described adverse events comprises chest pain, diarrhoea, gastricism, feels sick, leg cramps, bronchitis, lung disease, pharyngitis, pneumonia and urinary tract infection.

95. the method that is used to induce the bronchiectasis of patients with chronic obstructive pulmonary diseases or alleviates its bronchospasm said method comprising the steps of:

(a) provide pre-packing therapy system to the patient, described system comprises: one or more dosed administration containers; The equal prefill of these one or more containers the aseptic stabilized aqueous suction solution of about 3ml premixed, scheduled volume, described solution does not contain benzalkonium chloride; Described suction solution is made up of albuterol and ipratropium bromide that water, disodium edetate, sodium chloride, the pH that will suck solution transfer to the treatment effective dose of about 4 acid and unit dose, wherein, the amount of described albuterol is about 2.50mg/3ml, and the amount of described ipratropium bromide is about 0.5mg/3ml; Suction solution in described one or more container all is suitable for spraying with aerosol apparatus;

(b) provide dosage, usage, contraindication and the untoward reaction information of the pre-packing therapy system relevant to patient or prescription doctor with the suction solution in described one or more containers;

(c) wherein, described dosage and administration information comprises the recommended dose of informing the suction solution in patient or the described one or more containers of prescription doctor, described recommended dose is, about 2.5mg albuterol in the 3ml aqueous solution and about 0.5mg ipratropium bromide, this aqueous solution every day is through spray application 4 times, if needed, allow to use again extra maximum 2 recommended dose every day;

(d) wherein, described contraindication information comprises that expression avoids information with the suction solution in described one or more containers to atropine and derivant people hypersensitive thereof;

(e) wherein, described untoward reaction information notification patient or the following information of prescription doctor: after using the suction solution in one or more containers, type may take place, and described anaphylaxis comprises urticaria, angioedema, rash, Pruritus, oropharynx, edema, bronchospasm and anaphylaxis;

(f) wherein, described untoward reaction information notification patient or the following information of prescription doctor: after using the suction solution in described one or more container, the reaction of allergic effect type may take place, comprise erythra, pruritus and urticaria;

(g) wherein, described untoward reaction information notification patient or prescription doctor following information: after using the suction solution in described one or more container, may promote or aggravate angle-closure glaucoma, acute ophthalmalgia, blurred vision, eccentricity bronchospasm, stridulate, the increasing the weight of of symptoms of chronic obstructive pulmonary disease, sleepy, pain, flushing, upper respiratory tract infection, cardiopalmus, sense of taste abnormality, heart rate quickening, sinusitis, backache and throat pain; With

(h) described untoward reaction information comprises the prefabricated tabulation of contingent adverse events behind the relevant suction solution of using in one or more containers; Described adverse events comprises chest pain, diarrhoea, gastricism, feels sick, leg cramps, bronchitis, lung disease, pharyngitis, pneumonia and urinary tract infection.

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