CA2464735C

CA2464735C - An albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease

Info

Publication number: CA2464735C
Application number: CA2464735A
Authority: CA
Inventors: Imtiaz Chaudry; Partha Banerjee
Original assignee: Dey LP
Current assignee: Mylan Specialty LP
Priority date: 2001-10-26
Filing date: 2002-10-18
Publication date: 2011-03-22
Anticipated expiration: 2022-10-18
Also published as: CA2464735A1; MXPA04003927A; WO2003037159A2; EP1446045A4; EP1446045A2; CN1939279A; NZ552548A; CN1607940A; JP2006505486A; AU3297402A; WO2003037159A3

Abstract

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

Description

TITLE
An Albuterol and Ipratropium Inhalation Solution, System, Kit and Method for Relieving Symptoms of Chronic Obstructive Pulmonary Disease II. FIELD OF THE INVENTION

The present invention relates to a combination bronchodilator therapy for relieving symptoms associated with chronic obstructive pulmonary disease.

III. BACKGROUND OF INVENTION

Chronic obstructive pulmonary disease (COPD) is a slowly progressive airway disease that produces a decline in lung function that is not fully reversible.
The airway limitation in COPD is associated with an abnormal inflammatory response of the lungs to noxious particles or gases.

In the U.S., an estimated 16 million Americans have been diagnosed with some form of COPD, and as many as 16 million others have the condition but have not yet been diagnosed. According to the U.S. Centers for Disease Control and Prevention, COPD is the fourth leading cause of death in the U.S. (behind heart disease, cancer and stroke), claiming the lives of 112,000 Americans annually.

In terms of health care utilization, the number of physician visits for COPT) in the U.S. increased from 9.3 million to 16 million between 1985 and 1995. The number of hospitalizations for COPD in 1995 was estimated to be 500,000. Although prevalence, hospitalization and death rates for COPD are higher in men than women, death rates have risen faster in women in recent years. COPD is clearly a major and growing health care threat in the U.S. and throughout the rest of the world.

In the prior art, antimicrobial agents such as benzalkonium chloride (BAC) are often present in inhalation solutions used to treat COPD. The presence of BAC in these solutions generally does not affect the short-term (single dose) bronchodilator response. However, case reports suggest that repeated use of COPD treatments with BAC may result in paradoxic bronchoconstriction. When inhaled by COPD subjects, BAC may also cause dose-dependent bronchoconstriction. Despite these side effects, many commercially available inhalation solutions contain BAC.

Also, treatments for COPD often come in multiple dosage units and must be diluted to specific concentrations suitable for treating patients. This poses several problems. For instance, COPD treatments requiring administration of a single dose unit from multiple dosage units sometimes lack proper mixing or diluting instructions, or the instructions for preparing and using the COPD treatment may be hard to follow or can be easily lost. Of even greater import is haphazard diluting or mixing of COPD medications, which can result in administering the wrong dosage. This could be especially harmful for patients less tolerant to higher dosages of asthma medications. Incorrect mixing can also result in treatment failure such that additional medical attention is required, thereby increasing the time, expense and personnel costs associated with therapy.

There is, therefore, a need for an improved inhalation solution, system, kit and method for relieving symptoms associated with COPD.

IV. SUMMARY OF THE INVENTION

One object of the present invention is to provide a dual bronchodilator inhalation solution to relieve bronchospasm in patients suffering from COPD.

Another object of the present invention is to provide a prepackaged, sterile, premixed, premeasured albuterol and ipratropium inhalation solution for the relief of bronchospasm in patients suffering from COPD.

It is yet another object of the present invention to provide a BAC-free albuterol and ipratropium inhalation solution to treat bronchospasm associated with COPD.

A further object of the present invention is to provide a method of administering an albuterol and ipratropium inhalation formulation for relief of bronchospasm associated with COPD.

An additional object of the present invention is to provide a kit and/or system for administering a dual bronchodilator to relieve bronchospasm associated with COPD.

A further object of the present invention is to provide a process for making an albuterol and ipratropium inhalation solution for use in relieving bronchospasm associated with COPD.

Another object of the invention includes a device for use in relieving the symptoms of COPD.

Other objects, features and advantages of the present invention will be apparent to those of ordinary skill in the art in view of the following detailed description of the invention and accompanying drawings.

V. BRIEF DESCRIPTION OF THE DRAWINGS

Figures 1-4 depict a non-limiting example of administering the inhalation solution of the present invention by a nebulizer.

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

Figure 6 depicts a non limiting example of one or more pre-filled containers comprising the inhalation system of the present invention.

Figure 7 depicts a non-limiting example of a label utilized in the present invention.
VI. DETAILED DESCRIPTION OF THE INVENTION

Albuterol The present invention relies on the bronchodilation effects of albuterol to provide relief from symptoms associated with COPD. As used herein, the term "albuterol" includes, but is not limited to, any form of albuterol which is capable of producing a desired bronchodilation effect in patients, including, but not limited to, all tautomeric forms, enantomeric forms, stereoisomers, anhydrides, acid addition salts, base salts, solvates, analogues and derivatives of albuterol.

In the present invention, acceptable salts of albuterol may include, but are not limited tn; hydrochloride, sulfine; maleat4, +1--Irate, citretc and the like. These salts are desMibed in U.S. Patent No. 3,644,353.

In the present invention, the preferred salt of albuterol is sulfate. In an alternative embodiment, the inhalation solution of the present invention comprises the sulfate salt of racemic albuterol. Albutarol sulfate is a relatively selective beta-2-adrenergic bronchodilator with an empirical formula of C13H21N03. The chemical name for albuterol sulfate is al-[(tert-butylamino)methyl]-4 hydroxy-m-xylene-a, a'-diol sulfate (2:1)(salt), and its established chemical structure is as follows:

HO CHCH2NHC(CHa)a -H2SO4 Ipratropium The present invention also relies on the bronchodilation effect of ipratropium to provide relief from symptoms associated with COPD. Ipratropium is an anticholinergic bronchodilator. As used herein, the term "ipratropium" includes, but is not limited to, any form of ipratropium which is capable of producing a desired bronchodilation effect in patients suffering from COPD, including, but not limited to, all tautomeric forms, enantomeric forms, stereoisomers, anhadrides, acid addition salts, base salts, salvates, analogues and derivatives of ipratropium.

In the present invention, acceptable salts of ipratropium may include, but are not limited to, halide salts such as bromide, chloride and iodide. These and other acceptable salts are described in U.S. Patent No. 3,505,337.

In one embodiment of the present invention, the preferred salt of ipratropium is bromide, which is chemically described as 8-azoniabicyclo [3.2.1] -octane, 3-(3, hydroxyl-1-oxo-2-phenylpropoxy)-8methyl-8-(1-methylethyl)-bromide, monohydrate, (endo, syn)-, ( )-.
Ipratropium bromide has a molecular weight of 430.4 and the empirical formula C2oH3oBrNO3-H20. It is freely soluble in water and lower alcohol, and is insoluble in lipohilic solvents such as ether, chloroform and flourocarbon. The established chemical structure of ipratropium bromide is as follows:

In the present invention, the albuterol and ipratropium may be provided in a variety of pharmaceutically acceptable vehicles, including, but not limited to, water or other aqueous solutions comprising a pharmaceutically acceptable amount of an osmotic agent.

In one alternative embodiment, the inhalation solution of the present invention comprises a therapeutically effective amount of albuterol and ipratropium. As used herein, the phrase "therapeutically effective amount of albuterol and/or ipratropium"
means a safe and tolerable amount of both compounds, as based on industry and/or regulatory standards.
Such amount being sufficient to effectively induce bronchodilation and/or provide relief of bronchospasm in patients suffering form COPD.

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

In another alternative embodiment of the present invention, a therapeutically effective amount of albuterol may include from 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;

about 1.31 mg to about 1.40 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 2.01 mg to about 2.10 mg;
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; about 2.51 mg to about 2.60 mg; 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;
about 3.31 mg to about 3.40 mg; about 3.41 mg to about 3.50 mg; about 3.51 mg to about 3.60 mg; about 3.61 to about 3.70 mg; about 3.71 to about 3.80 mg; about 3.81 mg to about 3.90 mg; about 3.91 mg to about 4.0 mg; about 4.01 mg to about 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 4.61 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, a therapeutically effective amount of albuterol may include from about 0.75 mg to about 5.0 mg albuterol sulfate, including the following intermediate amounts: about 0.75 mg to about 0.80 mg;
about 0.81 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; about 1.31 mg to about 1.40 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 2.01 mg to about 2.10 mg; 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;

about 2.51 mg to about 2.60 mg; 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; about 3.31 mg to about 3.40 mg;
about 3.41 mg to about 3.50 mg; about 3.51 mg to about 3.60 mg; about 3.61 to about 3.70 mg; about 3.71 to about 3.80 mg; about 3.81 mg to about 3.90 mg; about 3.91 mg to about 4.0 mg; about 4.01 mg to about 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 4.61 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, a therapeutically effective amount of albuterol may include from about 0.020 % to about 0.14 % by weight albuterol, including the following intermediate ranges: about 0.020 wt % to about 0.029 wt %; 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 %; about 0.080 wt % to about 0.089 wt %; about 0.090 wt % to about 0.099 wt %;
about 0.10 wt % to about 0.14 wt %.

In yet another alternative embodiment of the present invention a therapeutically effective amount of albuterol may include from about 0.025 % to about 0.17 %
by weight albuterol sulfate, including the following intermediate ranges: about 0.025 wt % to about 0.029 wt %; 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 %; about 0.080 wt % to about 0.089 wt %; about 0.090 wt %
to about 0.099 wt %; about 0.10 wt % to about 0.17 wt %.

In another alternative embodiment of the present invention a therapeutically effective amount of ipratropium bromide may include from about 0.01 mg to about 1.0 mg of ipratropiumn bromide. Such therapeutically effective amount may also 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 to about 0.07 mg; about 0.08 mg to about 0.10 mg;
about 0.11 mg to about 0.13 mg; about 0.14 mg to about 0.16 mg; about 0.17 mg to about 0.19 mg;
about 0.20 mg to about 0.22 mg; 0.23 mg to about 0.25 mg; 0.26 mg to about 0.28 mg; about 0.29 mg to about 0.31 mg; about 0.32 to about 0.34 mg; about 0.35 mg to about 0.37 mg;
about 0.36 mg about 0.38 mg; about 0.39 mg to about 0.41 mg; about 0.42 mg to about 0.44 mg; about 0.45 mg to about 0.47 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; about 0.63 mg to about 0.65 mg; about 0.66 mg to about 0.68 mg;
about 0.69 mg to about 0.71 mg; about 0.72 mg to about 0.74 mg; about 0.75 mg to about 0.77 mg; about 0.79 mg to about 0.81 mg; about 0.82 mg to about 0.84 mg; about 0.85 mg to 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, a therapeutically effective amount of ipratropium may include from about 0.001% to about 0.030% by weight ipratropium bromide, including the following intermediate ranges of ipratropium bromide:
about 0.001 wt % to about 0.005 wt %; about 0.006 wt % to about 0.010 wt %;
about 0.011 wt % to about 0.015 wt %; about 0.0 16 wt % to about 0.020 wt %; about 0.021 wt % to about 0.025 wt %; 0.026 wt % to about 0.030 wt %.

Most pharmaceutical inhalation solutions contain the anti-microbial agent BAC.
One problem with these solutions is that the BAC may cause paradoxic bronchoconstriction if the solution is administered repeatedly over short intervals. Another problem is that, when inhaled by patients, the BAC can cause dose-dependent bronchoconstriction. The inhalation solution of the present invention may be provided without BAC, thereby making it suitable, especially in an emergency situation, where the inhalation solution is administered repeatedly over a short period of time. Also, administering a BAC-free inhalation solution to a patient reduces the concomitant liability of adverse effects associated with BAC. It also reduces the toxicity and other side effects associated with BAC.

The inhalation solution of the present invention may also be provided in sterile, unit dose treatments, thus eliminating the need to include BAC in the solution.
Moreover, as shown in Table 1, in its sterile form the formulation of the present invention (which comprises a therapeutically effective amount of albuterol sulfate and ipratropium bromide) provides a stable inhalation solution such that the formulation can be stored (e.g., on a shelf) for long periods of time.

Table 1 Stability Data 0.083 wt % Albuterol Sulfate and 0.017 wt %
I ratropium Bromide Assay* Osmolality Albuterol Ipratropium pH (mOsm/kg) sulfate bromide Time zero 98 98 3.3 283 25 C/35%RH 12 months 105 99 3.4 285 24 months 102 101 3.5 282 40 C/15%RH 3 months 100 99 3.5 284 6 months 103 102 3.4 283 * as percent of label claim (0.083 wt % albuterol sulfate and 0.017 wt %
ipratropium bromide) As stated, the compositions provided herein are stable. For example, the compositions provided herein are stored between about 15 C and about 30 C, and remain stable for a relatively long period of time. In one embodiment, the compositions are stored at 25 C.

In another embodiment, the stability of the compositions provided herein may contain greater than 80%, 85%, 90% or 95% of the initial amount of active ingredient, e.g., Albuterol and Ipratropium at a given temperature for a long period of time. Thus, for example, a composition that is stable for 30 days at 25 C would have greater than 80%, 85%, 90% or 95% of the initial amount of active ingredients present in the composition at 30 days following storage at 25 C.

In another embodiment, the compositions herein are stable during long term storage, in that the compositions are suitable for administration to a subject in need thereof when they have been stored for a length of time (i.e., shelf-life) for a period greater than 1, 2 or 3 years at 25 C. In other embodiments herein, using Arrhenius Kinetics, >80% or >85%
or >90% or >95% estimated bronchodilating agent remains after such storage, for example.

Other indications of the stability of the present compositions can be shown in terms of by-products or degradation products present over time, as shown in Tables 2 and 3 below.

Albuterol degradation products/related compounds Range at 6 to Range in drug as % of albuterol 24 25nt sat substance 1 5-2-((1,1-Dimethylethyl)amino-l-hydroxyethyl)-2- ND - 0.012%
hydroxybenzaldehyde w/w 2 Bis-(2-hydroxyO-5-(2-tertbutylamino-l-hydroxyethyl) phenylmethyl 0.09 -0.174%
ether w/w 3 2-tert-butylamino-l-(4-hydroxy-3-methoxymethylphenyl)-ethanol 0.01-0.12%
w/w 4 Tert-butylamino-3-chloro-4-hydroxy-5-hydroxymethylacetophenone ND - 0.0002%
w/w Tert-butylamino-4-hydroxy-5-hydroxymethylacetophenone ND - 0.002%
w/w 6 1-(4-hydroxy-3-methylphenyl)-2-(tert-butylamino) ethanol 0.0009-1 0.036% w/w 7 1-(5-chloro-4-hydroxy-3-hydroxymethylphenyl)-2-(tert-butylamino) ND
ethanol 8 Unknown 1 ND - 0.07%
by peak area ND - 0.025%

9 Any other unknown by peak area 1 Total 0.18-0.23%

ND=none detected Ipratropium degradation products/related compounds Range at upto Range in drug as % of ipratropium bromide 24 25nt sat substance 1 Tropic acid ND - 0.08%
w/w 2 8S-ipratropium bromide ND - 0.058%
w/w 3 N-isopropyl-noratro ine ND
4 Ipratropium alcohol ND - 0.038%
w/w Any other unknown ND
6 Atropic acid ND
7 Total (excluding APO-ipratropium) ND - 0.2%
ND=none detected In one embodiment, the compositions herein are at least substantially clear, based on color measurement tests set forth by the America Public Health Association ("APHA"). In another embodiment of the present invention, the APHA color results for compositions herein at upto 24 months at 25 C ranged from 0 to 5 units (mostly 0 units), as based on APHA
standards.

In one embodiment, the process of the present invention provides compositions having an albuterol content of about 2.5 mg to about 2.75 mg per vial. In another alternative embodiment, the process of the present invention provides compositions having an Ipratropium content of about 0.45 - 0.55 mg per vial. In yet another alternative embodiment, the process of the present invention provides an average fill volume of about 2.84 to about 3.30 ml into each vial.

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

1. Volatiles acetone about NMT 0.2 cg/ml or less ethyl acetate about NMT 0.3 (Dg/ml or less n-heptane NMT 0.1 (Dg/ml or less n-propylacetate NMT 0.3 (Dg/ml or less toluene NMT 0.3Dg/ml or less 2-butanone none detected (signal/nose NMT 3) unknowns 2. Leachables Irganox 129 none detect (NMT 0.02(Dg/ml) Extractable 1 none detected (signal/noise NMT 3) Extractable 2 none detected (signal/noise NMT 3) unknowns none detected (signal/noise NMT 3) In another alternative embodiment, compositions of the present invention may contain minimal amounts of particulate matter, including, but not limited to the following: NMT
about 1000 to 5000, preferably about 3800 particles/vial >2Iin; NMT about 10 to 100, preferably about 80 particles/vial >10mm; or NMT about 1 to 5, preferably about 3 particles/vial >25Jm.

Another benefit of a sterile inhalation solution is that it reduces the possibility of introducing contaminants into the patient when administered, thereby reducing the chance of an opportunistic infection in the patient.

Non-adherence to COPD medication therapy and medication error are considerable problems. These problems can be significantly reduced by providing COPD
patients a prepackaged, premixed, premeasured amount of albuterol and ipratropium.
Providing these compounds in this fashion makes COPD therapy simple because it increases convenience and eliminates confusion in preparing appropriate dosages. These advantages are especially significant where treatments often come in multiple dosage units and must be diluted to specific concentrations suitable for treating patients. As discussed previously, this poses several problems.

The present invention overcomes the aforementioned problems by providing therapeutically effective amounts of both albuterol and ipratropium in prepackaged, premixed, premeasured and/or unit dose amounts. In one embodiment, the present invention comprises one or more prefilled containers. The one or more containers each comprising a single unit dose of an aqueous solution comprising a therapeutically effective amount of albuterol and ipratropium for the treatment of COPD. Providing the inhalation solution in such a manner eliminates the need to dilute or mix COPD medications to obtain proper dosages for treatment. Also, no special pharmacy compounding is required, thereby reducing the chance of medication errors. Further, there is a lower risk of cross-contamination, and less waste of medication when providing an inhalation solution in a premixed, ready to use form.

Other features of the present invention include improved user compliance and quality of life as compared to conventional treatments for COPD. While the level of compliance of any COPD treatment depends in part on the motivation of the user and the skill of the individual dispensing the treatment, compliance nevertheless may be improved by controlling factors such as the ease with which the treatment may be administered, as well as the desirability of receiving the treatment.

The present invention provides a convenient, fast and reliable treatment for COPD
and clearly represents an improvement over traditional COPD treatments. Also, the present invention is designed to facilitate user compliance by providing one or more dispensing containers comprising a premixed, premeasured inhalation solution comprising a single unit dose of a therapeutically effective amount of albuterol and ipratropium for the treatment of COPD. Such containers may be utilized in a method of treating COPD or the containers may be incorporated in a system and/or kit for treating the same.

In one alternative embodiment, the present invention is a sterile, premixed, premeasured, BAC-free inhalation solution comprising a single unit dose of a therapeutically effective amount of albuterol and ipratropium in a single container. Each unit dose container comprises 3.0 mg/3 ml of albuterol sulfate (equivalent to 2.5 mg of albuterol) and 0.5 mg ipratropium bromide in a sterile, aqueous solution. Sodium chloride may be added to make the solution isotonic and hydrochloric acid may be added to adjust pH of the solution to about 4Ø The inhalation solution of the present invention may or may not include a chelating agent, such as EDTA.

In another alternative embodiment, the inhalation solution of the present invention may be supplied as a 3 ml, sterile, BAC-free, nebulizer solution comprising from about 0.20 to about 0.5 mg ipratropium bromide and from about 0.75 mg/3 ml to about 3.0 mg/3 ml of albuterol sulfate. The nebulizer solution is contained in a unit-dose, low-density polyethylene (LDPE) container. Each unit-dose container may be disposed in a foil pouch, and each foil pouch may contain 5 or more unit-dose containers. Each foil pouch containing the unit dose container may be disposed in a shelf carton.

The present invention provides an albuterol and ipratropium inhalation solution for treating different stages of COPD, including but not limited to, stages 0 to III. Some characteristics associated with the different stages of COPD are shown in Table 2. The information in this table is presented for illustrative purposes only. It is not intended to limit the scope of the invention.

Table 2 Stage Severity Description 0 At risk = Normal spirometry = Chronic symptoms (cough, sputum production) I Mild = FEVI/FVC < 70%
= FEVI > 80% predicted = With or without chronic symptoms II Moderate = FEV1/FVC < 70%
= 30% > FEV1 < 80% predicted (IIA: 50% > FEV1 < 80%) (IIB: 30% > FEV1 < 50%) = With or without chronic symptoms III Severe = FEVI/FVC < 70%
= FEVI < 30% predicted or less than 50% predicted with respiratory failure or clinical signs of right heart failure.
In the present invention, a therapeutically effective amount of albuterol and ipratropium is administered to induce bronchodilation and/or provide relief of bronchospasm associated with COPD. Such amount of albuterol and ipratropium may be administered to a patient after the onset of bronchospasm to reduce breathing difficulties resulting from COPD.
In another embodiment, the albuterol and ipratropium may be administered prophylactically, that is, to prevent COPD progression.

The quantity of albuterol and ipratropium to be administered will be determined on an individual basis, and will be based at least in part on consideration of the patient's size, the severity of the symptoms to be treated, and the results sought. The actual dosage (quantity of albuterol and ipratropium administered at a time) and the number of administrations per day will depend on the mode of administration, such as inhaler, nebulizer or oral administration.
For example, about 2.5 mg of albuterol and about 0.5 mg of ipratropium bromide administered by nebulization 4 times per day with up to 2 additional 3 ml doses allowed per day, if needed, would be adequate to produce the desired bronchodilation effect in most patients.

Further, the albuterol and ipratropium inhalation solution of the present invention may be administered together with one or more other drugs. For example, an antiasthmatic drug such as theophylline or terbutaline, or an antihistamine or analgesic such as aspirin, acetaminophen or ibuprofen, may be administered with or in dose temporal proximity to administration of a therapeutically effective amount of albuterol. The present invention and the one or more drugs may be administered in one formulation or as two separate entities.
According to the present invention, a therapeutically effective amount of albuterol and ipratropium, alone or in combination with another drug(s), may be administered to a individual periodically as necessary to reduce symptoms of COPD.

In another alternative embodiment, the inhalation solution of the present invention may be administered by nebulizer. Such nebulizer including, but not limited to, a jet nebulizer, ultrasonic nebulizer and breath actuated nebulizer. Preferably, the nebulizer is a jet nebulizer connected to an air compressor with adequate air flow. The nebulizer being equipped with a mouthpiece or suitable face mask. Specifically, a Pari-LC-PlusTM nebulizer (with face mask or mouthpiece) connected to a PRONEBTM compressor may be used to deliver the inhalation solution of the present invention to a patient.

In an alternative embodiment, the system and/or kit of the present invention comprises an inhalation solution comprising a therapeutically effective amount of albuterol and ipratropium in a prepackaged, premeasured, premixed and/or single unit dose form for the treatment of COPD. The inhalation solution may be sterile and/or BAC-free.

In another embodiment, the present invention provides a system and/or kit for organizing and storing one or more prefilled dispensing containers, each container comprising a premixed, premeasured inhalation solution. The inhalation solution comprising a single unit dose of a therapeutically effective amount of albuterol and ipratropium. Such system and/or kit may provide such containers in prepackaged form. The one or more containers may be comprised of plastic including, but not limited to, a semi-permeable plastic such as LDPE. The container may also comprise a Twist-FlexTM top, such top comprising an easy-to-grip tab-like handle such that the container may be opened, for example, by twisting off the tab by hand. The Twist-FlexTM top is advantageous in that it allows for easy dispensing of the solution, prevents spillage and eliminates the need to open the container by cutting off the top, or the like, thereby reducing cross-contamination. One or more of the semi-permeable single unit dose containers may be prepackaged in an aluminum foil pouch, such that the foil provides a protective barrier against environmental contaminants and light.
Such a barrier improves the shelf-life and stability of the inhalation solution.

In another alternative embodiment, the present invention comprises a prepackaged inhalation system and/or kit suitable for patients suffering from COPD. Such prepackaged system and/or kit comprising: (a) one or more single unit dosages of a therapeutically effective amount of albuterol and ipratropium; (b) administration instructions for the use of said unit dose as a treatment for COPD; and (c) a dispensing container prefilled with the one or more unit doses of albuterol and ipratropium.

In another alternative embodiment, the prepackaged inhalation system and/or kit of the present invention provides one or more premixed, premeasured single unit dose vials comprising a therapeutically effective amount of albuterol and ipratropium for the treatment of bronchospasm associated with COPD, and instructions for using the same.

In one alternative embodiment, the present invention is directed to a prepackaged therapeutic system and/or kit for inducing bronchodilation or providing relief of bronchospasm in a patient suffering from chronic obstructive pulmonary disease, the prepackaged therapeutic system comprising:

(a) one or more dispensing containers; the one or more containers each prefilled with about 3 ml of a sterile, benzlakonium chloride-free, premixed, premeasured aqueous inhalation solution comprising a unit dose of a therapeutically effective amount of albuterol and ipratropium bromide; wherein the dosage of albuterol is about 2.5 mg and the dosage of ipratropium bromide is about 0.5 mg; the inhalation solution in each of the one or more containers is suitable for nebulization in a nebulizer; the inhalation solution in each of the one or more containers has a long shelf life;

(b) one or more labels with indicia thereon, the indicia comprising efficacy dosage, administration, contraindication and adverse reaction data pertaining to the inhalation solution in each of the one or more containers;

(c) wherein the contraindication data comprises data indicating that the inhalation solution in each of the one or more containers is contraindicated for humans with hypersensitivity to atropine and derivatives thereof; and (d) wherein the adverse reaction data comprises data indicating that precipitation or worsening of narrow-angle glaucoma, acute eye pain, blurred vision, paradoxical bronchospasm, wheezing, exacerbation of chronic obstructive pulmonary disease symptoms, drowsiness, aching, flushing, upper respiratory tract infection, palpitations, taste perversion, elevated heart rate, sinusitis, back pain and sore throat may occur after administrating the inhalation solution in the one or more containers.

The dosage and administration data may comprise data indicating that the recommended dose of the inhalation solution in each of the one or more containers is about 2.5 mg of albuterol and about 0.5 mg impratropium bromide in 3 ml of an aqueous solution administered 4 times per day by nebulization with up to 2 additional recommended doses allowed per day, if needed. Also, the adverse reaction data may comprise data indicating that immediate hypersensitivity reactions to the inhalation solution in each of the one or more containers may occur after administration of the inhalation solution, said hypersensitivity reactions comprising urticaris, angioedema, rash, pruritis, oropharyngeal, edema, bronchospasm, and anaphylaxis. The adverse reaction data may also comprise data indicating that allergic-type reactions may occur after administrating the inhalation solution in the one or more containers, including skin rash, prurities, and urticaria. The adverse reaction data may further comprise data indicating a list of one or more adverse events that may occur after administrating the inhalation solution, said adverse events including chest pain, diarrhea, dyspepsia, nausea, leg cramps, bronchitis, lung disease, pharyngitis, pneumonia, and urinary tract infection.

In another alternative embodiment, the present prepackaged therapeutic system and/or kit for treating bronchospasm in a patient suffering from chronic obstructive pulmonary disease may comprise.

(a) one or more dispensing containers; the one more containers each prefilled with 3 ml of a sterile, stable, premixed, premeasured aqueous inhalation solution free of benzalkonium chloride; the inhalation solution consisting of sodium chloride, water, edetate disodium, an acid to adjust the pH of the inhalation solution to about 4, and a unit dose of a therapeutically effective amount of albuterol and ipratropium bromide, wherein the amount of albuterol is about 2.50 mg and the amount of ipratropium bromide is about 0.5 mg; the inhalation solution in each of the one or more containers is suitable for nebulization in a nebulizer; said inhalation solution having a long shelf life;

(b) one or more labels with indicia thereon; the indicia comprising efficacy, dosage, administration, contraindication and adverse reaction information pertaining to the inhalation solution in each of the one or more containers;

(c) wherein the dosage and administration data comprises data indicating that the recommended dose of the inhalation solution in each of the one or more containers is about 2.5 mg of albuterol and about 0.5 mg impratropium bromide in 3 ml of an aqueous solution administered 4 times per day by nebulization with up to 2 additional recommended doses allowed per day, if needed;

(d) wherein the contraindication data comprises data indicating that the inhalation solution in each of the one or more containers is contraindicated for humans with hypersensitivity to atropine and derivatives thereof;

(e) wherein the adverse reaction data comprises data indicating that immediate hypersensitivity reactions to the inhalation solution in each of the one or more containers may occur after administrating the inhalation solution, said hypersensitivity reaction including urticaris, angioedema, rash, pruritis, oropharyngeal, edema, bronchospasm, and anaphylaxis;

(f) wherein the adverse reaction data comprises data indicating that allergic-type reactions may occur after administrating the inhalation solution in the one or more containers; said allergic type reaction, including skin rash, prurities, and urticaria;

(g) wherein the adverse reaction data comprises data indicating that precipitation or worsening of narrow-angle glaucoma, acute eye pain, blurred vision, paradoxical bronchospasm, wheezing, exacerbation of chronic obstructive pulmonary disease symptoms, drowsiness, aching, flushing, upper respiratory tract infection, palpitations, taste perversion, elevated heart rate, sinusitis, back pain and sore throat may occur after administrating the inhalation solution in the one or more containers; and (h) the adverse reaction data includes a list of one or more adverse events that may occur after administration of the inhalation solution in each of the one or more containers; the adverse events including chest pain, diarrhea, dyspepsia, nausea, leg cramps, bronchitis, lung disease, pharyngitis, pneumonia, and urinary tract infection.

The prepackaged inhalation system and/or kit may be provided in one of any number of forms, including, but not limited to, a box containing one or more prepackaged, unit dose vials or a box containing individual packages or pouches comprising one or more unit dose vials. For example, an embodiment of a unified prepackaged system and/or kit for treating COPD in patients is depicted in Figure 5. Specifically, Figure 5 depicts support package (10). Support package (10) may include, but is not limited to, a box, carton or any other enclosed container. The support package comprising one or more prepackaged, pre-filled dispensing containers (21-25). Each container comprising a premixed, premeasured inhalation solution. The inhalation solution comprising a unit dose of a therapeutically effective amount of albuterol and ipratropium for treating COPD. The inhalation solution may be provided in sterile and/or BAC-free form.

Support package (10) may also incorporate one or more labels (13) therein. One or more labels (13) may comprise indicia (14) indicating that the inhalation solution can be used to relieve symptoms associated with COPD, such as bronchospasm. The label may also comprise indicia (15) which provides instructions for using the inhalation solution to relieve such symptoms. As used herein "indicia" includes, but is not limited to, wording, pictures, drawings, symbols and/or shapes. A non-limiting example of the indicia that may appear on the one or more labels (13) is shown in Figure 7. The one or more labels may be positioned on one or more surfaces of support package (10) or a separate sheet, or any combination thereof. Support package (10) may also incorporate lid (16) to enclose the packaging material therein.

The system and/or kit of the present invention may also include a label and/or instructions designed to facilitate user compliance. For example, in an embodiment, a system and/or kit of the present invention comprises packaging material containing one or more prepackaged vials comprising a sterile, premixed, premeasured unit dose of an inhalation solution comprising a therapeutic effective amount of albuterol and ipratropium. The packaging material may further comprise a label indicating that each vial can be used with a nebulizer for the relief of symptoms associated with COPD, such as bronchospasm. Such instructions may also include instructions on dosage for each nebulizer treatment, as well as instructions for administration, such as by nebulizer. The instructions may be positioned on one or more surfaces of the packaging material therein, or the instructions may be provided on a separate sheet, or any combination thereof.

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

In another embodiment, the present invention is directed to a method for inducing bronchodilation or providing relief of bronchospasm in a patient suffering from chronic obstructive pulmonary disease, said method comprising the step of:

(a) providing the patient a prepackaged therapeutic system comprising:

one or more dispensing containers; the one or more containers each prefilled with about 3 ml of a sterile, benzalkonium chloride-free, premixed, premeasured aqueous inhalation solution comprising a unit dose of a therapeutically effective amount of albuterol and ipratropium bromide; wherein the amount of albuterol is about 2.5 mg and the amount of ipratropium bromide is about 0.5 mg; the inhalation solution in each of the one or more containers is suitable for nebulization in a nebulizer; the inhalation solution in each of the one or more containers has a long shelf life;

(b) providing the patient or prescriber of the prepackaged therapeutic system dosage, administration, contraindication and adverse reaction data pertaining to the inhalation solution in each of the one or more containers;

(c) wherein the contraindication data comprises data indicating that the inhalation solution in each of the one or more containers is contraindicated for humans with hypersensitivity to atropine and derivatives thereof; and (d) wherein the adverse reaction data comprises data indicating that precipitation or worsening of narrow-angle glaucoma, acute eye pain, blurred vision, paradoxical bronchospasm, wheezing, exacerbation of chronic obstructive pulmonary disease symptoms, drowsiness, aching, flushing, upper respiratory tract infection, palpitations, taste perversion, elevated heart rate, sinusitis, back pain and sore throat may occur after administrating the inhalation solution in the one or more containers.

In the present method, the dosage and administration data may inform the patient or prescriber the recommended dose of the inhalation solution in each of the one or more containers is about 2.5 mg of albuterol and 0.5 mg impratropium bromide in 3 ml of an aqueous solution administered 4 times per day by nebulization with up to 2 additional recommended doses allowed per day, if needed. The adverse reaction may also inform the patient or prescriber that immediate hypersensitivity reactions to the inhalation solution in each of the one or more containers may occur after administration of the inhalation solution, said hypersensitivity reactions including urticaris, angioedema, rash, pruritis, oropharyngeal, edema, bronchospasm, and anaphylaxis. The adverse reaction data may further inform the patient or prescriber that allergic-type reactions may occur after administrating the inhalation solution in the one or more containers, including skin rash, prurities, and urticaria. Also, the adverse reaction data may include a preprinted list of one or more adverse events that may occur after administrating the inhalation solution, said adverse events comprising chest pain, diarrhea, dyspepsia, nausea, leg cramps, bronchitis, lung disease, pharyngitis, pneumonia, and urinary tract infection.

In another alternative embodiment, the present invention is directed to a method for inducing bronchodilation or providing relief of bronchospasm in a patient suffering from chronic obstructive pulmonary disease, said method comprising the step of:

(a) providing a patient the prepackaged therapeutic system comprising:

one or more dispensing containers; the one more containers each prefilled with about 3 ml of a sterile, stable, premixed, premeasured aqueous inhalation solution free of benzalkonium chloride; the inhalation solution consisting of water, edetate disodium, sodium chloride, and an acid to adjust the pH of the inhalation solution to about 4, and a unit dose of a therapeutically effective amount of albuterol and ipratropium bromide, wherein the amount of albuterol is about 2.50 mg/3 ml and the amount of ipratropium bromide is about 0.5 mg/3 nil;
the inhalation solution in each of the one or more containers is suitable for nebulization in a nebulizer;

(b) providing the patient or prescriber the prepackaged therapeutic system efficacy, dosage, administration, contraindication and adverse reaction data pertaining to the inhalation solution in each of the one or more containers;

(c) wherein the dosage and administration data informs the patient or prescriber that the recommended dose of the inhalation solution in each of the one or more containers is about 2.5 mg of albuterol and 0.5 mg impratropium bromide in 3 ml of an aqueous solution administered 4 times per day by nebulization with up to 2 additional recommended doses allowed per day, if needed;

(d) wherein the contraindication data comprises information indicating that the inhalation solution in each of the one or more containers is contraindicated for humans with hypersensitivity to atropine and derivatives thereof;

(e) wherein the adverse reaction data informs the patient or prescriber that immediate hypersensitivity reactions to the inhalation solution in each of the one or more containers may occur after administrating the inhalation solution in the on e or more containers, said hypersensitivity reaction including urticaris, angioedema, rash, pruritis, oropharyngeal, edema, bronchospasm, and anaphylaxis;

(f) wherein the adverse reaction data informs the patient or prescriber that possible allergic-type reactions may occur after administering the inhalation solution in the one or more containers, including skin rash, prurities, and urticaria;

(g) wherein the adverse reaction data informs the patient or prescriber that precipitation or worsening of narrow-angle glaucoma, acute eye pain, blurred vision, paradoxical bronchospasm, wheezing, exacerbation of chronic obstructive pulmonary disease symptoms, drowsiness, aching, flushing, upper respiratory tract infection, palpitations, taste perversion, elevated heart rate, sinusitis, back pain and sore throat may occur after administrating the inhalation solution in the one or more containers; and (h) the adverse reaction data includes a preprinted list of one or more adverse events that may occur after administration of the inhalation solution in each of the one or more containers; the adverse events comprising chest pain, diarrhea, dyspepsia, nausea, leg cramps, bronchitis, lung disease, pharyngitis, pneumonia, and urinary tract infection.

In an alternative embodiment, the method of the present invention comprises the step of administering to a patient a therapeutically effective amount of albuterol and ipratropium.
Such solution may also be prepackaged, premixed, premeasured, BAC-free and/or sterile.
Such solution may also be in a single unit dose vial.

In another alternative embodiment, the method of the present invention comprises the step of administering to a patient in need an inhalation solution comprising a therapeutically effective amount of albuterol and ipratropium. The inhalation solution being administered by nebulizer, more preferably a jet nebulizer connected to an air compressor with adequate air flow.

In yet another alternative embodiment, in reference to Figures 1-4, the method of the present invention comprises the steps: (i) placing an inhalation solution comprising a therapeutically effective amount of albuterol and ipratropium (1) into a nebulizer cup (2).
The nebulizer may be powered by attachment to compressed gas cylinders or an electrically driven compressor; (ii) using a "T" adapter (3) to fit the nebulizer cup lid (4) to a mouthpiece (5) or facemask (6); (iii) drawing the inhalation solution (1) up by the velocity of a gas jet and fragmenting it into an aerosol; (iv) passing the aerosol through the mouthpiece (5) or facemask (6) to the patient (7) afflicted with bronchospasm; and (v) the patient continues breathing until no more mist is formed in the nebulizer chamber (8). This may occur in about 5-15 minutes.

In one alternative embodiment, the usual starting dosage for patients may be about 2.50 mg albuterol and 0.5 mg ipratropium administered 3 or 4 times daily, as needed by nebulization. To administer these amounts of albuterol and ipratropium, the entire contents of one unit dose vial (e.g., about 3.0 mg/3 ml albuterol sulfate and 0.5 mg/3 ml ipratropium bromide) may be used. Preferably, the nebulizer flow rate is adjusted to deliver the albuterol and ipratropium over 5 to 15 minutes.

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

The present invention also provides a process for making a prepackaged, sterile, premixed, premeasured, and/or BAC-free inhalation solution comprising a single unit dose of a therapeutically effective amount of albuterol and ipratropium. In such an embodiment, the method of the present invention comprises one or more of the following steps:
(i) adding at least a therapeutically effective amount of albuterol and ipratropium in a carrier, such as water; (ii) sterilizing the solution and sealing the container. An osmotic adjusting agent may be added to adjust the isotonicity of the solution. Preferably, the solution of the present invention is isotonic, and an osmotic adjusting agent may be added to adjust the isotonicity of the solution to about 280 to about 320 mOsm/kg. Additionally, an acid (e.g., hydrochloride) may be added to adjust the pH of the solution to a level of about 3.0 to about 5.0, preferably about 4Ø

In another embodiment, a process for making an 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 in a carrier such as water; (ii) placing the mixture in a container, and sterilizing the mixture by steam sterilization, or any other sterilizing means known in the art. Each albuterol and ipratropium mixture being filled into a vial, and then packaged, stored and/or used directly. Here, the resulting mixture is stable, and after sterilization, it can be dispersed, if necessary, into multiple mixtures each containing a unit dose of a therapeutically effective amount of albuterol and ipratropium.

Osmotic adjusting agents which may be used include, but are not limited to, sodium chloride, potassium chloride, zinc chloride, calcium chloride and mixtures thereof. Other osmotic adjusting agents may also include, but are not limited to, mannitol, glycerol, and dextrose and mixtures thereof. In an alternative embodiment, the present invention may comprise about 0.4 to about 1.0 weight percent ionic salt. Preferably, the present invention comprises 0.9 wt % of an osmotic adjusting agent.

In an alternative embodiment, the inhalation solution of the present invention may be prepared as follows: (i) fitting a stainless steel formulation tank with a bottom drain and a tri-blender for mixing; (ii) filling the tank with approximately 95% of the required amount of Purified Water USP at a temperature of between 18 C to 25 C; while mixing, (iii) adding EDTA USP, hydrochloric acid, and at least a therapeutically effective amount of Albuterol Sulfate USP and Ipratropium Bromide to the tank; (iv) continue mixing until all chemical components are dissolved; (v) adding Purified Water USP to adjust the final volume, if necessary, thus producing an albuterol and ipratropium bromide mixture.

From the formulation tank, the albuterol and ipratropium mixture is pumped through sanitary delivery lines directly into a form-fill-seal (FFS) machine. The albuterol and ipratropium mixture passes through a 0.2 micron sterilizing cartridge filter, then into a reservoir tank, through a second 0.2 micron sterilizing cartridge filter to the filling nozzles within the sterile air shower compartment, and subsequently into formed vials of low density polyethylene (LDPE). The albuterol and ipratropium mixture being sterile filled into the vials such that each vial contains a single unit dose of a therapeutically effective amount of albuterol. The filled vials are then sealed. The FFS machine may form, fill and seal the vials in a continuous operation under aseptic conditions, thus producing a sterile product. For example, cards of five filled vials (Figure 6) may be overwrapped into a protective laminated foil pouch using an autowrapper machine. Six to twelve such pouches may then be packaged in a shelf carton, thus forming a prepackaged therapeutic system for treating COPD in patients. An appropriate label and instructions may be added in the shelf carton.

The present invention is also directed to a method of forming a unit-dose nebulizer solution comprising the step of. (i) preparing a mixture containing a therapeutically effective amount of albuterol and ipratropium bromide in a pharmaceutically acceptable carrier. Said mixture being suitable for nebulization in a nebulizer.

In an alternative embodiment, the present invention also comprises a device for use in the relief of symptoms associated with COPD, including bronchospasm. Such device may take the form of a label, written instructions or any other form incorporating indicia thereon.
The device may comprise indicia which indicates that a patient suffering from symptoms associated with COPD can be treated with at least one prepackaged, sterile, premixed, premeasured and/or BAC-free inhalation solution comprising a unit dose of a therapeutically effective amount of albuterol and ipratropium in a single vial. The inhalation solution being suitable for nebulization in a nebulizer. The device may also comprise indicia which provides instructions for utilizing the inhalation solution to treat said symptoms in patients.
Examples To evaluate the efficacy and safety of the inhalation solution of the present invention, a double-blind, randomized, positive control trial was performed. The design, results and conclusion of the study are described in detail below.

Patients A total of 863 patients were initially randomized for enrollment in the trial.
To be eligible for enrollment, patients had to meet the criteria described in Table 3.

Table 3 Inclusion/Exclusion Criteria Design Element Description Inclusion Criteria = Diagnosis with COPD with an FEVI between 25% and 65%
of the normal predicted value.
= Age >40 years.
= Regular use of one or more bronchodilators for a minimum of 3 months prior to enrollment.
= History of at least 10 pack-years of smoking.
= Ability to refrain from the use of theophylline, salmeterol and oral P2 agonists for the duration of the trial (as judged by the investigator).
= Ability to safely complete a 6-minute walk.
= Willingness to provide informed consent.
Exclusion Criteria = Diagnosis of anthracosis, silicosis, any parenchymal disease not attributable to COPD, polycythemia, or pulmonale, hypoxia, or a primary diagnosis attributable to allergic rhinitis, atopy, or COPD.
= Clinically significant obstructive urinary disease, narrow-angle glaucoma, unstable angina pectoris or myocardial infarction in the past 6 months, known drug abuse within the last 12 months, or hospitalization for pulmonary exacerbation within the past 2 months.
= Known hypersensitivity to any component of the study medications.
= Investigational drug use within 30 days of first dose of study medication.
= Pregnancy or breastfeeding.
Interventions The doses of each individual agent and the ipratropium and albuterol combination were as shown in Table 4 below. All study medications were administered 4 times per day (ideally every 6 hours) by inhalation using a Pari LC P1usTM nebulizer and Pari PronebTM
compressor. Concomitant use of bronchodilators was restricted during the trial. Oral and inhaled steroic use was permitted throughout the trial, provided that dosing remained constant.

Table 4 Study Medication Albuterol (base) I ratro ium bromide Albuterol alone 2.5 mg Ipratropium alone 0.5 mg Albuterol and 2.5 mg 0.5 mg Ipratropium Combination Efficacy Results Of the 863 patients who were randomized and began treatment, 289 withdrew prematurely from the trial, including 28 patients who did not meet the inclusion/exclusion criteria and were inappropriately enrolled. A total of 663 patients received both the inhalation solution of the present invention and at least one other study medication and completed at least one post-dose measurement of FEV1. These subjects contributed to the 647 evaluable comparisons in each portion of the primary analysis, as the majority of patients completed treatment on all three study medications.

The primary efficacy variable was the change from pre-dose to peak FEVI
measured within 3 hours after dosing during the crossover phase of the trial. As can be seen in Table 5, the mean increase in FEVI was significantly higher for the albuterol and ipratropium combination than for either agent used alone. The improvement for the combination over albuterol alone was 23.6% and over ipratropium alone was 37.2%. The time course of FEVI
response is shown in Table 6.

Table 5 Efficacy Results in Crossover Phase Parameter Combination vs. Albuterol Combination vs. Ipratropium n Combination Albuterol p value n Combination Ipratropium p value mean mean mean mean Peak FEVI (liters) 647 0.387 0.313 <0.001 647 0.387 0.282 <0.001 SUBSTITUTE SHEET (RULE 26) Table 6 Mean change in FEVI - Measured on Day 14 LO N

Hwy 42 A1b. ro <- 1pratroplum DuoNeb During the parallel phase of the trial, separate groups of patients self-administered only one of the three study medications during the final 6 weeks of the trial.
Results for the parallel phase yielded results essentially identical to the crossover phase.
The albuterol and ipratropium combination maintained the same magnitude of superiority over each component medication alone that was observed during the crossover phase in peak FEVI
response.

Safety/Tolerability Adverse reactions concerning the albuterol and ipratropium combination were evaluated from the clinical trials described above. Treatment-emergent adverse events that were reported by I% or greater of patients are summarized by medication in Table 6. As can be seen, there were no differences between the albuterol and ipratropium combination and the individual medication in incidence of patients with adverse events across body systems.

SUBSTITUTE SHEET (RULE 26) Table 6 Adverse Event Reports (ADVERSE EVENTS OCCURRING IN > 1% OF TREATMENT GROUP(S) AND WHERE THE
COMBINATION TREATMENT SHOWED THE HIGHEST PERCENTAGE) Body System Albuterol Ipratropium Albuterol and COSTART Term n (%) n (%) Ipratropium Combination n N (%) Patients with A 327 43.0 329 43.6 367 48.0) BODY AS A WHOLE
Pain 8(1.1) 4 0.5 10(1.3) Pain chest 11(1.4) 14(1.9) 20(2.6) DIGESTIVE
Diarrhea 5(0.7) 9(1.2) 14(1.8) Dyspepsia 7(0.9) 8(1.1) 10(1.3) Nausea 7(0.9) 6(0.8) 11(1.4) MUSCULO-SKELETAL
Cramps leg 8(1.1) 6(0.8) 11(l.4) RESPERATORY
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) 10Q.3) UROGENITAL
Infection urinary tract 3(0.4) 9(1.2) 12(1.6) Additional adverse reactions reported in more than 1 % of patients treated with the albuterol and ipratropium combination included constipation and voice alterations.

The figures and attachments herein are presented for illustrative proposes only. They are not intended to limit the scope of the invention. Further, it should be understood that various changes and modifications to the presently preferred embodiment described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its attendant advantages. It is therefore intended that such changes and modifications be covered by the appended claims.

Also, the invention may suitably comprise, consist of or consist essentially of the elements described herein further, and the invention described herein suitably may be practiced in the absence of any element which is not specifically disclosed herein.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. An inhalation solution comprising: a premixed, premeasured aqueous formulation comprising, in a single container, a single unit dose of a therapeutically effective amount of from about 0.60 mg to about 5.0 mg of albuterol and from about 0.01 mg to about 1.0 mg of ipratropium bromide for inducing bronchodilation or providing relief of bronchospasm in patients suffering from chronic obstructive pulmonary disease, wherein the solution is sterile and free of antimicrobial preservative yet has a relatively long period of stability such that after storage for 12 months at a temperature of 25 °C, greater than 95% of the albuterol and greater than 95% of the ipratropium bromide originally present in the solution still remains in the solution.

2. The inhalation solution of claim 1, wherein after storage for 12 months at a temperature of 25 °C, the inhalation solution contains no degradation products associated with the degradation of albuterol, said degradation products being selected from the group consisting of 5-2-((1,1-dimethylethyl)amino-1-hydroxyethyl)-2-hydroxybenzaldehyde; bis-(2-hydroxy)-5-(2-tertbutylamino-1-hydroxyethyl) phenylmethyl ether; 2-tert-butylamino-1-(4-hydroxy-3-methoxymethylphenyl)-ethanol;
tert-butylamino-3-chloro-4-hydroxy-5-hydroxymethylacetophenone; tert-butylamino-4-hydroxymethylacetophenone; 1-(4-hydroxy-3-methylphenyl)-2-(tert-butylamino) ethanol; and 1-(5-chloro-4-hydroxy-3-hydroxymethylphenyl)-2-(tert-butylamino) ethanol.

3. The inhalation solution of claim 1, wherein after storage for 12 months at a temperature of 25 °C, the inhalation solution contains no degradation products associated with the degradation of ipratropium bromide, said degradation products being selected from the group consisting of tropic acid, 8S-ipratropium bromide, N-isopropyl-noratropine, ipratropium alcohol, and atropic acid.

4. The inhalation solution of claim 1, wherein the inhalation solution is free of benzalkonium chloride.

5. The inhalation solution of claim 1, wherein the pH of the inhalation solution ranges from about 3.0 to about 4Ø

6. The inhalation solution of claim 1, wherein the pH of the inhalation solution is about 4Ø

7. The inhalation solution of claim 1, wherein the albuterol is in the form of an acid addition salt thereof.

8. The inhalation solution of claim 7, wherein the acid addition salt of albuterol is albuterol sulfate.

9. The inhalation solution of claim1, wherein the albuterol is in the form of a racemic mixture.

10. The inhalation solution of claim 1, wherein the amount of albuterol in the inhalation solution ranges from about 2.00 mg to about 3.00 mg.

11. The inhalation solution of claim1, wherein the amount of albuterol in the solution is about 2.5 mg.

12. Use of an inhalation solution according to claim 1 for the manufacture of a premixed, premeasured medicament for inducing bronchodilation or providing relief of bronchospasm in a patient suffering from chronic obstructive pulmonary disease.

13. A kit for relieving bronchospasm in a patient suffering from chronic obstructive pulmonary disease, said kit comprising: one or more single dispensing containers each comprising an inhalation solution according to claim 1.

14. The kit of claim 13, wherein after storage for 12 months at a temperature of 25 °C, the inhalation solution contains no degradation products associated with the degradation of albuterol, said degradation products being selected from the group consisting of 5-2-((1,1-dimethylethyl)amino-1-hydroxyethyl)-2-hydroxybenzaldehyde;
bis-(2-hydroxy)-5-(2-tertbutylamino-1-hydroxyethyl) phenylmethyl ether; 2-tert-butylamino-1-(4-hydroxy-3-methoxymethylphenyl)-ethanol; tert-butylamino-3-chloro-4-hydroxy-5-hydroxymethylacetophenone; tert-butylamino-4-hydroxymethylacetophenone; 1-(4-hydroxy-3-methylphenyl)-2-(tert-butylamino) ethanol; and 1-(5-chloro-4-hydroxy-3 -hydroxymethylphenyl)-2-(tert-butylamino) ethanol.

15. The kit of claim 13, wherein after storage for 12 months at a temperature of 25 °C, the inhalation solution contains no degradation products associated with the degradation of ipratropium bromide, said degradation products being selected from the group consisting of tropic acid, 8S-ipratropium bromide, N-isopropyl-noratropine, ipratropium alcohol, and atropic acid.

16. The kit according to claim 13, wherein the inhalation solution is free of benzalkonium chloride.

17. The kit according to claim 13, wherein the amount of albuterol in the inhalation solution ranges from about 2.0 mg to about 3.0 mg albuterol.

18. The kit according to claim 13, wherein the amount of albuterol in the inhalation solution is about 2.50 mg.

19. The kit according to claim 13, further comprising a label which indicates that the inhalation solution can be used to relieve bronchospasm in patients suffering from chronic obstructive pulmonary disease.

20. The kit according to claim 13, further comprising instructions for using the inhalation solution to relieve bronchospasm associated with chronic obstructive pulmonary disease.

21. The kit according to claim 13, wherein the one or more containers are packaged in the same pouch or box.

22. The kit of claim 21, wherein said one or more containers comprise semi-permeable plastic and are packaged in an aluminum foil pouch.

23. A method of making a single container having therein an inhalation solution according to claim 1, said method comprising the steps: (a) placing a single unit dose of a therapeutically effective amount of from about 0.60 mg to about 5.0 mg of albuterol and from about 0.01 mg to about 1.0 mg of ipratropium bromide in a vehicle to form a solution; and (b) providing the inhalation solution in a single container so that the solution is sterile and free of antimicrobial preservative yet has a relatively long period of stability such that after storage for 12 months at a temperature of 25 °C, greater than 95% of the albuterol and greater than 95% of the ipratropium bromide originally present in the solution still remains in the solution.

24. The method of claim 43, further comprising the step of adding hydrochloric acid to adjust the pH of the inhalation solution to a level ranging from about 3.0 to about 4Ø

25. The method of claim 23, further comprising the step of adding an osmotic adjusting agent to adjust the isotonicity of the inhalation solution.

26. The method of claim 25, wherein the osmotic adjusting agent is selected from the group consisting of sodium chloride, potassium chloride, zinc chloride, calcium chloride, and mixtures thereof.

27. The method of claim 23, further comprising the step of sterilizing the inhalation solution by passing it through a filter.

28. The method of claim 23, further comprising the step of sterilizing the inhalation solution by steam sterilization.

29. The method of claim 23, further comprising the step of adding hydrochloric acid to adjust the pH of the inhalation solution to about 3.5.

30. A method of making an inhalation solution according to claim 1, said method comprising the steps:

a) mixing water, EDTA, hydrochloric acid, an osmotic adjusting agent, albuterol sulfate and ipratropium bromide into a stainless steel tank at a temperature between 18°C
and 25 °C to form an inhalation solution having the following characteristics:
i) the final concentration of the albuterol and ipratropium bromide in the inhalation solution ranges from about 0.06 wt. % to about 0.1 wt. % albuterol and about 0.03 wt. % to about 0.1 wt. % ipratropium;
ii) there is sufficient hydrochloric acid so that the pH of said solution is about 3.0 to about 4.0; and iii) there is sufficient osmotic adjusting agent so that the isotonicity of said solution is about 280 to about 320 mOsm/kg;
b) passing the inhaltion solution through at least one sterilizing filter into a form-fill seal (FFS) machine;
c) sterile filling the inhalation solution into one or more low density polyethylene dispensing containers, each container being filled with about 3 ml of the sterile, premixed, premeasured aqueous inhalation solution comprising a unit dose of a therapeutically effective amount of from about 0.6 mg to about 5.0 mg of albuterol and from about 0.01 mg to about 1.0 mg of ipratropium bromide and d) sterile sealing each of the one or more dispensing containers containing the inhalation solution;

wherein the inhalation solution in the one or more dispensing containers is sterile and free of antimicrobial preservative yet has a relatively long period of stability such that after storage for 12 months at a temperature of 25 °C, greater than 95% of the albuterol and greater than 95% of the ipratropium bromide originally present in the solution still remains in the solution.

31. The method of claim 30, wherein the albuterol is in the form of an acid addition salt thereof.

32. The method of claim 31, wherein the acid addition salt of albuterol is albuterol sulfate.

33. The method of claim 30, wherein the albuterol is in the form of a racemic mixture.

34. The method of claim 30, wherein the osmotic adjusting agent is selected from the group consisting of sodium chloride, potassium chloride, zinc chloride, calcium chloride and mixtures thereof.

35. The method of claim 30, wherein the osmotic agent is sodium chloride.

36. The method of claim 30, wherein the osmotic adjusting agent is selected from the group consisting of mannitol, glycerol, dextrose and mixtures thereof.

37. The method of claim 30, wherein the inhalation solution in the one or more dispensing containers comprises about 0.4 wt. % to about 1.0 wt. % ionic salt.

38. The method of claim 30, wherein the inhalation solution in the one or more dispensing containers comprises about 0.9% of an osmotic adjusting agent.

39. The method of claim 30, further comprising the step of. packaging the one or more dispensing containers in an aluminum foil pouch.

40. The method of claim 30, wherein the sterilizing filter is a 0.2 micron sterilizing cartridge filter.

41. The method of claim 30, further comprising the step of passing the inhalation solution through a second sterilizing filter.

42. The method of claim 41, wherein the second sterilizing filter is a 0.2 micron sterilizing cartridge.

43. A method of making an inhalation solution according to claim 1, said method comprising the steps:
a) adding purified water into a stainless steel tank at a temperature of between 18°C to 25 °C;
b) while mixing, adding an acid, an osmotic adjusting agent, and at least a therapeutically effective amount of albuterol sulfate and ipratropium bromide to the tank until dissolved, thus forming the inhalation solution; and c) filling each of the dispensing containers with about 3 ml of the inhalation solution such that each container contains a sterile, unit dose of albuterol and ipratropium bromide.

44. The method of claim 43, wherein the albuterol is in the form of an acid addition salt thereof.

45. The method of claim 44, wherein the acid addition salt of albuterol is albuterol sulfate.

46. The method of claim 43, wherein the albuterol is in the form of a racemic mixture.

47. The method of claim 43, wherein the osmotic adjusting agent is selected from the group consisting of sodium chloride, potassium chloride, zinc chloride, calcium chloride and mixtures thereof.

48. The method of claim 43, wherein the osmotic adjusting agent is sodium chloride.

49. The method of claim 43, wherein the osmotic adjusting agent is selected from the group consisting of mannitol, glycerol, dextrose and mixtures thereof.

50. The method of claim 43, wherein step b) further comprises adding EDTA.

51. The method of claim 43, wherein the acid comprises hydrochloric acid.

52. The method of claim 43, further comprising, after step b), adding an additional volume of purified water to adjust the final concentration of the albuterol sulfate and the ipratropium bromide in the inhalation solution.

53. The method of claim 43, wherein the final concentration of the albuterol sulfate in the inhalation solution ranges from about 0.06 wt. % to about 0.1 wt. %.

54. The method of claim 43, wherein the final concentration of the ipratropium bromide in the inhalation solution ranges from about 0.03 wt. % to about 0.1 wt. % ipratropium.

55. The method of claim 43, wherein the acid is added in an amount such that the pH of the inhalation solution is about 3.0 to about 4Ø

56. The method of claim 43, wherein osmotic adjusting agent is added in an amount such that the isotonicity of the inhalation solution is about 280 to about 320 mOsm/kg.

57. The method of claim 43, further comprising, prior to step c), passing the inhalation solution through a 0.2 micron sterilizing cartridge filter.

58. The method of claim 57, further comprising passing the inhalation solution through a second 0.2 micron sterilizing cartridge filter.

59. The method of claim 58, wherein the second cartridge filter is connected to at least one filling nozzle positioned within a sterile air shower compartment.

60. The method of claim 43, wherein said filling step comprises passing the inhalation solution through a filling nozzle into one or more preformed low density polyethylene dispensing containers.

61. The method of claim 43, wherein the inhalation solution comprises about 0.4 wt. % to about 1.0 wt. % ionic salt.

62. The method of claim 43, wherein the inhalation solution comprises about 0.9 wt. % of an osmotic adjusting agent.

63. The method of claim 43, further comprising, after step c), sterile sealing each of the dispensing containers containing the inhalation solution.

64. The method of claim 43, wherein the dispensing containers are formed, filled with the inhalation solution, and sealed, said forming, filling, and sealing being performed in one continuous operation.

65. The method of claim 43, further comprising packaging the dispensing containers in an aluminum foil pouch.

66. A prepackaged therapeutic system for inducing bronchodilation or providing relief of bronchospasm in a patient suffering from chronic obstructive pulmonary disease, the prepackaged therapeutic system comprising:
a) one or more dispensing containers, each prefilled with about 3 ml of an inhalation solution according to claim 1, and (b) one or more labels with indicia thereon, the indicia comprising efficacy dosage, administration, contraindication and adverse reaction data pertaining to the inhalation solution in each of the one or more containers.

67. The prepackaged therapeutic system of claim 66, wherein the albuterol is in the form of an acid addition salt.

68. The prepackaged therapeutic system of claim 67, wherein the acid addition salt of the albuterol is albuterol sulfate.

69. The prepackaged therapeutic system of claim 66, wherein the contraindication data comprises data indicating that the inhalation solution in each of the one or more containers is contraindicated for humans with hypersensitivity to atropine and derivatives thereof.

70. The prepackaged therapeutic system of claim 66, wherein the dosage and administration data comprises data indicating that the recommended dose of the inhalation solution in each of the one or more containers is about 2.5 mg of albuterol and about 0.5 mg impratropium bromide in 3 ml of an aqueous solution administered 4 times per day by nebulization with up to 2 additional recommended doses allowed per day, if needed.

71. The prepackaged therapeutic system of claim 66, wherein the adverse reaction data comprises data indicating that precipitation or worsening of conditions may occur after administrating the inhalation solution, said conditions selected from the group consisting of narrow-angle glaucoma, acute eye pain, blurred vision, paradoxical bronchospasm, wheezing, exacerbation of chronic obstructive pulmonary disease symptoms, drowsiness, aching, flushing, upper respiratory tract infection, palpitations, taste perversion, elevated heart rate, sinusitis, back pain, and sore throat.

72. A prepackaged therapeutic system for treating bronchospasm in a patient suffering from chronic obstructive pulmonary disease, said prepackaged therapeutic system comprising:
(a) one or more dispensing containers; the one more containers each prefilled with 3 ml of an inhalation solution consisting of sodium chloride, water, edetate disodium, an acid to adjust the pH of the inhalation solution to about 4, and a unit dose of a therapeutically effective amount of albuterol and ipratropium bromide, wherein the amount of albuterol is about 2.50 mg and the amount of ipratropium bromide is about 0.5 mg; wherein the inhalation solution in the one or more dispensing containers is sterile and free of antimicrobial preservative yet has a relatively long period of stability such that after storage for 12 months at a temperature of 25 °C, greater than 95% of the albuterol and greater than 95% of the ipratropium bromide originally present in the solution still remains in the solution; and (b) one or more labels with indicia thereon; the indicia comprising efficacy, dosage, administration, contraindication and adverse reaction information pertaining to the inhalation solution in each of the one or more containers;
wherein:
(i) the dosage and administration data comprises data indicating that the recommended dose of the inhalation solution in each of the one or more containers is about 2.5 mg of albuterol and about 0.5 mg impratropium bromide in 3 ml of an aqueous solution administered 4 times per day by nebulization with up to 2 additional recommended doses allowed per day, if needed;
(ii) the contraindication data comprises data indicating that the inhalation solution in each of the one or more containers is contraindicated for humans with hypersensitivity to atropine and derivatives thereof;

(iii) the adverse reaction data comprises data indicating that immediate hypersensitivity reactions to the inhalation solution in each of the one or more containers may occur after administrating the inhalation solution, said hypersensitivity reaction including urticaris, angioedema, rash, pruritis, oropharyngeal, edema, bronchospasm, and anaphylaxis;
(iv) the adverse reaction data comprises data indicating that allergic-type reactions may occur after administrating the inhalation solution in the one or more containers; said allergic type reaction, including skin rash, prurities, and urticaria;
(v) the adverse reaction data comprises data indicating that precipitation or worsening of a condition may occur after administrating the inhalation solution, said condition selected from the group consisting of narrow-angle glaucoma, acute eye pain, blurred vision, paradoxical bronchospasm, wheezing, exacerbation of chronic obstructive pulmonary disease symptoms, drowsiness, aching, flushing, upper respiratory tract infection, palpitations, taste perversion, elevated heart rate, sinusitis, back pain, and sore;
and (vi) the adverse reaction data includes a list of one or more adverse events that may occur after administration of the inhalation solution, adverse event being selected from the group consisting of chest pain, diarrhea, dyspepsia, nausea, leg cramps, bronchitis, lung disease, pharyngitis, pneumonia, and urinary tract infection.