NZ550304A - An antimicrobial preservative-free albuterol inhalation solution for the relief of bronchospasm in children with asthma - Google Patents

Abstract

Disclosed is an albuterol inhalation solution, system, kit and method for relieving bronchospasm in children suffering from asthma. In one alternative embodiment, the solution of disclosed is a sterile, premixed, premeasured single unit dose of albuterol for asthmatic patients 2 to 12 years of age. The present solution may be free of anti-microbial preservatives, such as benzalkonium chloride. In another alternative embodiment, the solution comprises about 0.63 mg or about 1.25 mg albuterol.

Description

*10052659320* 55 03 0 4 NEW ZEALAND PATENTS ACT, 1953 No: Divided out of NZ 532974 Date: Dated 18 October 2002 COMPLETE SPECIFICATION ALBUTEROL INHALATION SOLUTION, SYSTEM, KIT AND METHOD FOR RELIEVING SYMPTOMS OF PEDIATRIC ASTHMA We, DEY, L.P., of 2751 Napa Valley Corporation Drive, Napa, California 94558, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by la) INTELLECTUAL PROPERTY OFFICE OF NZ 0 4 OCT 2006 RF<"!FI\/Fn ALBUTEROL INHALATION SOLUTION, SYSTEM, KIT AND METHOD FOR RELIEVING SYMPTOMS OF PEDIATRIC ASTHMA L CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority from: U.S. Application Serial No. 10/034,829, filed December 27,2001; U.S. Provisional Application Serial No. 60/348,203 filed October 26, 2001; Australian Patent Application No. 32975/02 filed April 5, 2002; and Japanese Patent Application No. 2002-145456 filed April 11,2002. The entire disclosure of these prior applications are incorporated herein by reference in their entirety.

II. FIELD OF INVENTION The present invention relates to an albuterol inhalation solution, system and kit. A method for relieving symptoms associated with asthma in children is described herein.

III. BACKGROUND OF INVENTION Asthma is a pulmonary disease marked by (I) labored breathing; (2) wheezing; and (3) coughing. Asthma is characterized by: (1) airway inflammation; (2) airway hypenresponsiveness; and (3) airway obstruction (or airway narrowing) that is partially or completely reversible, either spontaneously or with treatment. Common symptoms of asthma include wheezing, shortness of breath, tightness in 1he chest and a persistent cough. The severity of the symptoms vary widely from patient to patient, and even from one episode (attack) to the next.

A key condition of asthma is chronic inflammation of the linings of the lungs. This inflammation is associated with an increase in airway sensitivity (hyperresponsiveness) to stimuli such as allergens, irritants, cold air and viruses. When exposed to these triggers, the linings undergo an allergic reaction, causing spasms that constrict the airways. This la (followed by 2) intellectual property office of n.z 2 7 MAR 2008 rfp.eived bronchoconstriction, in combination with edema and the release of thickened secretions, reduces movement of air through the lungs, resulting in the symptoms commonly associated with asthma.

Asthma is the most common chronic lung disease in children. Asthma prevalence in children has reportedly increased in the United States by 160%. Asthma hospitalization rates are also higher in young children due, in part, to difficulties in using currently available drug delivery devices and failure to use optimal doses of asthma therapies.

Despite progress in emergency and critical care medicine, the pediatric mortality rate from asthma ranges from 0.2 to 0.4 per 100,00 population, depending on age. Pediatric asthma ranks as the 7th leading cause of death among children ages 10 to 14 years. Approximately 0.05% of known children with asthma die annually from the disease.

Short-acting inhaled beta-agonists, such as albuterol, are the first choice treatment for relieving symptoms of acute asthma in children. Albuterol is currently available as a 2.5 mg unit dose (0.083%) inhalation solution for use in nebulizers. Although this dose has been approved for use by adults, the FDA has recently expanded labeling guidelines to include this amount of albuterol for use by pediatric asthmatic patients as young as 2 years old. However, when administered on a regular basis to a child, the 2.5 mg formulation may provide more albuterol than needed, thereby increasing the risk of adverse drug effects.

In the recently revised guidelines for asthma treatment, the National Institutes of Health recommended that pediatric patients use the lowest beta-agonist doses needed to control symptoms. However, using lower doses of albuterol in patients under age 12 to reduce the risk of side effects necessitates dilution of currently available asthma medications. This poses several problems because parents, care givers, teachers and others typically do not have adequate experience diluting these medications, resulting in contamination or inappropriate dosing, among other problems.

Also, antimicrobial preservatives, such as benzalkonium chloride (BAC), are often present in inhalation solutions used to treat asthma and chronic obstructive pulmonary disease (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 asthma treatments with BAC may result in paradoxic bronchoconstriction. When inhaled by asthmatic subjects, BAC may also cause dose-dependent bronchoconstriction. Despite these side effects, many commercially available albuterol inhalation solutions contain BAC.

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

IV. SUMMARY OF THE INVENTION One object of the present invention is to provide an albuterol inhalation solution for the relief of bronchospasm in children with asthma; and/or to provide a prepackaged, sterile, premixed, premeasured, reduced-dosage albuterol inhalation solution for the relief of bronchospan in patients 2 to 12 years of age with asthma; and/or to provide an antimicrobial preservative-free albuterol inhalation solution to relieve bronchospan in a pediatric patient with asthma; and/or to provide a kit or system for relief of bronchospan in a pediatric patient with asthma; and/or 3 intellectual property office of n.z. 2 7 MAR 2008 to provide a process for making an inhalation solution for relief of bronchospasm in a pediatric patient with asthma; and/or to at least provide the public with a useful choice.

In a first aspect, the present invention provides a pediatric inhalation solution comprising: a premixed, premeasured aqueous formulation comprising a single unit dose of an active ingredient consisting essentially of racemic albuterol sulfate in a therapeutically effective pediatric amount for inducing bronchodilation or providing relief of bronchospasm in a child 2-12 years of age-suffering from asthma, wherein the amount of racemic albuterol sulfate in the inhalation solution ranges from about 0.08 mg to about 1.90 mg; 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 active ingredient originally present in the solution still remains in the solution.

In a further aspect, the present invention provides use of an aqueous formulation for the manufacture of a premixed, premeasured medicament for inducing bronchodilation or providing relief of bronchospasm in a child 2-12 years of age suffering from asthma; wherein the formulation comprises an active ingredient consisting essentially of racemic albuterol sulfate in a therapeutically effective pediatric amount of about 0.08 mg 10 about 1.90 mg; and wherein the medicament 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 active ingredient originally present in the medicament still remains in the medicament.

In a yet further aspect, the present invention provides a kit for relieving bronchospasm in a child 2-12 years of age suffering from asthma, said kit comprising: one or more single dispensing containers, each comprising a premixed, premeasured aqueous inhalation solution comprising a single unit dose of an active ingredient consisting essentially of racemic albuterol sulfate in a therapeutically effective pediatric amount of about 0.08 mg to about 1.90 mg; wherein the solution i$ nebulizable in a nebulizer; and 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 active ingredient originally 4 (followed by 4a) intellectual property office of n.2 27 MAR 2008 DFrci\/f n present in the solution still remains in the solution.

In another aspect, the present invention provides a method of making a premixed, premeasured inhalation solution for relieving bronchospasm in a child 2-12 years of age suffering from asthma, said solution provided in single containers, each comprising a single unit dose of said solution; said method comprising the steps: (a) preparing the inhalation solution by a method comprising: (i) filling a tank with a defined volume of purified water at a temperature of between 18 °C and 25 °C while mixing; (ii) adding to the water an acid, an osmotic adjusting agent, and a therapeutically effective pediatric amount of an active ingredient consisting essentially of racemic albuterol sulfate to form the inhalation solution such that a unit dose of said solution comprises 0.08 mg to 1.90 mg of said racemic albuterol sulfate; (iii) mixing to complete dissolution; and (iv) optionally adding an additional amount of purified water to said solution; and (b) providing the inhalation solution in single container vials such that each vial contains racemic albuterol sulfate in single unit dose of a therapeutically effective pediatric amount of 0.08 mg to 1.90 mg.

In another aspect, the present invention provides a prepackaged therapeutic system for inducing bronchodilation in a child suffering from asthma, the prepackaged therapeutic system comprising: (a) one or more dispensing containers; each prefilled with about 3 ml of a premixed, premeasured aqueous inhalation solution comprising a unit dose of an active ingredient consisting essentially of racemic albuterol sulfate in a therapeutically effective pediatric amount of about 0.08 mg to about 1.90 mg; wherein the inhalation solution in each of the one or more containers is nebulizable in a nebulizer; and wherein the inhalation solution in each of the one or more 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 active ingredient originally present in the solution still remains in the solution; and (b) indicia comprising indication, adverse reaction, dosage and administration data pertaining to the inhalation solution 4a (followed by 4b) intellectual property office of n.z. 2 7 MAR 2008 received in each of the one or more containers.

In another aspect, the present invention provides a premixed, premeasured inhalation solution, when made by a method of the invention.

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.

The term "comprising" as used in this specification means "consisting at least in part of'. When interpreting each statement in this specification that includes the term "comprising", features other than that or those prefaced by the term may also be present. Related terms such as "comprise" and "comprises" are to be interpreted in the same manner.

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 described herein.

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 pediatric asthma. 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 pediatric patients, including, but not limited to, all tautomeric forms, enantomeric forms, stereoisomers, anhydrides, acid addition salts, base salts, solvates, analogues and derivatives of albuterol. 4b (followed by 5) intellectual property office of n.2 2 7 MAR 2008 RECtlv r D In the present invention, acceptable salts of albuterol may include, but are not limited to, hydrochloride, sulfate, maleate, tartrate, citrate and the like. These and other acceptable salts are described in U.S. Patent No. 3,644,353, which is incorporated herein by reference in its entirety.

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. Albuterol sulfate is a relatively selective beta-2-adrenergic bronchodilator with an empirical formula of C13H21NO3. Hie chemical name for albuterol sulfate is a1-l(tert- butylamino)methyl]-4-hydroxy-w-xylene-a, a'-diol sulfate (2:lXsalt), and its established chemical structure is as follows: In the present invention, the albuterol 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 pediatric amount of albuterol. As used herein the phrase "therapeutically effective pediatric amount of albuterol" means a safe and tolerable amount of albuterol for pediatric patients, as based on industry and/or regulatory standards. Such amount being sufficient to effectively induce bronchodilation and/or provide relief of bronchospasm in children.

In the inhalation solution of the present invention, a therapeutically effective pediatric amount of albuterol may include about 0.63 mg or about 1.25 mg albuterol. Here, the potency of the albuterol is equivalent to about 0.75 mg and about 1.50 mg of albuterol sulfate, respectively. In an alternative embodiment, a therapeutically effective pediatric amount of albuterol may include from about 0.63 mg to about 1.25 mg of albuterol. In another alternative embodiment, such pediatric amount comprises no more than about 1.25 mg of albuterol, or it comprises 1.25 mg of albuterol or less.

In another alternative embodiment of the present invention, a therapeutically effective pediatric amount of albuterol may include from about 0.08 mg to about 1.90 mg albuterol, including the following intennediate amounts of albuterol: about 0.08 mg to about 0.20 mg; about 0.21 mg to about 0.50 mg; about 0.51 mg to about 0.60 mg; about 0.61 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 1.0 mg; about 1.01 mgto about 1.05 mg; about 1.06 mg to about 1.10 mg; about 1.11 mg to about 1.15 mg; about 1.16 mg to about 1.20 mg; about 1.21 mg to about 1.25 mg; about 1.26 mg to about 1.30 mg; about 1.31 mg to about 1.35 mg; about 1.36 mg to about 1.40 mg; about 1.41 mg to about 1.45 mg; about 1.46 mg to about 1.50 mg; about 1.51 mg to about 1.55 mg; about 1.56 mg to about 1.60 mg; about 1.61 mg to about 1.65 mg; about 1.66 mg to about 1.70 mg; about 1.71 mg to about 1.75 mg; about 1.76 mg to about 1.80 mg; about 1.81 mg to about 1.85 mg; about 1.86 mgto about 1.90 mg.

In another alternative embodiment of the present invention, a therapeutically effective pediatric amount of albuterol may include from about 0.1 mg to about 2.5 mg albuterol sulfate, including the following intermediate amounts of albuterol sulfate: about 0.1 mg to about 0.2 mg; about 0.3 mg to about 0.4 mg; about 0.5 mg to about 0.6 mg; about 0.7 mg to about 0.8 mg; about 0.9 mg to about 1.00 mg; about 1.01 mgto about 1.20 mg; about 1.21 mg to about 1.40 mg; about 1.41 mg to about 1.60 mg; about 1.61 mg to about 1.80 mg; about 1.81 mg to about 2.00 mg; about 2.01 mg to about 2.20 mg, about 2.21 mg to about 2.40 mg; about 2.41 mg to about 2.50 mg.

In another alternative embodiment of the present invention, a therapeutically effective pediatric amount of albuterol may include from about 0.002 % to about 0.075 % by weight albuterol, including the following intermediate amounts of albuterol: about 0.002 wt % to about 0.010 wt %; about 0.011 wt % to about 0.020 wt %; about 0.021 wt % to about 0.030 wt %; about 0.031 wt % to about 0.040 wt %; about 0.041 wt % to about 0.050 wt %; about 0.051 wt % to about 0.060 wt %; about 0.061 wt % to about 0.070 wt %; about 0.071 wt % to about 0.075 wt %.

In another alternative embodiment of the present invention, a therapeutically effective pediatric amount of albuterol may include from about 0.003 % to about 0.1 % by weight albuterol sulfate in solution, including the following intennediate amounts of albuterol sulfate: about 0.003 wt % to about 0.010 wt %; about 0.011 wt % to about 0.020 wt %; about 0.021 wt % to about 0.030 wt %; about 0.031 wt % to about 0.040 wt %; about 0.041 wt % to about 0.050 wt %; about 0.051 wt % to about 0.060 wt %; about 0.061 wt % to about 0.070 wt %; about 0.071 wt % to about 0.080 wt %; about 0.081 wt % to about 0.090 wt %; about 0.091 wt % to about 0.10 wt %. 7 Most pharmaceutical inhalation solutions contain an antimicrobial preservative such as BAC or EDTA. One problem with BAC-containing 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 asthmatic patients, the BAC can cause dose-dependent bronchoconstriction. Hie inhalation solution of the present invention may be provided without BAC, thereby making it more suitable for pediatric patents, especially in an emergency situation where the inhalation solution is administered repeatedly over a short period of time. Also, administering a B AC-firee inhalation solution to a pediatric 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 pediatric amount of albuterol) provides a stable pediatric inhalation solution such that the formulation can be stored (e.g., on a shelf) for long periods of time.

Table 1 Stability Data 0.021 wt % Albuterol 0.042 wt % Albuterol Assay* pH Osmolality (mOsm/kg) Assay* pH Osmolality (mOsm/kg) Time zero 98 3.5 289 100 3.5 291 °C/35%RH 12 months 99 3.5 289 100 3.5 291 24 months 101 3.5 294 100 3.5 292 40°C/15%RH 3 months 99 3.6 290 100 3.6 291 6.5 months 96 3.5 290 99 3.5 292 * as percent of label c aim (0.021 I wt % and 0.042 wt % albutero , respectively). 8 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.

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, i.e., Albuterol, 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 ingredient 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 the compositions 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 overtime, as shown in Table 2 below.

TABLE2 Degradation products/related compounds as % of albuterol Range at 6 to 18 months at 25°C Range in drug substance 1 -2-((l,l-Dimethylethyl)amino-l-hydroxyethyl)-2-hydroxybenzaldehyde ND-0.012% w/w 2 Bis-(2-hydroxy0-5-(2-tertbutylamino-l-hydroxyethyl)phenylmethyl ether 0.09-0.174% w/w 3 2-tert-butylamino-l-(4-hydroxy-3-methoxymethylphenyl)-ethanol 0.01-0.12% w/w 4 Tert-butylanuno-3-chloro-4-hydroxy-5-hydroxymethylacetophenone ND-0.0002% w/w Tert-butylamino-4-hydroxy-5-hydroxymethylacetophenone ND-0.002% w/w 6 l-(4-hydroxy-3-methylphenyl)-2-(tert-butylamino) ethanol 0.0009-0.036% w/w 7 l-(5-chloro-4-hydroxy-3-hydroxymethylphenyl)-2-(tert-butylamino) ethanol ND 8 Any other unknown ND - 0.06% by peak area 9 Total 0.1-0.38% ND=none detected In one embodiment, the compositions produced herein are at least substantially clear, based on color measurement tests set forth by the America Public Health Association ("APHA"). For example, the APHA color results for compositions herein at upto 24 months at 25°C may range from less than 10 units, or preferably 0 to 5 units, most preferably 0 units as based on APHA standards.

In one embodiment, the process of the present invention provides compositions having an albuterol content of about 0.021% or 0.042% per vial. In another alternative embodiment, the process of the present invention provides compositions having an albuterol content of about 0.0197% to about 0.0218%w/v, about 0.0201% to about 0.0214% w/v, about 0.0394% to about 0.0436% w/v and about 0.0403% to about 0.0428% w/v per vial. In yet another alternative embodiment, the process of the present invention provides an average fill volume of about 2.80 ml to about 3.30 ml into each vial.

In another alternative embodiment, the process of the present invention provides compositions that may contain minimal amounts of contaminants including, but not limited to the following: TABLE 3 1. Volatiles acetone none detected to about NMT 0.2 mcg/ml ethyl acetate none detected to about NMT 0.3 mcg/ml n-heptane none detected to about NMT 0.1 mcg/ml or less n-propyl acetate none detected to about NMT 0.3 mcg/ml toluene none detected to about NMT O.lmcg/ml 2-butanone none detected to about NMT 0.3mcg/ml unknowns 2. Leachables Irganox 129 none detect to about NMT 0.02mcg/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, such compositions may also contain minimal amounts of particulate matter, including, but not limited to the following: about NMT1000 to 5000 particles, preferably about NMT 3800 particles/vial >2mm; about NMT 10 to about 100 particles, preferably about 80 particles/vial >10mcm; or about NMT 1 to about 5 particles, preferably about NMT 3 particles/vial >25mcm. 11 Adherence to asthma medication therapy and prevention of asthma medication error are considerable problems. These problems can be significantly reduced by providing asthmatic patients a prepackaged, premixed, premeasured amount of albuterol. Providing albuterol in this fashion makes asthma therapy simple because it increases convenience and eliminates confusion in preparing appropriate dosages. These advantages are especially significant in the treatment of pediatric asthma, where treatments often come in multiple dosage units and must be diluted to specific concentrations suitable for treating a pediatric patient. This poses several problems. For instance, asthma 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 asthma treatment may be hard to follow or can be easily lost. Of even greater importance is haphazard diluting or mixing of asthma medications, which can result in administering the wrong dosage. This could be especially harmful for pediatric patients, who often are less tolerant to higher dosages of albuterol. 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.

The present invention overcomes the aforementioned problems by providing therapeutically effective pediatric amounts of albuterol 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 pediatric amount of albuterol for the relief of bronchospasm associated with pediatric asthma. Providing the inhalation solution in such a manner eliminates the need to dilute or mix asthma medications to obtain proper dosages for treatment Also, no special pharmacy compounding is required, 12 and the chance of medication errors are reduced. 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 relieving bronchospasm in children. While the level of compliance of any asthma treatment depends in part on the motivation and skill of the individual dispensing the treatment, compliance nevertheless may be improved by controllable 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 relieving bronchospasm in children, and clearly represents an improvement over traditional asthma 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 pediatric amount of albuterol for the relief of bronchospasm in children. Said containers may be utilized in a method of relieving such bronchospasm, or the containers may be incorporated in a system and/or kit for treating the same.

In one alternative embodiment, the formulation of the present invention is a sterile, premixed, premeasured, BAC-free inhalation solution comprising a single unit dose of a therapeutically effective pediatric amount of albuterol in a single container. Each unit dose container comprises either 0.75 mg/3 ml of albuterol sulfate (equivalent to 0.63 mg of albuterol) or 1.50 mg/3 ml of albuterol sulfate (equivalent to 1.25 mg of albuterol) in a sterile, aqueous solution. Sodium chloride may be added to adjust the isotonicity of the solution and 13 sulfuric acid may be added to adjust pH of the solution to about 3.5. 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 0.75 mg/3 ml to about 1.50 mg/3 ml of albuterol sulfate (equivalent to about 0.63 mg to about 1.25 mg of albuterol, respectively). 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 inhalation solution for relieving bronchospasm in a pediatric patient with asthma, including, but not limited to, allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, occupational asthma and aspirin sensitive asthma. The present invention also provides an albuterol inhalation solution for relieving bronchospasm associated with different classes of pediatric asthma including, but not limited to, severe persistent asthma, moderate persistent asthma, mild persistent asthma and mild intermittent asthma. Some characteristics associated with the different classes of asthma 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. 14 Table 4 Type of Asthma Description Severe Persistent • Continual symptoms during the day; • Frequent symptoms at night; • 60% of lower predicted values for DEV; and >60% or lower of personal best PEF, and more than 30% PEF variability.

Moderate Persistent • Some symptoms every day; • Nighttime symptoms five or more nights a month; and >60% and <80% of PEF or FEV! and greater than 30% FEVi variability.

Mild Persistent • Daytime symptoms 3-6 days a week; • Symptoms at night 3-4 times a month; and 80% or higher PEF or FEYi and PEF variability of 20-30%.

Mild Intermittent • Daytime symptoms 2 or fewer times a week; • Nighttime symptoms 2 or fewer times a month; and 80% or higher PEF or FEV! and PEF variability <20%.

In the present invention, a therapeutically effective pediatric amount of albuterol is administered to induce bronchodilation and/or provide relief of bronchospasm in pediatric patients with asthma. Such amount of albuterol may be administered to a pediatric patient after the onset of bronchospasm to reduce breathing difficulties resulting from asthma. In another embodiment, the albuterol may be administered prophylactically, that is, to prevent or to reduce the extent of bronchospasm.

The quantity of albuterol 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 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 0.63 mg to about 1,25 mg of albuterol given by nebulization one or more times per day would be adequate to produce the desired bronchodilation effect in most children.

In an alternative embodiment, the inhalation solution of the present invention provides relief of bronchospasm in patients 2 to 12 years of age. For example, a 0.63 mg unit dose of albuterol inhalation solution is effective for children ages 10 years and younger, children weighing < 40 kg or children with less severe asthma. A 1.25 mg unit dose of albuterol is effective for prolonged use in children ages 11-12 years, children weighing > 40 kg or in children with more severe asthma.

Further, the albuterol 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 pediatric amount of albuterol. The albuterol 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 pediatric amount of albuterol, alone or in combination with another drug(s), may be administered to a pediatric individual periodically as necessary to reduce symptoms of asthma.

In an alternative embodiment of the present invention, relief of severe persistent asthma may include administration of a therapeutically effective pediatric amount of albuterol for quick relief of symptoms and a high dose of inhaled corticosteroids using a spacer or holding chamber with a face mask. If needed, oral corticosteroids (2mg/kg/day) may be administered. Oral corticosteroid should be reduced to the lowest daily or alternate-day dose that stabilizes symptoms. 16 For moderate persistent asthma, treatment may include administering therapeutically effective pediatric amounts of albuterol for quick relief of symptoms and an inhaled corticosteroid at a mid-level dose, delivered using a spacer or holding chamber with a facemask. As symptom control is achieved, the inhaled corticosteroid dose may be lowered, and either inhaled nedocromil or theophylline may be added.

For mild persistent asthma, treatment may include administering therapeutically effective pediatric amount(s) of the present formulation for quick relief of symptoms and daily anti-inflammatory medication such as low-dose inhaled corticosteroid using a spacer or holding chamber with a facemask or a trial of cromolyn by nebulizer or nedocromily by MDI. For mild intermittent asthma, aside from administering a therapeutically effective pediatric amount of albuterol, no daily drug therapy is ordinarily required.

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, Ihe 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.

In an alternative embodiment, the system and/or kit of the present invention comprises an inhalation solution comprising a therapeutically effective pediatric amount of albuterol in a prepackaged, premeasured, premixed and/or single unit dose form for the relief of bronchospasm in children. The inhalation solution may be sterile and/or antimicrobial preservative-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 comprising a single unit dose of a 17 therapeutically effective pediatric amount of albuterol. 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, for example, LDPE. The container may also comprise a Twist-Flex™ 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-Flex™ 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 Ihe top, or the like, thereby reducing cross-contamination. One or more of the semi-permeable single unit dose containers may be disposed in a sealed 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 Ihe inhalation solution.

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

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 pediatric amount of albuterol for the relief of bronchospasm associated with pediatric asthma, and instructions for using the same.

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 18 vials. For example, an embodiment of a unified prepackaged system and/or kit for relieving bronchospasm in children is depicted in Figure 5. Specifically, Figure 5 depicts a support package, box, carton or container (10) 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 pediatric amount of albuterol for relieving bronchospasm in a child suffering from asthma. The inhalation solution may be provided in sterile and/or antimicrobial preservative-free form.

Support package, box, carton or container (10) may 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 bronchospasm in children. The label may also comprise indicia (15) which provides instructions for using the inhalation solution to relieve bronchospasm in children. 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 the support package, box, carton or container (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 pediatric amount of albuterol. The packaging material may further comprise a label indicating that each vial can be used with each 19 nebulizer treatment for the relief of bronchospasm associated with pediatric asthma. 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, or the instructions may be provided on a separate sheet, or any combination thereof.

In an alternative embodiment, the present invention is directed to a prepackaged therapeutic system and/a kit for inducing bronchodilation in a child suffering from asthma, 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, benzalkonium chloride-free, premixed, premeasured aqueous inhalation solution comprising a unit dose of a therapeutically effective pediatric amount of racemic albuterol; wherein the dosage of racemic albuterol is about 0.63 or about 1.25 mg; the inhalation solution in each of the one or more containers is suitable for nebulization in a nebulizer; wherein the inhalation solution in each of the one or more containers has a long shelf life; (b) indicia comprising indication, adverse reaction, dosage and administration data pertaining to the inhalation solution in each of the one or more containers; (c) wherein the indication data comprises data that the inhalation solution in each of the one or more containers is indicated for the relief of bronchospasm in patients 2 to 12 years of age with asthma; and (d) wherein the adverse reaction data comprises data indicating that otitis media and skin-appendage infection might occur after administering the inhalation solution in the one or more containers.

In another alternative embodiment, the prepackaged therapeutic system of the present invention comprises data that the dosage for patients 2 to 12 years of age is 0.63 mg or 1.25 mg of albuterol administered 3 to 4 times daily by nebulization over 5 to 15 minutes. Also, the adverse reaction data may include a list of one or more preprinted adverse events that may occur after administering the inhalation solution in each of the one or more containers, the adverse events comprising asthma exacerbation, allergic reaction, gastroenteritis, flu syndrome, lymphadenopathy, urticaria, migraine, chest pain, bronchitis or nausea.

In another alternative embodiment, the prepackaged therapeutic system and/a kit is adapted to induce bronchodilation in a child suffering from asthma, the prepackaged therapeutic system may comprise: (a) one or more dispensing containers; the one or more containers each prefilled with about 3 ml of a sterile, stable, benzalkonium chloride-free, premixed, premeasured aqueous inhalation solution consisting essentially of a unit dose of a therapeutically effective pediatric amount of racemic albuterol; wherein the dosage of racemic albuterol is about 0.63 or about 1.25 mg; wherein the racemic albuterol is in the form of an acid addition salt; wherein the acid addition salt is albuterol sulfate; the inhalation solution in each of the one or more containers is suitable for nebulization in a nebulizer; wherein the inhalation solution in each of the one or more containers has a long shelf life; (b) indicia comprising indication, adverse reaction, and dosage and administration data pertaining to the inhalation solution in each of the one or more containers; 21 (c) wherein the indication data comprises data that ihe inhalation solution in each of the one or more containers is indicated for the relief of bronchospasm in patients 2 to 12 years of age with asthma; (d) wherein the adverse reaction data comprises a list of preprinted adverse events that may occur after administering the inhalation solution in each of the one or more containers; the adverse events comprising otitis media, skin-appendage infection, asthma exacerbation, allergic reaction, gastroenteritis, flu syndrome, lymphadenopathy, urticaria, migraine, chest pain, bronchitis or nausea; and (e) wherein the dosage and administration data comprises data that the dosage for patients 2 to 12 years of age is 0.63 mg or 1.25 mg of albuterol administered 3 to 4 times daily by nebulization over 5 to 15 minutes.

Described herein is a method of treating bronchospasm associated with pediatric asthma, wherein albuterol is administered as a unit dose from about 0.63 mg to about 1.25 mg of albuterol. Such unit dose may be in the form of a nebulizer solution.

In an alternative embodiment, the method described herein comprises the step of administering to a patient 2 to 12 years old in need thereof an inhalation solution comprising a therapeutically effective pediatric amount of albuterol. Such solution may comprise from about 0.63 mg to about 1.25 mg albuterol. Such solution may also be premixed, premeasured, antimicrobial preservative-free and/or sterile. Such solution may also be in a single unit dose vial.

In another alternative embodiment, the method described herein comprises the step of administering to a pediatric patient in need thereof an inhalation solution comprising a therapeutically effective pediatric amount of albuterol. The inhalation solution being 22 intellectual property office of n.z. 2 7 MAR 2008 received 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 described herein comprises the steps: (i) placing an inhalation solution comprising a therapeutically effective pediatric amount of albuterol (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 cup lid (4) to a mouthpiece (5) or facemask (6); (iii) drawing the albuterol solution 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 pediatric 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 2 to 12 years of age is about 1.25 mg or about 0.63 mg of albuterol administered 3 or 4 times daily, as needed by nebulization. To administer these amounts of albuterol, the entire contents of a one unit-dose vial (e.g., 1.50 mg/3 ml or 0.75 mg/3 ml albuterol sulfete) may be used by nebulization. Preferably, the nebulizer flow rate is adjusted to deliver the albuterol sulfete over 5 to 15 minutes. Patients 6 to 12 years of age with more severe asthma (baseline EEVi less than 60% predicated), weight >40kg or patients 11 to 12 years of age may achieve a better initial response with about a 1.25 mg dose.

Further, in an alternative embodiment, the method described herein comprises the steps: (i) preparing an inhalation solution comprising a therapeutically effective pediatric amount of albuterol solution by diluting one or more solutions comprising albuterol; and (ii) administering the inhalation solution to a pediatric patient in need thereof. 23 ntellectual property office of n.Z. 27 mar received Described herein is a method of inducing bronchodilation in a child suffering from asthma, said method comprising the step of: (a) providing the child or prescriber a prepackaged therapeutic system comprising: one or more dispensing containers; the one or more containers each prefilled with about 3 ml of a sterile, stable, benzalkonium chloride-free, premixed, premeasured aqueous inhalation solution comprising a unit dose of a therapeutically effective pediatric amount of racemic . albuterol; wherein the dosage of racemic albuterol is about 0.63 or about 1.25 mg; the inhalation solution in each of the one or more containers is suitable for nebulization in a nebulizer; wherein the inhalation solution in each of the one or more containers has a long shelf life; (b) providing the child or prescriber of the prepackaged therapeutic system indication, adverse reaction, dosage and administration data pertaining to the inhalation solution in each of the one or more containers; (c) wherein the indication data informs the patient or prescriber that the inhalation solution in each of the one or more containers is indicated for the relief of bronchospasm in patients 2 to 12 years of age with asthma; and (d) wherein the adverse reaction data informs the patient or prescriber that otitis media and skin-appendage infection might occur after administering Ihe inhalation solution in the one or more containers. 24 intellectual property office of n.z 2 7 MAR DFTFIVED In another alternative embodiment, the dosage and administration data informs the patient or prescriber that the dosage for children 2 to 12 years of age is 0.63 mg or 1.2S mg of albuterol administered 3 to 4 times daily by nebulization over 5 to 15 minutes. Also, in the adverse reaction data may include a list of one or more preprinted adverse events that may occur after administering the inhalation solution in each of the one or more containers, the adverse events comprising asthma exacerbation, allergic reaction, gastroenteritis, flu syndrome, lymphadenopathy, urticaria, migraine, chest pain, bronchitis or nausea.

In another embodiment, the method described herein is directed to inducing bronchodilation in a child suffering from asthma. Such method may comprise the step of: (a) providing the child or prescriber a prepackaged therapeutic system comprising: one or more dispensing containers; the one or more containers each prefilled with about 3 ml of a sterile, stable, benzalkonium chloride-free, premixed, premeasured aqueous inhalation solution consisting essentially of a unit dose of a therapeutically effective pediatric amount of racemic albuterol; wherein the dosage of racemic albuterol is about 0.63 or about 1.25 mg; wherein the racemic albuterol is in the form of an acid addition salt; wherein the acid addition salt is albuterol sulfate; the inhalation solution in each of the one or more containers is suitable for nebulization in a nebulizer; wherein the inhalation solution in each of the one or more containers has a long shelf life; intellectual property office of n.z. 2 7 MAR 2008 Dcrc l\/FD (b) providing the child or prescriber of the prepackaged therapeutic system indication, adverse reaction, dosage and administration data pertaining to the inhalation solution in each of the one or more containers; (c) wherein the indication data informs the patient or prescriber that the inhalation solution in each of the one or more containers is indicated for the relief of bronchospasm in patients 2 to 12 years of age with asthma; (d) wherein the adverse reaction data informs the patient or prescriber that otitis media, skin-appendage infection, asthma exacerbation, allergic reaction, gastroenteritis, flu syndrome, lymphadenopathy, urticaria, migraine, chest pain, bronchitis or nausea might occur after administering the inhalation solution in the one or more containers; and (e) wherein the dosage and administration data comprises data that informs the patient or prescriber that Ihe dosage for patients 2 to 12 years of age is 0.63 mg or 1.25 mg of albuterol administered 3 to 4 times daily by nebulization ova- 5 to 15 minutes.

The present invention also provides a process for making a sterile, premixed, premeasured, and/or BAC-free inhalation solution comprising a single unit dose of a therapeutically effective pediatric amount of albuterol. In such an embodiment, the process of the present invention comprises one or more of the following steps: (i) adding at least a therapeutically effective pediatric amount of albuterol in a vehicle, such as water; (ii) optionally sterilizing the solution and sealing the container. An osmotic adjusting agent may be added to adjust the isotonicity of the solution. In one embodiment of the present 26 intellectual property office of n.z. 27 MAR 2008 received invention, the solution of the present invention is isotonic. Isotonicity may be achieved by adding an osmotic adjusting agent to adjust the isotonicity of the solution from about 280 to about 320 mOsm/kg. In addition, an acid (e.g., sulfuric acid) may be added to adjust the pH of the solution to a level ranging from about 3.0 to about 4.0, preferably about 3.5.

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 pediatric amount of albuterol in a vehicle 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 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 pediatric amount of albuterol.

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 mixture 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 about 0.9 weight percent of an osmotic adjusting agent.

In an alternative embodiment, the inhalation solution of the present invention may be prepared as follows: (i) fitting a high density polyethylene (HDPE) or stainless steel formulation tank with a bottom drain and peristaltic recirculation system (for HDPE) or tri-blender (for stainless steel) for mixing; (ii) filling the tank with approximately 90% of the required amount of Purified Water USP at a temperature of between 18°C to 25°C; while mixing, (iii) adding sulfuric acid, Sodium Chloride USP, and at least a therapeutically 27 effective pediatric amount of Albuterol Sulfete USP 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 mixture.

From the formulation tank, the albuterol mixture is pumped through sanitary delivery lines directly into a form-fill-seal (FFS) machine. The albuterol mixture passes through a 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 mixture being sterile filled into the vials such that each vial contains a single unit dose ofa therapeutically effective amount of albuterol. The filled vials are then sealed. The 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) are overwrapped into a protective laminated foil pouch using an autowrapper machine. Five or twelve such pouches may then be packaged in a shelf carton, thus forming a prepackaged therapeutic system for relieving bronchospasm in children suffering from asthma. 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 an admixture containing a therapeutically effective pediatric amount of albuterol in a pharmaceutically acceptable vehicle.

Described herein is a device for use in the relief of bronchospasm associated with pediatric asthma. 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 bronchospasm can be treated with at least one prepackaged, sterile, premixed, premeasured and/or antimicrobial preservative-free inhalation solution comprising a unit dose of a therapeutically effective 28 intellectual property office of n.z. 2 7 MAR 2008 pediatric amount of albuterol in a single vial. The inhalation solution being suitable for nebulization in a nebulizer. The device also comprising indicia which provides instructions for utilizing the inhalation solution to relieve said bronchospasm in the patient.

Examples Patients were randomized to receive a nebulizer solution comprising either 0.63 mg/3 ml or 1.25 mg/3 ml of albuterol sulfate, or a placebo. The inhalation solution was administered via a Pari LC Plus™ nebulizer and a Pari PRONEB™ compressor. Both of these products are commercially available.

In this study, qualifying children ages 6 to 12 were randomized to receive 1 of the following three treatments twice daily (TD) for 4 weeks, each in 3.0 mL volume: (1) 1.25 mg albuterol sulfate inhalation solution; (2) 9.63 mg albuterol sulfate inhalation solution; or (3) placebo (saline). Each patient was provided with a personal compressor-driven PARI LC PLUS™ nebulizer, by Pari Respirator Equipment, Inc., Richmond, VA, for the duration of ttie study.

A screening visit was followed by a 2-week placebo run-in phase to confirm the need for regular symptomatic beta-agonist therapy, and to give patients experience with daily diaries and peak flow measurements, as well as to demonstrate compliance. The 4-week study period began with the initial dose, to be taken in the morning, administered at the study site. Pre-dose pulmonary function tests and pulmonary function tests 30 minutes after the end of nebulization and hourly thereafter for 6 hours were performed.

After 11 days, patients returned for exchange of study medication and diaries and pulmonary function tests before and 30 minutes after the morning dosing. After completing 28 days of treatment, patients returned to the test site for a repeat of the 6-hour evaluation of safety and efficacy following administration of study medication. Diaiy cards were used to 29 record asthma symptoms, night awakenings, peak flow measurements, supplemental albuterol use, change in medication and adverse events. The safely profiles of each unit dose mid placebo were determined by collecting vital signs (heart rate, blood pressure, respiration rate, and body temperature) as well as electrocardiograms.

Patients A total of 349 children (220 males and 129 females) were initially randomized, and 28$ completed the double-blind 4-week treatment period. Demographic and other baseline characteristics were comparable between the three treatment groups. To be eligible for enrollment, patients had to meet the criteria described in Table 3 below.

Table 5 Inclusion/Exclusion Criteria Design Element Description Inclusion Criteria • Documented history (26 months) of moderately severe persistent asthma confirmed by a physician and requiring daily asthma medication.

• Generally good health apart from asthma.

• FEVj between 50% and 80% of predicted values at baseline and at the beginning of the double-blind treatment phase.

• At least 15% reversibility in FEVj following the administration of inhaled nebulized albuterol at the screening visit • Symptomatic asthma requiring the use of beta-agonists on at least 6 of the 14 days of observation during the placebo-controlled run-in-period.

• Willingness of patient and caregiver to provide informed consent Exclusion Criteria • Severe asthma or any serious medical condition.

• Use of prescription medication for which albuterol sulfate is contraindicated.

• Known hypersensitivity to albuterol of similar agents.

• Active pulmonary disease other than bronchial asthma.

• Upper respiratory tract infection within 4 weeks of the start of the placebo phase.

• Any other chronic condition that could have interfered with successful completion of the study or confounded its interpretation.

• Acute use of corticosteroids or other treatments which might interfere with the study within 4 weeks of the screening visit • Inability or unwillingness to perform the requirements of the protocol.

Interventions Patients meeting the inclusion criteria and on regularly prescribed asthma medications were permitted to continue on those medications during the course of the study if the doses remained stable. Patients were required to withhold their morning dose before each study visit and during the entire study session. After Ihe patient completed the study session, the regularly scheduled dosing resumed for that day. All medication used to treat chronic 31 conditions, including immunotherapy, had to be initiated at least 30 days prior to the start of the study, and the dosing regimen had to be stabilized by the initial visit. Racemic albuterol delivered by a chlorofluorocarbon (CFC) MDI or nebulizer was used on an as-needed basis as the rescue medication.

Efficacy Results The primary efficacy endpoint was the area under the percent change from pre-dose FEV, versus time curve for the initial closing visit (Day 1) and the final closing visit (Day 28). Compared to placebo, both unit doses of albuterol produced significant improvement in FEV, following both the initial dose and the dose given at visit 4 after 4 weeks of TD treatment. Hie mean percent change from baseline in the area under the 6-hour curve for FEV i for both active treatment regimens compared with placebo, is shown in Table 4 (for Day 1) mid Table 5 (for Day 28).

Table 6 % Change from Pre-Dose FEVi Intent-to-Treat Population Day 1 IffttfeftJftttKUft «8 m *» Hours fromPw-fiose m m Figure 3. Percent change ii FEVj time course after treatment on Day 1.

Table 7 32 % Change from Pre-Dose FEVi Intent-to-Treat Population Day 28 UlSMtmUl W W M «• » «l &» MO Hours from Fra-Dosa plwrtt Figure 4. Percent change n FEVj time course after treatment on Day 28.

The onset of a 15% increase in FEVi over baseline for both doses of AccuNeb was seen at 30 minutes. The mean time to speak effect was approximately 30 to 60 minutes for both doses on day 1 and after 4 weeks of treatment. The mean duration of effect, as measured by a >15% increase from baseline in FEVi was approximately 2.5 hours for both doses on day 1 and approximately 2 hours for both doses after 4 weeks of treatment In some patients, the duration of effect was as long as 6 hours.

Subgroup analysis was performed to determine whether the overall efficacy of AccuNeb was consistent across all age, weight and disease severity groups. In all age groups, weight categories and disease severity groups, the 1.25 mg dose provided a statistically significant improvement over placebo on both Day 1 and Day 28. However, at the lower 0.63 mg dose, children 11 to 12 years of age, children heavier than 40 kg and children with more severe disease (classified as an FEVi <60% of predicted) did not have a statistically 33 significant improvement in FEVi over placebo at Day 29. As a result, older children, heavier children or children with more severe disease may have a better response at the 1.25 mg dose.

Safetv/Tolerabilitv Adverse reaction information to the albuterol solution used in the study was derived from the 4-week controlled clinical trial described above. Adverse events were reported in >1% of patients receiving the present solution, more frequently than adverse events reported by patients receiving placebo, as shown in Table 6. In the study, there was one case of ST segment depression in the 1.25 mg treatment group, but no clinically relevant laboratory abnormalities related to administration were observed.

Table 8 Adverse Event Reports (ADVERSE EVENTS WITH AN INCIDENCE OF 0.1% OF PATIENTS RECEIVING THE PRESENT ALBUTEROL SOLUTION AND GREATER THAN PLACEBO (EXPRESSED AS % OF TREATMENT GROUP)) 1.25 mg AccuNeb 0.63 mg AccuNeb Placebo (N=115) (N=117) (N=117) Asthma Exacerbation 13 11.1 8.5 Otitis Media 43 0.9 0 Allergic Reaction 0.9 3.4 1.7 Gastroenteritis 0.9 3.4 0.9 Cold Symptoma 0 3.4 1.7 Fly Syndrome 2.6 2.6 1,7 Lymphadenopathy 2.6 0.9 1.7 Skin/Appendage injection 1.7 0 0 Urticaria 1.7 0.9 0 Migrane 0.9 1.7 0 Chest Pain 0.9 1.7 0 Bronchitis 0.9 1.7 0.9 Nausea 1.7 0.9 0.9 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 34 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, the invention described herein suitably may be practiced in the absence of any element which is not specifically disclosed herein.

Claims (37)

What we claim is:

1. A pediatric inhalation solution comprising: a premixed, premeasured aqueous formulation comprising a single unit dose of an active ingredient consisting essentially of racemic albuterol sulfate in a therapeutically effective pediatric amount for inducing bronchodilation or providing relief of bronchospasm in a child 2-12 years of age-suffering from asthma, wherein the amount of racemic albuterol sulfate in the inhalation solution ranges from about 0.08 mg to about 1.90 mg; 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 active ingredient originally present in the solution still remains in the solution.

2. The pediatric 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 said active ingredient, said degradation products being selected from the group consisting of 5-2-((l,l-dimethylethyl)amino-l-hydroxyethyl)-2-hydroxybenzaldehyde; bis-(2-hydroxy)-5-(2-tertbutylamino-l-hydroxyethyl) phenylmethyl ether; 2-tert-butylamino-l-(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 l-(5-chloro-4-hydroxy-3-hydroxymethylphenyl)-2-(tert-butylamino) ethanol.

3. The pediatric inhalation solution of claim 1, wherein the antimicrobial preservative is benzalkonium chloride.

4. The pediatric inhalation solution of claim 1, wherein the pH of the inhalation solution ranges from about 3.0 to about 4.0.

5. The pediatric inhalation solution of claim 1, wherein the pH of the inhalation solution is about 3.5.

6. The pediatric inhalation solution of claim 1, wherein the amoui tN5ElXECTUA^ PROPERTY 2 7 MAR 2008 36 received % albuterol sulfate in the inhalation solution ranges from about 0.75 mg to about 1.50 mg.

7. The pediatric inhalation solution of claim 1, wherein the inhalation solution further comprises an osmotic adjusting agent selected from the group consisting of sodium chloride, potassium chloride, zinc chloride, calcium chloride, and mixtures thereof.

8. Use of an aqueous formulation for the manufacture of a premixed, premeasured medicament for inducing bronchodilation or providing relief of bronchospasm in a child 2-12 years of age suffering from asthma; wherein the formulation comprises an active ingredient consisting essentially of racemic albuterol sulfate in a therapeutically effective pediatric amount of about 0.08 mg 10 about 1.90 mg; and wherein the medicament 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 active ingredient originally present in the medicament still remains in the medicament.

9. The use of claim 8, wherein the amount of racemic albuterol sulfate in the inhalation solution ranges from about 0.75 mg to about 1.50 mg.

10. A kit for relieving bronchospasm in a child 2-12 years of age suffering from asthma, said kit comprising: one or more single dispensing containers, each comprising a premixed, premeasured aqueous inhalation solution comprising a single unit dose of an active ingredient consisting essentially of racemic albuterol sulfate in a therapeutically effective pediatric amount of about 0.08 mg to about 1.90 mg; wherein the solution is nebulizable in a nebulizer; and 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 active ingredient originally present in the solution still remains in the solution.

11. The kit of claim 10, wherein after storage for 12 months at a temperature of 25 °C, the inhalation solution contains no degradation products associated with the degradation of said active ingredient, said degradation products being 37 property office of n2 27 MAR 2008 RFP.F IVED the group consisting of 5-2-((l,l-dimethylethyl)amino-l-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; l-(4-hydroxy-3-methylphenyl)-2-(tert-butylamino) ethanol; and l-(5-chloro-4-hydroxy-3-hydroxymethylphenyl)-2-(tert-butylamino) ethanol.

12. The kit of claim 10, wherein the amount of racemic albuterol sulfate in the inhalation solution ranges from about 0.75 mg to about 1.50 mg.

13. The kit of claim 10, wherein the inhalation solution is free of benzalkonium chloride.

14. The kit of claim 10, wherein the pH of the inhalation solution ranges from about 3.0 to about 4.0.

15. The kit of claim 10, wherein the pH of the inhalation solution is about 3.5.

16. The kit of claim 10, wherein the inhalation solution further comprises an osmotic adjusting agent selected from sodium chloride, potassium chloride, zinc chloride, calcium chloride, or mixtures thereof.

17. The kit of claim 10, wherein the nebulizer is a jet nebulizer, ultrasonic nebulizer, or breath actuated nebulizer.

18. The kit of claim 10, wherein the one or more containers are packaged in the same pouch or box.

19. The kit of claim 10, wherein said containers comprise semi-permeable plastic and are packaged in an aluminum foil pouch.

20. A method of making a premixed, premeasured inhalation solution for relieving bronchospasm in a child 2-12 years of age suffering from asthmej^ty} (=r,T| |A| pRnppRTV office of n.z 38 2 7 MAR 2008 RECEIVED solution provided in single containers, each comprising a single unit dose of said solution; said method comprising the steps: (a) preparing the inhalation solution by a method comprising: (i) filling a tank with a defined volume of purified water at a temperature of between 18 °C and 25 °C while mixing; (ii) adding to the water an acid, an osmotic adjusting agent, and a therapeutically effective pediatric amount of an active ingredient consisting essentially of racemic albuterol sulfate to form the inhalation solution such that a unit dose of said solution comprises 0.08 mg to 1.90 mg of said racemic albuterol sulfate; (iii) mixing to complete dissolution; and (iv) optionally adding an additional amount of purified water to said solution; and (b) providing the inhalation solution in single container vials such that each vial contains racemic albuterol sulfate in single unit dose of a therapeutically effective pediatric amount of 0.08 mg to 1.90 mg.

21. The method of claim 20, wherein said providing step (b) comprises transferring the inhalation solution from said tank through sanitary delivery lines, through a 0.2 micron sterilizing filter, and into sterile vials.

22. The method of claim 20, wherein said providing step (b) comprises sterilizing the solution using steam sterilization.

23. The method of claim 20, wherein the acid is added in an amount to adjust the pH of the inhalation solution to a level ranging from about 3.0 to about 4.0.

24. The method of claim 23, wherein the acid is added in an amount to adjust the pH of the solution to 3.5.

25. The method of claim 20, wherein the acid comprises sulfuric acid.

26. The method of claim 20, wherein the osmotic adjusting agent is added in 39 intellectual property office of n.z ? 7 MAR 7008 an amount to adjust the isotonicity of the inhalation solution from 280 to 320 mOsm/kg.

27. The method of claim 20, wherein the osmotic adjusting agent is selected from sodium chloride, potassium chloride, zinc chloride, calcium chloride, or mixtures thereof.

28. A prepackaged therapeutic system for inducing bronchodilation in a child suffering from asthma, the prepackaged therapeutic system comprising: (a) one or more dispensing containers; each prefilled with about 3 ml of a premixed, premeasured aqueous inhalation solution comprising a unit dose of an active ingredient consisting essentially of racemic albuterol sulfate in a therapeutically effective pediatric amount of about 0.08 mg to about 1.90 mg; wherein the inhalation solution in each of the one or more containers is nebulizable in a nebulizer; and wherein the inhalation solution in each of the one or more 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 active ingredient originally present in the solution still remains in the solution; and (b) indicia comprising indication, adverse reaction, dosage and administration data pertaining to the inhalation solution in each of the one or more containers.

29. The prepackaged therapeutic system of claim 28, wherein the indication data comprises data that the inhalation solution in each of the one or more containers is indicated for the relief of bronchospasm in patients 2 to 12 years of age with asthma; and wherein the adverse reaction data comprises data indicating that otitis media and skin-appendage infection might occur after administering the inhalation solution in the one or more containers.

30. The prepackaged therapeutic system of claim 28, wherein the dosage and administration data comprises data that the dosage for patients 2 to 12 years of age is 0.75 mg or 1.50 mg of albuterol sulfate administered 3 to 4 times daily by nebulization over 5 to 15 minutes. intellectual property office of n.z 2 7 MAR 2008 n irr*c i w c r\

31. The prepackaged therapeutic system of claim 28, wherein the adverse reaction data comprises a list of one or more preprinted adverse events that may occur after administering the inhalation solution in each of the one or more containers, the adverse events comprising asthma exacerbation, allergic reaction, gastroenteritis, flu syndrome, lymphadenopathy, urticaria, migraine, chest pain, bronchitis or nausea.

32. A premixed, premeasured inhalation solution, when made by a method as claimed in any one of claims 20 to 27.

33. A pediatric inhalation solution, as defined in claim 1, substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.

34. Use, as defined in claim 8, substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.

35. A kit, as defined in claim 10, substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.

36. A method, as defined in claim 20, substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.

37. A prepackaged therapeutic system, as defined in claim 28, substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures. 41 intellectual property office of n.z. 27 MAR 2008