CN1607940A - Albuterol and ipratropium inhalation solutions, systems, kits and methods for the relief of symptoms of chronic obstructive pulmonary disease - Google Patents

Abstract

The present invention relates to dual bronchodilator inhalation solutions, systems, kits, and methods for relieving bronchospasm in patients with chronic obstructive pulmonary disease (COPD). In an alternative embodiment, the solution of the present invention is a premixed, premeasured, prepackaged sterile solution containing unit doses of albuterol and ipratropium bromide for use in COPD patients. The solution of the present invention does not contain antimicrobial preservatives such as benzalkonium chloride. In another alternative embodiment, the solution of the present invention contains approximately 2.50 mg of albuterol and approximately 0.50 mg of ipratropium bromide.

Description

Albuterol and ipratropium inhalation solutions, systems, kits and methods for the relief of symptoms of chronic obstructive pulmonary disease

Related application reference

This application is a continuation-in-part of U.S. Application Serial No. 10/034,657, filed December 28, 2001, which claims under 35 U.S.C. §119(e) U.S. Provisional Application No. 60/346,078, filed October 26, 2001 number priority. The entire disclosures of these prior applications are hereby incorporated by reference.

technical field

The present invention relates to combinations of bronchodilator therapies for the relief of symptoms associated with chronic obstructive pulmonary disease.

Background technique

Chronic obstructive pulmonary disease (COPD) is a slowly progressive airway disease that causes an incompletely reversible decline in lung function. Airway limitation in COPD is associated with an abnormal inflammatory response of the lungs to noxious particles or gases.

In the United States, an estimated 16 million Americans have been diagnosed with some type of COPD, and an additional 16 million people have the condition but are undiagnosed. According to the Centers for Disease Control and Prevention, COPD is the fourth leading cause of death in the United States (after heart disease, cancer, and stroke), claiming 112,000 American lives each year.

In terms of health care, the number of COPD visits by US physicians increased from 9.3 million to 16 million between 1985 and 1995. The number of hospitalizations due to COPD in 1995 was estimated at 500,000. Although the morbidity, hospitalization rate, and mortality rate of COPD in men are higher than those in women, the mortality rate of female patients has also increased rapidly in recent years. COPD is clearly a major and growing threat to health care in the United States and other countries around the world.

In the prior art, inhalation solutions used to treat COPD often contain antimicrobial agents such as benzalkonium chloride (BAC). The presence of BAC in these solutions generally does not affect the effects of short-acting (single-dose) bronchodilators. However, case reports suggest that repeated COPD therapy with BACs may lead to paradoxical bronchoconstriction. BAC may also cause dose-dependent bronchoconstriction when inhaled in COPD subjects. Despite these side effects, many commercially available inhalation solutions contain BAC.

At the same time, COPD treatments are usually in the form of multiple dosage units, which must be diluted to a specific concentration suitable for treating the patient. This creates some problems. For example, COPD treatment requires administration of single dosage units divided from multiple dosage units, but instructions for proper mixing or dilution are sometimes lacking, or instructions for preparing and using COPD treatment can be difficult to follow or easily lost. An even more significant problem is that casual dilution or mixing of COPD medications can lead to wrong dosing. This is particularly disadvantageous for those patients who have low tolerance to high doses of asthma medications. Improper mixing may also lead to treatment failure, requiring additional medical care and thus increasing time, cost and personnel expenditures associated with treatment.

Accordingly, there is a need to provide improved inhalation solutions, systems, kits and methods for alleviating symptoms associated with COPD.

Contents of the invention

It is an object of the present invention to provide an inhalation solution of a dual bronchodilator to relieve bronchospasm in COPD patients.

Another object of the present invention is to provide a prepackaged, predetermined amount of albuterol and ipratropium premixed sterile inhalation solution for relieving bronchospasm in COPD patients.

Another object of the present invention is to provide a BAC-free albuterol and ipratropium inhalation solution for use in the treatment of bronchospasm associated with COPD.

Another object of the present invention is to provide a method of administering albuterol and ipratropium inhalation formulations for the relief of bronchospasm associated with COPD.

Another object of the present invention is to provide a kit and/or system for administering dual bronchodilators for the relief of bronchospasm associated with COPD.

Another object of the present invention is to provide a preparation method of albuterol and ipratropium inhalation solution, which is used for relieving bronchospasm associated with COPD.

Another object of the invention includes a device for alleviating the symptoms of COPD.

Through the following detailed description and accompanying drawings of the present invention, those skilled in the art will easily understand other objects, features and advantages of the present invention.

Description of drawings

Figures 1-4 depict non-limiting examples of nebulizer administration of inhalation solutions of the present invention.

Figure 5 depicts a non-limiting example of an overall prepackaged kit or system of the invention.

Figure 6 depicts a non-limiting example of one or more prefilled containers having an inhalation system of the present invention.

Figure 7 depicts non-limiting examples of tags used in the present invention.

Detailed ways

salbutamol

The present invention is based on the bronchodilation effect of albuterol to provide relief of symptoms associated with COPD. The term "albuterol" as used herein includes, but is not limited to, any form of albuterol that produces the desired bronchodilatory effect on the patient, including but not limited to: all tautomers, enantiomers of albuterol , stereoisomers, anhydrides, acid addition salts, base salts, solvates, analogs and derivatives.

In the present invention, acceptable salbutamol salts include but not limited to hydrochloride, sulfate, maleate, tartrate, citrate and the like. These salts are described in US Patent 3,644,353, the disclosure of which is incorporated herein by reference in its entirety.

In the present invention, the preferred albuterol salt is its sulfate salt. In an alternative embodiment, the inhalation solution of the present invention comprises racemic albuterol in sulfuric acid. Salbutamol sulfate is a relatively selective β-2-adrenergic bronchodilator with an experimental formula of C ₁₃ H ₂₁ NO ₃ . The chemical name of albuterol sulfate is α ¹ -[(tert-butylamino)methyl]-4-hydroxyl-m-xylene-α, α'-diol sulfate (2:1) (salt), and its chemical structure is determined as follows :

Ipratropium

Meanwhile, the present invention is based on the bronchodilation effect of ipratropium to provide the effect of relieving symptoms associated with COPD. Ipratropium is an anticholinergic bronchodilator. The term "Ipratropium" as used herein includes, but is not limited to, any form of Ipratropium that produces the desired bronchodilation effect in COPD patients, including but not limited to: all interactions of Ipratropium Isomers, enantiomers, stereoisomers, anhydrides, acid addition salts, base salts, solvates, analogs and derivatives.

In the present invention, acceptable salts of ipratropium include, but are not limited to, halide salts such as bromide, chloride and iodide. These and other acceptable salts are described in US Patent No. 3,505,337, the disclosure of which is incorporated herein by reference in its entirety.

In one embodiment of the present invention, the preferred salt of ipratropium ammonium is its bromide, chemical name 8-azoniumbicyclo[3.2.1]-octane, 3-(3-hydroxy-1-oxo -2-Phenylpropoxy)-8-methyl-8-(1-methylethyl)-bromide, monohydrate, (endo, cis)-, (±)-. The molecular weight of ipratropium bromide is 430.4, and the experimental formula is C ₂₀ H ₃₀ BrNO ₃ ·H ₂ O. It is readily soluble in water and lower alcohols, and insoluble in lipophilic solvents such as ether, chloroform and fluorocarbons. The chemical structure of ipratropium bromide has been determined as follows:

In the present invention, albuterol and ipratropium can be loaded in various pharmaceutically acceptable carriers, including but not limited to water or other aqueous solutions containing pharmaceutically acceptable amounts of osmotic agents.

In an alternative embodiment, the inhalation solution of the present invention comprises a therapeutically effective amount of albuterol and ipratropium. The phrase "therapeutically effective amount of albuterol and/or ipratropium" as used herein refers to safe and tolerable amounts of both compounds according to industry and/or regulatory standards. Such an amount is sufficient to effectively induce bronchodilation and/or relieve bronchospasm in COPD patients.

In the inhalation solution of the present invention, the therapeutically effective amount of albuterol comprises about 0.63 mg to about 4.2 mg of albuterol. Here, salbutamol has a potency equivalent to about 0.75 mg to about 5 mg of salbutamol sulfate. In an alternative embodiment, the therapeutically effective amount of albuterol may comprise about 2.5 mg of albuterol.

In another alternative embodiment of the present invention, the therapeutically effective amount of albuterol may comprise about 0.60 mg to about 5.0 mg albuterol, including the following intermediate ranges of albuterol: about 0.60 mg to about 0.70 mg; about 0.71 mg to About 0.80 mg; about 0.81 mg to about 0.90 mg; about 0.91 mg to about 1.00 mg; about 1.01 mg to about 1.10 mg; about 1.11 mg to about 1.20 mg; about 1.21 mg to about 1.30 mg; mg; about 1.41 mg to about 1.50 mg; about 1.51 mg to about 1.60 mg; about 1.61 mg to about 1.70 mg; about 1.71 mg to about 1.80 mg; about 1.81 mg to about 1.90 mg; about 1.91 mg to about 2.00 mg; About 2.01mg to about 2.10mg; About 2.11mg to about 2.20mg; About 2.21mg to about 2.30mg; About 2.31mg to about 2.40mg; About 2.41mg to about 2.50mg; About 2.51mg to about 2.60mg; About 2.61 mg to about 2.70 mg; about 2.71 mg to about 2.80 mg; about 2.81 mg to about 2.90 mg; about 2.91 mg to about 3.00; about 3.01 to about 3.10; about 3.11 to about 3.20; about 3.21 to about 3.30 mg; mg～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; mg; about 4.01mg to about 4.10mg; about 4.11mg to about 4.20mg; about 4.21mg to about 4.30mg; about 4.31mg to about 4.40mg; about 4.41mg to about 4.50mg; About 4.61 mg to about 4.70 mg; about 4.71 mg to about 4.80 mg; about 4.81 mg to about 4.90 mg; about 4.91 mg to about 5.00 mg.

In another alternative embodiment of the present invention, the therapeutically effective amount of salbutamol comprises about 0.75 mg to about 5.0 mg of salbutamol sulfate, including the following intermediate amounts of salbutamol sulfate: about 0.75 mg to about 0.80 mg; about 0.81 ~ about 0.90 mg; about 0.91 mg ~ about 1.00 mg; about 1.01 mg ~ about 1.10 mg; about 1.11 mg ~ about 1.20 mg; about 1.21 mg ~ about 1.30 mg; 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 2.11 mg to about 2.20 mg; about 2.21 mg to about 2.30 mg; about 2.31 mg to about 2.40 mg; about 2.41 mg to about 2.50 mg; 2.71mg～2.80mg; 2.81mg～2.90mg; 2.91mg～3.00; 3.01～3.10; 3.11～3.20; 3.21～3.30mg; 3.31mg～3.40mg; 3.41mg～3.50mg; 3.51mg～3.60mg; 3.61～3.70mg; 3.71～3.80mg; 3.81mg～3.90mg; 3.91mg～4.0mg; 4.01mg～3.90mg 4.10 mg; about 4.11 mg to about 4.20 mg; about 4.21 mg to about 4.30 mg; about 4.31 mg to about 4.40 mg; about 4.41 mg to about 4.50 mg; about 4.51 mg to about 4.60 mg; ; 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 therapeutically effective amount of albuterol comprises about 0.020% by weight to about 0.14% by weight of albuterol, including the following intermediate ranges of albuterol: about 0.020% by weight to about 0.029% by weight; About 0.030 wt% to about 0.039 wt%; about 0.040 wt% to about 0.049 wt%; about 0.050 wt% to about 0.059 wt%; about 0.060 wt% to about 0.069 wt%; about 0.070 wt% to about 0.079 wt%; From about 0.080% to about 0.089% by weight; from about 0.090% to about 0.099% by weight; from about 0.10% to about 0.14% by weight.

In another alternative embodiment of the present invention, the therapeutically effective amount of salbutamol comprises about 0.025% to about 0.17% by weight of salbutamol sulfate, including the following intermediate ranges of salbutamol sulfate: about 0.025% to about 0.029% by weight %; about 0.030 wt% to about 0.039 wt%; about 0.040 wt% to about 0.049 wt%; about 0.050 wt% to about 0.059 wt%; about 0.060 wt% to about 0.069 wt%; %; about 0.080% to about 0.089% by weight; about 0.090% to about 0.099% by weight; about 0.10% to about 0.17% by weight.

In another alternative embodiment of the invention, the therapeutically effective amount of ipratropium bromide comprises about 0.01 mg to about 1.0 mg ipratropium bromide. The therapeutically effective amount may include the following intermediate ranges of ipratropium bromide: about 0.01 mg to about 0.02 mg; about 0.02 mg to about 0.04 mg; about 0.05 mg to about 0.07 mg; about 0.08 mg to about 0.10 mg; about 0.11 mg～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; mg; about 0.32 mg to about 0.34 mg; about 0.35 mg to about 0.37 mg; about 0.36 mg to about 0.38 mg; about 0.39 mg to about 0.41 mg; about 0.42 mg to about 0.44 mg; About 0.48 mg to about 0.50 mg; about 0.51 mg to about 0.53 mg; about 0.54 mg to about 0.56 mg; about 0.57 mg to about 0.59 mg; about 0.60 mg to about 0.62 mg; mg～0.68mg; 0.69mg～0.71mg; 0.72mg～0.74mg; 0.75mg～0.77mg; 0.79mg～0.81mg; 0.82mg～0.84mg; about 0.87 mg; about 0.88 mg to about 0.91 mg; about 0.92 mg to about 0.94 mg; about 0.95 mg to about 0.97 mg; about 0.98 mg to about 1.00 mg.

In another alternative embodiment of the present invention, about 0.001% to about 0.030% by weight of ipratropium bromide is included, including the following intermediate ranges of ipratropium bromide: about 0.001% to about 0.005% by weight %; about 0.006% to about 0.010% by weight; about 0.011% to about 0.015% by weight; about 0.016% to about 0.020% by weight; about 0.021% to about 0.025% by weight; .

Most pharmaceutical inhalation solutions contain the antimicrobial agent BAC. A problem associated with these solutions is that BAC may induce paradoxical bronchoconstriction when these solutions are administered repeatedly in short intervals. Another problem is that BAC can cause dose-dependent bronchoconstriction when patients inhale it. The inhalation solution according to the invention can be BAC-free and is therefore particularly suitable for emergency situations where repeated administration of the inhalation solution is required within a short period of time. At the same time, administration of BAC-free inhalation solutions to patients reduces the concomitant likelihood of BAC-related adverse effects. Toxicity and other side effects associated with BACs are also reduced.

The inhalation solutions of the present invention may also be presented as sterile unit dose preparations, thus avoiding the use of BACs in the solution. Furthermore, as shown in Table 1, the sterile form formulation of the present invention, which comprises a therapeutically effective amount of salbutamol sulfate and ipratropium bromide, provides a stable solution for inhalation, thus allowing the formulation to be stored (e.g., on the shelf) for a longer period of time. for a while.

Table 1 Stability data 0.083 wt% salbutamol sulfate and 0.017 wt% ipratropium bromide analysis ^* pH Osmolality (mOsm/kg) salbutamol sulfate ipratropium bromide 0 time 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

^* Percentage of label value (0.083% by weight albuterol sulfate and 0.017% by weight ipratropium bromide). mOsm/kg: milliosm/kg

As noted above, the compositions provided herein are stable. For example, the compositions provided herein can be stored at about 15-30°C and remain stable for relatively long periods of time. In one embodiment, the composition is stored at 25°C.

In another embodiment, the stability of the compositions provided herein is greater than 80%, 85%, 90%, or 95% of the original amount of active ingredients such as albuterol and isopropyl Tropium. For example, a composition that is stable for 30 days at 25°C should contain greater than 80%, 85%, 90%, or 95% of the original amount of active ingredient after storage for 30 days at 25°C.

In another embodiment, the composition is stable during long-term storage, that is, the composition is still suitable for administration to a subject in need thereof after storage at 25° C. for more than 1, 2 or 3 years (i.e., storage period). tester. In other embodiments, >80%, >85%, >90%, or >95% of the bronchodilation remains after such storage, e.g., as estimated using the Arrhenius kinetic equation. agent.

Other indicators of the stability of the compositions of the present invention may be by-products or degradation products that occur over time as shown in Tables 2 and 3 below.

Table 2 Percentage of albuterol degradation products/related compounds in albuterol (%) 25°C, range at 6-24 months range in medicine 1 5-2-((1,1-Dimethylethyl)amino-1-hydroxyethyl)-2-hydroxybenzaldehyde ND～0.012% by weight 2 Bis(2-hydroxy)-5-(2-tert-butylamino-1-hydroxyethyl)benzyl ether 0.09～0.174% by weight 3 2-tert-Butylamino-1-(4-hydroxy-3-methoxymethylphenyl)-ethanol 0.01～0.12% by weight 4 tert-Butylamino-3-chloro-4-hydroxy-5-hydroxymethylacetophenone ND～0.0002% by weight 5 tert-Butylamino-4-hydroxy-5-hydroxymethylacetophenone ND～0.002% by weight 6 1-(4-Hydroxy-3-methylphenyl)-2-(tert-butylamino)ethanol 0.0009～0.036% by weight 7 1-(5-Chloro-4-hydroxy-3-hydroxymethylphenyl)-2-(tert-butylamino)ethanol ND 8 Unknown 1 ND～0.07% calculated from peak area 9 any other unknown ND～0.025% calculated from peak area 10 total 0.18～0.23%

ND = not detected

table 3 Ipratropium degradation products/related compounds as a percentage of ipratropium bromide 25°C, range up to 24 months range in medicine 1 Tropic acid ND～0.08% by weight 2 8S-Ipratropium Bromide ND～0.058% by weight 3 N-isopropyl-nortropine ND 4 Ipratropium alcohol ND～0.038% by weight 5 any other unknown ND 6 Atropic acid ND 7 Total (excluding APO-ipratropium) ND～0.2%

ND = not detected

In one embodiment, the composition is at least substantially clear as determined based on the chromogenic method prescribed by the American Public Health Association (APHA). In another embodiment of the present invention, after being stored at 25°C for up to 24 months, the composition has an APHA color result of 0-5 units (mostly 0 units) based on the APHA standard.

In one embodiment, the method of the present invention provides a composition comprising an albuterol content of about 2.5 mg/vial to about 2.75 mg/vial. In another alternative embodiment, the method of the present invention provides a composition having an ipratropium content of about 0.45 mg/vial to about 0.55 mg/vial. In another alternative embodiment, the method of the present invention provides an average fill volume of about 2.84 ml/vial to about 3.30 ml/vial.

In another alternative embodiment, the compositions of the present invention may contain minimal amounts of impurities including, but not limited to:

Table 4 1. Volatile matter acetone About NMT0.2Φg/ml or lower ethyl acetate About NMT0.3Φg/ml or lower n-heptane NMT0.1Φg/ml or lower n-Propyl acetate NMT0.3Φg/ml or lower Toluene NMT0.3Φg/ml or lower 2-butanone Not measured (signal/noise NMT3) unknown 2. Filterable matter Irganox 129 Not detected (NMT0.02Φg/ml) Extractables 1 Not measured (signal/noise NMT3) Extractable 2 Not measured (signal/noise NMT3) unknown Not measured (signal/noise NMT3)

(NMT: not greater than)

In another alternative embodiment, the compositions of the present invention may contain a minimum amount of particulate matter including, but not limited to: NMT about 1000 to 5000, preferably about 3800 particles/bottle > 2Φm; NMT about 10-100, preferably about 80 particles/bottle>10Φm; or NMT about 1-5, preferably about 3 particles/bottle>25Φm.

Another benefit of sterile inhalation solutions is the reduced possibility of introducing impurities into the patient when administering the drug, thereby reducing the chance of opportunistic infections in the patient.

Issues worth considering are non-adherence to COPD drug therapy and dosing errors. Providing COPD patients with prepackaged, premixed, predetermined doses of albuterol and ipratropium significantly reduces these problems. Providing these compounds in this manner simplifies COPD therapy as it increases convenience and eliminates confusion in formulating the proper dosage. These advantages of the present invention are particularly evident with respect to the fact that multiple dosage units are often used for treatment and must be diluted to a specific concentration suitable for the patient's treatment (which, as previously mentioned, can create problems).

The present invention overcomes the aforementioned problems by providing a therapeutically effective amount of albuterol and ipratropium in pre-packaged, pre-mixed, pre-measured and/or unit dosage form. In one embodiment, the invention includes one or more prefilled containers. Each of the one or more containers contains a single dose of an aqueous solution comprising a therapeutically effective amount of albuterol and ipratropium for the treatment of COPD. Providing an inhalation solution in this manner avoids the need to dilute or mix COPD medications to obtain a therapeutically appropriate dose. At the same time, there is no need for special pharmaceutical ingredients, thereby reducing the chance of medication errors. In addition, the risk of cross-contamination is also reduced, and the use of the inhalation solution in a pre-mixed ready-to-use form also reduces waste in administration.

Among other features of the present invention is that the present invention improves user compliance and quality of life compared to conventional COPD treatments. Although the level of compliance with any COPD treatment depends in part on the motivation of the user and the skill of the individual in dispensing the medication, compliance can nonetheless be improved by controlling factors such as the ease with which the treatment is administered and the desirability with which it is received.

The present invention provides a convenient, rapid and reliable treatment for COPD, clearly representing an improvement over conventional COPD treatment. The present invention is designed to facilitate user compliance by providing one or more dosing containers containing premixed, predetermined quantities of an inhalation solution comprising a single dose of a therapeutically effective amount of albuterol for the treatment of COPD and ipratropium. The containers can be used in methods of treating COPD, or incorporated into systems and/or kits for treating COPD.

In an alternative embodiment, the invention is a single container, sterile, premixed, pre-measured, BAC-free inhalation solution comprising a single dose of a therapeutically effective amount of albuterol and iso Pratropium. Each unit dose container contains 3.0 mg/3 ml of albuterol sulfate (equivalent to 2.5 mg albuterol) and 0.5 mg ipratropium bromide in sterile aqueous solution. Sodium chloride may be added to make the solution isotonic, and hydrochloric acid may be added to adjust the pH of the solution to about 4.0. Inhalation solutions of the invention may or may not contain chelating agents such as EDTA.

In another alternative embodiment, the inhalation solution of the present invention is a BAC-free 3ml sterile nebulizer solution containing about 0.20mg to about 0.5mg of ipratropium bromide and about 0.75mg/3ml to about 3.0 mg/3ml of salbutamol sulfate. The nebulizer solution is supplied in a low-density polyethylene (LDPE) unit dose container. Each unit dose container can be placed in a foil pouch, each foil pouch can hold 5 or more unit dose containers. Foil pouches containing unit-dose containers can be placed in shelf cartons.

The present invention provides albuterol and ipratropium inhalation solution for treating COPD in different stages (including but not limited to stage 0-III). The relevant characteristics of COPD at different stages are shown in Table 2, and the information in this table is for illustrative purposes only. It is not intended to limit the scope of the invention.

Table 2 stage Severity describe 0 risky ^* Normal spirometry ^* Chronic symptoms (cough, phlegm) I slight ^* FEV ₁ /FVC < 70% ^* FEV ₁ > 80% predicted ^* With or without chronic symptoms II medium ^* FEV ₁ /FVC<70% ^* 30% ≥ FEV ₁ < 80% predicted value (IIA: 50% ≥ FEV ₁ < 80%) (IIB: 30% ≥ FEV ₁ < 50%) ^* With or without chronic symptoms III serious ^* FEV ₁ /FVC < 70% ^* FEV ₁ < 30% predicted or less than 50% predicted with clinical signs of respiratory failure or right heart failure

(FEV ₁ : Forced Breathing Volume in 1 second; FVC: Forced Vital Capacity)

In the present invention, a therapeutically effective amount of albuterol and ipratropium is administered to induce bronchodilation and/or relieve bronchospasm associated with COPD. Said amount of albuterol and ipratropium can be administered to the patient after the onset of bronchospasm to relieve dyspnea caused by COPD. In another embodiment, albuterol and ipratropium may be administered prophylactically, ie to prevent the development of COPD.

The amount of albuterol and ipratropium to be administered can be determined on an individual basis, at least in part, taking into account the size of the patient, the severity of the symptoms to be treated, and the desired effect. The actual dose (amount of albuterol and ipratropium per administration) and frequency of daily administration depends on the mode of administration, eg via inhaler, nebulizer or orally. For example, about 2.5 mg of albuterol and about 0.5 mg of ipratropium bromide administered by nebulization per day, allowing up to two additional 3 ml doses per day if needed, is sufficient to produce the desired bronchodilation effect in most patients .

Furthermore, the albuterol and ipratropium inhalation solution of the present invention can be used in combination with one or more other drugs. For example, anti-asthma drugs such as theophylline or terbutaline, or antihistamines or analgesics such as aspirin, acetaminophen, or ibuprofen, may be given in combination with or in close proximity to a therapeutically effective amount of albuterol apply. The agent of the invention and one or more agents described above may be administered by one formulation or by two separate entities. According to the present invention, therapeutically effective amounts of albuterol and ipratropium are administered to the subject alone or in combination with other drugs periodically as needed to reduce symptoms of COPD.

In another alternative embodiment, the inhalation solutions of the present invention may be administered using nebulizers including, but not limited to, jet nebulizers, ultrasonic nebulizers, and breathactuated nebulizers. Preferably, the nebulizer is a jet nebulizer connected to an air compressor with sufficient air flow. The nebulizer is fitted with a mouthpiece or a suitable face mask. Specifically, the inhalation solution of the present invention can be delivered to the patient using a Pari-LC-Plus ^™ nebulizer (equipped with a face mask or mouthpiece) connected to a PRONEB ^™ compressor.

In an alternative embodiment, the systems and/or kits of the invention comprise prepackaged, pre-measured, pre-mixed and/or single unit dose forms of the inhalation solution, wherein the inhalation solution contains A therapeutically effective amount of albuterol and ipratropium for the treatment of COPD. Solutions for inhalation may be sterile and/or BAC-free.

In another embodiment, the present invention provides a system and/or kit for assembling and storing one or more prefilled dosing containers, each container containing a premixed, predetermined amount of inhaled solution. The inhalation solution comprises a single unit dose of a therapeutically effective amount of albuterol and ipratropium. Such systems and/or kits may provide such containers in prepackaged form. The one or more containers may be made of plastic including, but not limited to, semi-permeable plastics such as LDPE. The container may also have a Twist-Flex( ^TM ) top with an easy-to-grip tab-like handle so that the container can be opened, eg, by twisting the handle off by hand. The advantage of the Twist-Flex ^TM cap is that it allows for easier application of the solution, prevents run-off, and reduces cross-contamination by eliminating the need to cut the cap to open the container, etc. One or more of such semipermeable single unit dose containers may be prepackaged in aluminum foil pouches such that the aluminum foil provides a protective barrier against environmental contamination and light. This barrier improves the shelf life and stability of the inhalation solution.

In another alternative embodiment, the present invention includes prepackaged inhalation systems and/or kits for COPD patients. Such prepackaged systems and/or kits include: (a) one or more single unit doses of a therapeutically effective amount of albuterol and ipratropium; (b) instructions for using said unit doses in the treatment of COPD and (c) a dosing container prefilled with said one or more unit doses of albuterol and ipratropium.

In another alternative embodiment, the prepackaged inhalation systems and/or kits of the present invention provide one or more premixed, pre-measured single unit dose vials and instructions for their use. Comprising a therapeutically effective amount of albuterol and ipratropium for treating bronchospasm associated with COPD.

In another alternative embodiment, the present invention relates to a prepackaged therapeutic system and/or kit for inducing bronchodilation and relieving bronchospasm in patients with chronic obstructive pulmonary disease, said prepackaged therapeutic system comprising:

(a) one or more dosing containers; each of said one or more containers is prefilled with a premixed, predetermined volume of approximately 3 ml of a sterile aqueous inhalation solution without benzalkonium chloride (BAC), so Described solution comprises the salbutamol of the therapeutically effective amount of unit dose and different third detroponium bromide; Wherein the amount of salbutamol is about 2.5mg, the amount of different third detroponium bromide is about 0.5mg; Said in said one or more containers The inhalation solution is suitable for spraying with a nebulizer; the inhalation solution in the one or more containers has a long shelf life;

(b) one or more labels having indicia thereon including efficacy, dosage, usage, contraindications and adverse reaction information related to each inhalation solution in said one or more containers;

(c) wherein said contraindication information includes information indicating that persons allergic to atropine and its derivatives should not use the inhalation solution in said one or more containers; and

(e) wherein the adverse reaction information includes the following information: administration of the inhalation solution in the one or more containers may promote or exacerbate angle-closure glaucoma, acute eye pain, blurred vision, paradoxical bronchospasm, Wheezing, exacerbation of COPD symptoms, drowsiness, pain, flushing, upper respiratory infection, palpitations, abnormal taste, fast heart rate, sinusitis, back pain, and sore throat.

The dosage and administration information may include a recommended dosage representing the inhalation solution in the one or more containers, the recommended dosage being about 2.5 mg albuterol and about 0.5 mg ipratropium bromide in 3 ml of aqueous solution, the aqueous The solution is administered by spray 4 times per day, with an additional maximum of 2 additional recommended doses per day if needed. In addition, the adverse reaction information may also include information indicating that an immediate hypersensitivity reaction to the inhalation solution, including urticaris, may occur after administration of the inhalation solution in the one or more containers. , angioedema, rash, itching, oropharyngeal, edema, bronchospasm, and anaphylaxis. The adverse reaction information may also include information indicating allergic-type reactions that may occur after administration of the one or more containers of the inhalation solution, including rash, itching, and hives. The adverse reaction information may further include a list representing one or more adverse events that may occur after administration of the inhalation solution, including chest pain, diarrhea, digestive disturbance, nausea, leg cramps, bronchitis, Lung disease, pharyngitis, pneumonia and urinary tract infection.

In another alternative embodiment, the prepackaged inhalation system and/or kit for treating bronchospasm in patients with chronic obstructive pulmonary disease provided by the present invention may include:

(a) one or more dosing containers; each of said one or more containers is prefilled with a premixed, pre-measured, stabilized sterile aqueous inhalation solution free of benzalkonium chloride, said inhalation solution Consists of: sodium chloride, water, edetate disodium, an acid to adjust the pH of the inhalation solution to about 4, a therapeutically effective amount of albuterol and ipratropium bromide in a unit dose; wherein the amount of albuterol is about It is 2.50mg, and the amount of different third detropammonium bromide is about 0.5mg; Each inhalation solution in described one or more containers is all suitable for nebulizer spray; Described inhalation solution has longer shelf life;

(b) one or more labels with indicia including efficacy, dosage, usage, contraindications and adverse reaction information related to each inhalation solution in said one or more containers;

(c) wherein said dosage and administration information includes a recommended dosage representing the inhalation solution in said one or more containers, said recommended dosage being, about 2.5 mg albuterol and about 0.5 mg ipratropium bromide in 3 ml of aqueous solution Ammonium, an aqueous solution administered as a spray 4 times per day, with an additional maximum of 2 additional recommended doses per day if needed;

(d) wherein said contraindication information includes information indicating that persons allergic to atropine and its derivatives should not use the inhalation solution in said one or more containers;

(e) wherein the adverse reaction information includes the following information: after administration of the inhalation solution in the one or more containers, an immediate hypersensitivity reaction may occur, and the allergic reaction includes urticaria, angioedema, rash, rash; Itching, oropharynx, edema, bronchospasm, and anaphylaxis.

(f) wherein said adverse reaction information includes information that allergic reactions may occur after administration of said one or more containers of inhalation solutions; said allergic reactions include rash, itching and urticaria.

(g) wherein said adverse reaction information includes a notification that administration of the inhalation solution in said one or more containers may promote or exacerbate angle-closure glaucoma, acute eye pain, blurred vision, paradoxical bronchospasm, asthma Wheezing, worsening of COPD symptoms, drowsiness, pain, flushing, upper respiratory infection, palpitations, abnormal taste, fast heart rate, sinusitis, back pain, and sore throat; and

(h) wherein said adverse reaction information includes a list of one or more adverse events that may occur following administration of the inhalation solution in said one or more containers; said adverse events include chest pain, diarrhea, digestive disturbances, nausea, Leg cramps, bronchitis, lung disease, pharyngitis, pneumonia and urinary tract infections.

The prepackaged inhalation system and/or kit may be in one of a variety of forms including, but not limited to: a box containing one or more prepackaged unit dose vials, or a box containing one or more Individually packaged or box of sachets of multiple unit dose vials. For example, a standardized prepackaged system and/or kit for treating COPD patients is shown in FIG. 5 . In particular, FIG. 5 depicts supportive packaging 10 . The supportive package 10 may include, but is not limited to, a box, carton, or any other enclosed container. The supportive package houses one or more prepackaged, prefilled dosing containers 21-25. Each container contains a premixed, predetermined amount of inhalation solution. The inhalation solution contains a unit dose of a therapeutically effective amount of albuterol and ipratropium bromide for the treatment of COPD. The inhalation solution may be in sterile and/or BAC-free form.

One or more labels 13 may also be attached to the carrier package 10 . The one or more labels may have indicia 14 indicating that the solution is used to relieve symptoms associated with COPD, such as bronchospasm. The label may also have indicia 15 providing instructions for using the inhalation solution to relieve the symptoms described above. "Mark" as used herein includes, but is not limited to, text, photographs, diagrams, symbols and/or styles. A non-limiting example of such indicia that may appear on one or more labels 13 is shown in FIG. 7 . The one or more labels may be affixed to one or more surfaces of the supportive package 10, either in the form of a single sheet, or any combination thereof. The supportive package 10 may also include a lid 16 for enclosing the packaging material therein.

The systems and/or kits of the invention may also include labels and/or instructions designed to promote user compliance. For example, in one embodiment, the systems and/or kits of the invention include packaging material containing one or more prefilled vials containing premixed, pre-measured unit doses of sterile aqueous inhalation A solution comprising a therapeutically effective amount of albuterol and ipratropium bromide. The packaging material may further have a label stating that each vial is for use with the nebulizer for the relief of symptoms associated with COPD, such as bronchospasm. The instructions may also include instructions for dosage and usage of each spray treatment, eg, instructions for administration with a nebulizer. The instructions may be attached to one or more surfaces of the packaging material, or the instructions may be a single sheet of paper or any combination thereof.

The invention also relates to a method of treating symptoms associated with COPD, including bronchospasm, wherein a therapeutically effective amount of albuterol and ipratropium bromide may be administered in a unit dose. The unit dose may be in the form of a nebulizer solution.

In another embodiment, the present invention relates to a method of inducing bronchodilation or relief of bronchospasm in patients with chronic obstructive pulmonary disease, said method comprising the steps of:

(a) providing the patient with a prepackaged therapeutic system comprising: one or more dosing containers; each of the one or more containers prefilled with about 3 ml of premixed, pre-measured, benzalkonium chloride-free An aqueous inhalation solution of ammonium, said inhalation solution containing albuterol and ipratropium bromide in a unit dose of a therapeutically effective amount; wherein the content of albuterol is about 2.5 mg, and the content of ipratropium bromide is about 0.5 mg; said one The inhalation solution in one or more containers is suitable for spraying with a nebulizer; the inhalation solution in the one or more containers has a longer shelf life;

(b) provide the patient or prescriber with information regarding the inhalation solution in said one or more containers, that is, the dosage, administration, contraindications, and adverse reaction information of the prepackaged therapeutic system;

(c) wherein said contraindication information includes information indicating that persons allergic to atropine and its derivatives should not use the inhalation solution in said one or more containers; and

(d) wherein the adverse reaction information includes the following information: administration of the inhalation solution in the one or more containers may promote or exacerbate angle-closure glaucoma, acute eye pain, blurred vision, paradoxical bronchospasm, Wheezing, exacerbation of COPD symptoms, drowsiness, pain, flushing, upper respiratory infection, palpitations, abnormal taste, fast heart rate, sinusitis, back pain, and sore throat.

In this method, the dosage and administration information may indicate to the patient or prescribing physician a recommended dosage of each inhalation solution in the one or more containers of about 2.5 mg albuterol and about 0.5 mg of ipratropium bromide as an aqueous solution administered by spray 4 times daily, with an additional maximum of 2 additional recommended doses per day if needed. The adverse reaction information may also inform the patient or prescribing physician of immediate hypersensitivity reactions, including urticaria, angioedema, rash, rash, that may occur following administration of the inhalation solution in the one or more containers. Itching, oropharynx, edema, bronchospasm, and anaphylaxis. The adverse reaction information may further inform the patient or prescribing physician of allergic-type reactions that may occur after administration of the inhalation solution in the one or more containers, including rash, itching, and hives. Additionally, the adverse reaction information includes a preformed list of one or more adverse events that may occur after administration of the inhalation solution, including chest pain, diarrhea, digestive disturbances, nausea, leg cramps, bronchitis, Lung disease, pharyngitis, pneumonia and urinary tract infection.

In another alternative embodiment, the present invention relates to a method of inducing bronchodilation or relieving bronchospasm in a patient with chronic obstructive pulmonary disease, said method comprising the steps of:

(a) providing the patient with a prepackaged therapeutic system comprising: one or more dosing containers; each container prefilled with about 3 ml of a premixed, pre-measured, stabilized sterile aqueous inhalation solution , said solution does not contain benzalkonium chloride; said inhalation solution consists of water, edetate disodium, sodium chloride, an acid for adjusting the pH value of the inhalation solution to about 4, a therapeutically effective amount of albuterol in a unit dose, and iso Pratropium bromide, wherein the amount of salbutamol is about 2.50mg/3ml, and the amount of ipratropium bromide is about 0.5mg/3ml; the inhalation solution in the one or more containers is suitable for nebulizer spraying;

(b) provide the patient or prescribing physician with information regarding the inhalation solution in said one or more containers, that is, the efficacy, dosage, administration, contraindications, and adverse reaction information of the prepackaged therapeutic system;

(c) wherein the dosage and administration information informs the patient or prescribing physician of the recommended dosage of the inhalation solution in the one or more containers, which recommended dosage is about 2.5 mg albuterol and about 0.5 mg albuterol in 3 ml of aqueous solution ipratropium bromide, an aqueous solution administered by spray 4 times daily, with an additional maximum of 2 additional recommended doses per day if needed;

(d) wherein said contraindication information includes information indicating that persons allergic to atropine and its derivatives should not use the inhalation solution in said one or more containers;

(e) wherein the adverse reaction information includes informing the patient or prescribing physician that following administration of the inhalation solution in the one or more containers, an immediate hypersensitivity reaction may occur, including urticaria, angioedema, , rash, itching, oropharynx, edema, bronchospasm and anaphylaxis;

(f) wherein said adverse reaction information informs the patient or prescribing physician that allergic reactions may occur after administration of said one or more containers of inhalation solution; said allergic reactions include rash, itching and hives;

(g) where the adverse reaction information informs the patient or prescribing physician that administration of the inhalation solution in the one or more containers may promote or exacerbate angle-closure glaucoma, acute eye pain, blurred vision, abnormal Bronchospasm, wheezing, exacerbation of COPD symptoms, drowsiness, pain, flushing, upper respiratory infection, palpitations, abnormal taste, fast heart rate, sinusitis, back pain, and sore throat; and

(h) The adverse reaction information includes a preformed list of one or more adverse events that may occur after administration of the inhalation solution, including chest pain, diarrhea, digestive disturbance, nausea, leg cramps, bronchitis , lung disease, pharyngitis, pneumonia and urinary tract infections.

In an alternative embodiment, the methods of the invention comprise the step of administering to the patient a therapeutically effective amount of albuterol and ipratropium. Such solutions may also be pre-packaged, pre-mixed, pre-measured, BAC-free and/or sterile. Such solutions may also be presented in single unit dose vials.

In another alternative embodiment, the method of the present invention comprises the step of administering to a patient in need thereof an inhalation solution comprising a therapeutically effective amount of albuterol and ipratropium. The inhalation solution may be administered using a nebulizer, more preferably a jet nebulizer connected to an air compressor with sufficient airflow.

In another alternative embodiment, referring to FIGS. 1 to 4, the method of the present invention comprises the steps of: (i) filling the inhalation solution containing a therapeutically effective amount of albuterol and ipratropium 1 into a nebulizer cup 2, It can be connected with a compressed air cylinder or an electric compressor to transmit power to the nebulizer; (ii) adopt the "T" shape joint 3 to assemble the nebulizer cup cover 4 on the mouthpiece 5 or the mask 6; (iii) through the gas injection Speed suction inhalation solution 1, and make it break up into aerosol; (iv) make this aerosol enter in the bronchospasm patient 7 through mouthpiece 5 or mask 6; And (v) this patient continues breathing, until spray chamber 8 until no more fine mist is formed. This operation can be completed in about 5 to 15 minutes.

In an alternative embodiment, a typical initial dose administered to a patient is approximately 2.50 mg albuterol and 0.5 mg ipratropium administered by nebulization 3 or 4 times daily as required. To administer the above amounts of albuterol and ipratropium bromide, the entire contents of one unit dose vial (eg, about 3.0 mg/3 ml albuterol sulfate and 0.5 mg/3 ml ipratropium bromide) can be used. Preferably, the nebulizer flow rate is adjusted to administer the albuterol and ipratropium over 5 to 15 minutes.

In an alternative embodiment, the method of the present invention further comprises the steps of: (i) preparing a therapeutically effective amount of albuterol and ipratropium by diluting one or more solutions containing ipratropium or albuterol and (ii) administering said inhalation solution to a patient in need thereof.

The present invention also provides a process for the preparation of a prepackaged, sterile, pre-measured, pre-mixed and/or BAC-free inhalation solution comprising a single unit dose of a therapeutically effective amount of salbutamine and isobutamine Pratropium. In this embodiment, the method of the invention comprises one or more of the following steps: (i) adding at least a therapeutically effective amount of albuterol and ipratropium to a carrier such as water; (ii) sterilizing the solution and sealing the container. Tonicity regulators may be added to adjust the isotonicity of the solution. Preferably, the solution of the present invention is isotonic, and an osmotic pressure regulator may be added to adjust the isotonicity of the solution to about 280-320 mOsm/kg. Additionally, an acid such as hydrochloride may be added to adjust the pH of the solution to a level of about 3.0 to about 5.0, preferably about 4.0.

In another embodiment, the method for preparing the inhalation solution of the present invention comprises one or more of the following steps: (i) adding at least a therapeutically effective amount of albuterol and ipratropium to a carrier such as water; (ii) charging the resulting mixture into container and sterilize the mixture by steam sterilization or any other sterilization method known in the art. Each albuterol and ipratropium mixture was filled into vials and packaged, stored and/or used directly. The mixture obtained here is stable, and if necessary it may be divided after sterilization into a plurality of mixtures, each mixture containing a unit dose of a therapeutically effective amount of albuterol and ipratropium.

Tonicity regulators that can be used include, but are not limited to, sodium chloride, potassium chloride, zinc chloride, calcium chloride, and mixtures thereof. Other osmolarity regulators may also be employed including, but not limited to, mannitol, glycerol, dextrose, and mixtures thereof. In an alternative embodiment, the present invention may comprise from about 0.4% to about 1.0% by weight of an ionic salt. Preferably, the present invention comprises 0.9% by weight of an osmotic pressure regulator.

In an alternative embodiment, the inhalation solution of the present invention may be prepared as follows: (i) a stainless steel preparation tank equipped with a bottom drain and a tri-blender for stirring; (ii) Under agitation, put about 95% of the required amount of purified water USP (United States Pharmacopoeia grade) at 18°C to 25°C into the tank; (iii) add EDTA USP, hydrochloric acid and at least a therapeutically effective amount of albuterol sulfate to the tank USP and ipratropium bromide; (iv) continue stirring until all chemical components are dissolved; (v) if necessary, add purified water USP to adjust final volume, thereby making a mixture of albuterol and ipratropium bromide.

From the formulation tank, the albuterol and ipratropium mixture was pumped through a clean transfer line directly into a form fill seal (FFS) machine. Pass the albuterol and ipratropium mixture through a sterile 0.2 micron cartridge filter, then into the storage tank, through a second sterile 0.2 micron cartridge filter into the priming nozzle of the sterile air shower, and into the In vials molded from low-density polyethylene (LDPE). Vials are filled with the sterilized albuterol and ipratropium mixture so that each vial contains a single unit dose of a therapeutically effective amount of albuterol. The filled vial is then sealed. Form, fill and seal pharmaceutical vials in a continuous operation using FFS machines under aseptic conditions to produce sterile products. For example, an automatic packaging machine can be used to package a row of five filled vials (Figure 6) in protective laminated foil pouches. Six to twelve of these capsules are packaged in shelf cartons to form a prepackaged therapeutic system for treating COPD patients. Appropriate labeling and directions for use can be added to the shelf carton.

The invention also relates to a method of forming a unit dose nebulizer solution comprising the steps of: (i) formulating a mixture comprising a therapeutically effective amount of albuterol and ipratropium bromide in a pharmaceutically acceptable carrier. The mixture is suitable for spraying with a nebulizer.

In an alternative embodiment, the invention also includes a device for the relief of symptoms associated with COPD, including bronchospasm. Such means takes the form of a label, written instructions or any other form on which markings are affixed. The device may have indicia stating that patients with symptoms associated with COPD may receive at least one prepackaged, sterile, premixed, pre-measured and/or BAC-free inhalation solution. treatment, said inhalation solution comprising a unit dose of a therapeutically effective amount of albuterol and ipratropium in a single vial. The inhalation solution is suitable for nebulizer nebulization. The device may also have indicia directing the use of said inhalation solution to treat a patient with said condition.

Example

In order to evaluate the efficacy and safety of the inhalation solution of the present invention, a double-blind, randomized, positive control experiment was carried out. The design, results and conclusions of the study are detailed below.

patient

A total of 863 patients were initially randomly enrolled into the trial. Patients who meet the criteria in Table 3 are eligible to join.

Table 3. Inclusion/Exclusion Criteria design elements describe selection criteria ^* Diagnosed with COPD, ^whose FEV ₁ is 25-65% of the normal predicted value ^* Age > 40 years old ^* Previous regular use of one or more bronchodilators for at least 3 months ^* Smoking history of at least 10 years Theophylline, salmeterol and oral β2 agonists were controlled during the trial (judged by the researcher). ^* Able to complete 6 minutes of walking safely ^* Volunteer to provide informed consent exclusion criteria ^* Diagnosed with pneumoconiosis, silicosis, any organic disease not attributable to COPD, polycythemia, or pulmonary disease (pulmonale), hypoxia, or newly diagnosed disease related to allergic rhinitis, atopy or COPD ^* Clinically significant obstructive urinary tract disorder, angle-closure glaucoma, unstable angina, or myocardial infarction in the past 6 months, known substance abuse in the past 12 months, or exacerbation of pulmonary disease within the past 2 months Hospitalization ^* Known allergic reaction to any component of the test drug ^* Use of the test drug within 30 days before taking the first dose of the test drug ^* Pregnant or breastfeeding

treat

The doses of the individual drugs and the combination of ipratropium and albuterol are shown in Table 4 below. All test drugs were administered by inhalation 4 times a day (ideally every 6 hours) using a Pari LC Plus ^™ nebulizer and a Pari Proneb ^™ compressor. Concomitant use of bronchodilators should be limited during the trial. During the trial, oral and inhaled steroids were allowed, provided that the dose remained constant.

Table 4 drug to be tested Salbutamol (main ingredient) ipratropium bromide albuterol alone 2.5mg ipratropium alone 0.5mg Albuterol and ipratropium in combination 2.5mg 0.5mg

efficacy results

Of the 863 patients who were randomized and started treatment, 289 withdrew from the trial early, including 28 patients who did not meet the inclusion/exclusion criteria and should not have been enrolled. A total of 663 patients received the inhalation solution of the present invention and at least one other drug to be tested, and measured FEV ₁ at least once after administration. Because most patients completed treatment with all 3 test drugs, these subjects contributed 647 comparative data for evaluation in each part of the primary analysis.

During the crossover trial, the primary efficacy variable was the change in peak _FEV1 measured from pre-dose to 3 hours post-dose. As shown in Table 5, the mean increase in FEV ₁ was significantly greater with the combination of albuterol and ipratropium than with either drug alone. Among them, the combination group was 23.6% higher than the single use of albuterol, and 37.2% higher than the single use of ipratropium. The change in FEV ₁ response over time is shown in Table 6.

Table 5. Efficacy Results for the Crossover Period parameter Combination vs albuterol Combination vs ipratropium n combination albuterol p-value mean mean n combination ipratropium p-value mean mean Peak FEV ₁ (L) 647 0.387 0.13 <0.001 647 0.387 0.282 <0.001

Table 6. Changes in FEV1 Measured at Day 14

During the parallel trial, separate groups of patients self-administered only 1 of the 3 test drugs during the final 6 weeks of the trial. The results of the parallel period are basically the same as the crossover period. As with the peak FEV ₁ response observed during the crossover period, the combination of albuterol and ipratropium also maintained values higher than either drug component alone.

safety/tolerability

Adverse effects associated with the combination of albuterol and ipratropium were evaluated based on the above clinical trials. Adverse events were reported in 1% or more of patients during treatment, and the results by drug are shown in Table 6. As can be seen from the table, there was no difference between the albuterol and ipratropium combination and the drugs administered alone in terms of the incidence of patients with adverse events in the overall body system.

Table 6. Adverse Event Reports

(adverse event rate ≥ 1% of treatment group, with combination therapy presenting highest percentage) Body System COSTART Terminology Salbutamoln(%) Ipratropium n(%) Combination of salbutamol and ipratropium n(%) number of patients 761 754 765 Patients with adverse reactions n (%) 327 (43.0) 329 (43.6) 367(48.0) whole body pain 8(1.1) 4(0.5) 10(1.3) chest pain 11(1.4) 14(1.9) 20(2.6) digestive system diarrhea 5(0.7) 9(1.2) 14(1.8) indigestion 7(0.9) 8(1.1) 10(1.3) nausea 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)

Adverse effects, including constipation and voice changes, were also reported in more than 1% of patients treated with the combination of albuterol and ipratropium.

The drawings herein are for illustration only. They do not limit the scope of the invention. Next, it should be understood that changes and modifications to the preferred aspects of the invention described herein will be apparent to those skilled in the art. Such changes and modifications can be made in the present invention without departing from the scope and spirit of the invention and without diminishing the attendant advantages. It is therefore intended to cover such changes and improvements in the appended claims.

Meanwhile, the present invention may also suitably include, consist of, or consist essentially of elements further described herein, and may be suitably practiced in the absence of any element not specifically disclosed herein. The invention described herein.

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 benzene hole oronain.

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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