AU2006202584A1 - An albuterol inhalation solution, system, kit and method for relieving symptoms of pediatric asthma - Google Patents

Description

S&F Ref: 593029D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Dey, of, Napa, California, United States of America Imtiaz Chaundry, Partha Banerjee Spruson Ferguson St Martins Tower Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) An albuterol inhalation solution, system, kit and method for relieving symptoms of pediatric asthma The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c SAn Albuterol Inhalation Solution, System, Kit and Method for Relieving Symptoms of Pediatric Asthma CCROSS REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. 119 from U.S. Provisional Application Serial -s 5 No. 60/348,203, filed October 26, 2001, which is incorporated herein by reference in its entirety.

_FIELD OF THE INVENTION The present invention relates to an albuterol inhalation solution, system, kit and method for relieving symptoms associated with asthma in children.

00 BACKGROUND OF INVENTION Asthma is a pulmonary disease marked by labored breathing; wheezing; and (3) coughing. Asthma is characterized by: airway inflammation; airway hyperresponsiveness; and O(3) airway obstruction (or airway narrowing) that is partially or completely reversible, either N spontaneously or with treatment. Common symptoms of asthma include wheezing, shortness of breath, tightness in the 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 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 7 t h 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 LibC/593029spec because parents, care givers, teachers and others typically do not have adequate experience diluting 0 these medications, resulting in contamination or inappropriate dosing, among other problems.

NC- 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) Sbronchodilator 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 00 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.

SSUMMARY 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. Another object of the present invention is to provide a prepackaged, sterile, premixed, premeasured, reduced-dosage albuterol inhalation solution for the relief of bronchospasm in patients 2 to 12 years of age with asthma.

It is yet another object of the present invention to provide an antimicrobial preservative-free albuterol inhalation solution to relieve bronchospasm in a pediatric patient with asthma.

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

An additional object of the present invention is to provide a kit or system for relief of bronchospasm in a pediatric patient with asthma.

A further object of the present invention is to provide a process for making an inhalation solution for relief of bronchospasm in a pediatric patient with asthma.

Another object of the invention includes a device for use in relieving bronchospasm in a pediatric patient with asthma.

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.

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.

LibC/593029speci 3 DETAILED DESCRIPTION OF THE INVENTION 0Albuterol 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 n. 5 limited to, any form of albuterol which is capable of producing a desired bronchodilation effect in IOD 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.

In the present invention, acceptable salts of albuterol may include, but are not limited to, 00 hydrochloride, sulfate, maleate, tartrate, citrate and the like. These and other acceptable salts are c- 10 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, IN the inhalation solution of the present invention comprises the sulfate salt of racemic albuterol.

O Albuterol sulfate is a relatively selective beta-2-adrenergic bronchodilator with an empirical formula of

C

13

H

21 N0 3 The chemical name for albuterol sulfate is ol-[(tert-butylamino)methyll-4-hydroxy-mxylene-x, c'-diol sulfate (2:1)(salt), and its established chemical structure is as follows:

H

3 C CH 3 HO CH3 H o N .H 2 SO4

-OH

2 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 intermediate 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 mg to about LibC/593029spec 4 IND 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 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 i s 5 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 mg to 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

O

00 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 N 1.00 mg; about 1.01 mg to about 1.20 mg; about 1.21 mg to about 1.40 mg; about 1.41 mg to about 01.60 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 (N 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 intermediate 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 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.

The 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 BAC-free 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 on a shelf) for long periods of time.

ULbC/593029spec Table 1 Stability Data 0.021 wt Albuterol 0.042 wt Albuterol SOsmolality AOsmolality Assay* pH (mOsm/kg) Assay pH (mOsm/kg) Time zero 98 3.5 289 100 3.5 291 25 0 C/35%RH 12 months 99 3.5 289 100 3.5 291 25°C/35%RH 24 months 101 3.5 294 100 3.5 292 3 months 99 3.6 290 100 3.6 291 0 C/15%RH 96 3.5 290 99 3.5 292 6.5 months 96 3.5 290 99 3.5 292 as percent of label claim (0.021 wt and 0.042 wt% albuterol, respectively).

OO

in Another benefit of a sterile inhalation solution is that it reduces the possibility of introducing O 5 contaminants into the patient when administered, thereby reducing the chance of an opportunistic infection in the patient.

Adherence to asthma medication therapy and prevention of asthma medication error are N 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, and the chance of medication errors are reduced. Further, there is a lower 3o 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 LIbC/593029speci Sdispensing 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 00 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, 0premeasured, BAC-free inhalation solution comprising a single unit dose of a therapeutically effective (Ni 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 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 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.

Table 2 Type of Asthma Description Severe Persistent Continual symptoms during the day; Frequent symptoms at night; of lower predicted values for DEV; and 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 and <80% of PEF or FEVi and greater than 30% FEVi variability.

Mild Persistent Daytime symptoms 3-6 days a week; UbC/593029spec Type of Asthma Description IND Symptoms at night 3-4 times a month; and O 80% or higher PEF or FEVi 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 or higher PEF or FEVi and PEF variability t 'n 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 Sbronchospasm to reduce breathing difficulties resulting from asthma. In another embodiment, the 00 i 5 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 Sbe based at least in part on consideration of the patient's size, the severity of the symptoms to be rC 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.

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.

LibC/593029soed For mild persistent asthma, treatment may include administering therapeutically effective O pediatric amount(s) of the present formulation for quick relief of symptoms and daily anti-inflammatory CK1 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 0 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 N face mask.

OIn an alternative embodiment, the system and/or kit of the present invention comprises an c-i 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 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-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-FlexrM 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 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 the 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: one or more single unit dosages of a therapeutically effective pediatric amount of albuterol; administration instructions for the use of said unit dose as an asthma treatment for pediatrics; and 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 LibC/593029specd Icontaining individual packages or pouches comprising one or more unit dose vials. For example, an C 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 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.

O0 0 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 N be used to relieve bronchospasm in children. The label may also comprise indicia (15) which provides Oinstructions for using the inhalation solution to relieve bronchospasm in children. As used herein 0 "indicia" includes, but is not limited to, wording, pictures, drawings, symbols and/or shapes. A nonlimiting 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 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.

The present invention is also directed to 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 of the present invention 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 of the present invention 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 administered by nebulizer, more preferably a jet nebulizer connected to an air compressor with adequate air flow.

LibC/S93029speci IIn yet another alternative embodiment, in reference to Figures 1-4, the method of the present invention comprises the steps: placing an inhalation solution comprising a therapeutically effective pediatric amount of albuterol into a nebulizer cup the nebulizer may be powered by attachment to compressed gas cylinders or an electrically driven compressor; (ii) using a adapter to fit the cup lid to a mouthpiece or facemask (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 or facemask to the pediatric patient afflicted with bronchospasm; and the patient continues breathing until no more mist is formed in the nebulizer chamber This may occur in about 5-15 00 tminutes.

o 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 N 1.50 mg/3 ml or 0.75 mg/3 ml albuterol sulfate) may be used by nebulization. Preferably, the nebulizer flow rate is adjusted to deliver the albuterol sulfate over 5 to 15 minutes. Patients 6 to 12 years of age with more severe asthma (baseline FEV1 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 of the present invention comprises the steps: 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.

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 method of the present invention comprises one or more of the following steps: 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 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 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 In another embodiment, a process for making an inhalation solution of the present invention comprises one or more of the following steps: 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.

LibC/593029SpeC 11 IND In an alternative embodiment, the present invention may comprise about 0.4 to about 1.0 weight 0 percent ionic salt. Preferably, the present invention comprises about 0.9 weight percent of an osmotic Sadjusting agent.

In an alternative embodiment, the inhalation solution of the present invention may be prepared as follows: 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 0 C to 25 0 C; while mixing, (iii) adding sulfuric acid, Sodium Chloride USP, 00 and at least a therapeutically effective pediatric amount of Albuterol Sulfate USP to the tank; (iv) continue mixing until all chemical components are dissolved; adding Purified Water USP to adjust the final volume, if necessary, thus producing an albuterol mixture.

SFrom the formulation tank, the albuterol mixture is pumped through sanitary delivery lines rN 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 of a 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: preparing an admixture containing a therapeutically effective pediatric amount of albuterol in a pharmaceutically acceptable vehicle.

In an alternative embodiment, the present invention also comprises 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 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

T

M nebulizer and a Pari PRONEBTM 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: 1.25 mg albuterol sulfate LibC/593029spec 12 1 O inhalation solution; 9.63 mg albuterol sulfate inhalation solution; or placebo (saline). Each patient was provided with a personal compressor-driven PARI LC PLUS' nebulizer, by Pari N Respirator Equipment, Inc., Richmond, VA, for the duration of the 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 00 were performed.

io After 11 days, patients returned for exchange of study medication and diaries and pulmonary cfunction tests before and 30 minutes after the morning dosing. After completing 28 days of treatment, Opatients returned to the test site for a repeat of the 6-hour evaluation of safety and efficacy following Sadministration of study medication. Diary cards were used to record asthma symptoms, night awakenings, peak flow measurements, supplemental albuterol use, change in medication and adverse events. The safety profiles of each unit dose and 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 288 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 3 InclusionlExclusion 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.

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

At least 15% reversibility in FEV 1 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.

LibC/593029speci Interventions Patients meeting the inclusion criteria and on regularly prescribed asthma medications were Spermitted 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 the patient completed the study session, the regularly scheduled dosing resumed for that day. All medication used to treat chronic 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 00 nebulizer was used on an as-needed basis as the rescue medication.

Efficacy Results 0The primary efficacy endpoint was the area under the percent change from pre-dose FEV, ^D versus time curve for the initial closing visit (Day 1) and the final closing visit (Day 28). Compared to 0placebo, 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. The mean percent change from baseline in the area under the 6-hour curve for FEV1 for both active treatment regimens compared with placebo, is shown in Table 4 (for Day 1) and Table 5 (for Day 28).

Table 4 Change from Pre-Dose FEVi Intent-to-Treat Population Day 1 0O.O 0.50 V7 l 1.60 2.00 2.50 30 3. 4.00 L00 LOO Hours from Pre-Dose flthlrnanl: albutarol 1.25mg albuirol 0.63 rl pla- siesbo Figure 3. Percent change i FEV, time course after treatment on Day 1.

LibC/593029speci 14 INO Table Change from Pre-Dose FEVI Intent-to-Treat Population Day 28 D03Y 28

;Z

00&O N 025 0.50 3 73 I 3.00 Z.50 3Do 3.50 4.00 S0M B.0 CKI Hours trom Pre-Dose Treatmsoft in- alb ol 1.25 mO aZ llo n Figure 4. Percent change n FEV, time course after treatment on Day 28.

The onset of a 15% increase in FEV, over baseline for both doses of AccuNeb was seen at 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 FEV was approximately 2.5 hours for both doses on day 1 and approximately 2 hours for lo 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 FEV, of predicted) did not have a statistically significant improvement in FEV, 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.

Safetyrrolerability Adverse reaction information to the albuterol solution used in the study was derived from the 4week controlled clinical trial described above. Adverse events were reported in 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.

LibC/593029sped Table 6 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 Otitis Media 4.3 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 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.

LIbC/S93029spec

Claims (40)

1. A pediatric inhalation solution comprising: Sa premixed, premeasured aqueous formulation comprising a single unit dose of a therapeutically effective pediatric amount of albuterol for inducing bronchodilation or providing relief of bronchospasm in children suffering from asthma, wherein the amount of albuterol in the inhalation solution ranges from about 0.08 mg to about 1.90 mg; the solution being provided in a single container.

2. The pediatric inhalation solution of claim 1, wherein the inhalation solution is sterile. 00

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

4. The pediatric inhalation solution of claim 3, wherein the antimicrobial preservative is 0benzalkonium chloride. rl 5. The pediatric inhalation solution of claim 1, wherein the pH of the inhalation solution ranges from about 3.0 to about is 6. The pediatric inhalation solution of claim 1, wherein the pH of the inhalation solution is about

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

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

9. The pediatric inhalation solution of claim 1, wherein the albuterol is in the form of a racemic mixture. The pediatric inhalation solution of claim 1, wherein the amount of albuterol in the inhalation solution ranges from about 0.63 mg to about 1.25 mg.

11. The pediatric inhalation solution of claim 1, wherein the amount of albuterol in the solution is about 0.63 mg or about 1.25 mg.

12. The pediatric inhalation solution of claim 1, wherein the inhalation solution is suitable for nebulization in a nebulizer.

13. The pediatric inhalation solution of claim 12, wherein said nebulizer is selected from the group consisting of a jet nebulizer, ultrasonic nebulizer or breath actuated nebulizer.

14. A pediatric inhalation solution comprising: a sterile, premixed, premeasured aqueous formulation free of benzalkonium chloride comprising a single unit dose of a therapeutically effective pediatric amount of albuterol for inducing bronchodilation or providing relief of bronchospasm in children suffering from asthma, wherein the amount of albuterol in the solution ranges from about 0.63 mg to about 1.25 mg, the solution being provided in a single container and wherein the inhalation solution is suitable for nebulization in a nebulizer. A method of inducing bronchodilation or providing relief of bronchospasm in a child suffering from asthma, said method comprising the step: administering to said child the pediatric inhalation solution of claim 1. LibCJ593029speci S16. The method of claim 15, wherein the pediatric inhalation solution is sterile when administered to the child. C1 17. The method of claim 15, wherein the pediatric inhalation solution is free of antimicrobial preservative.

18. The method solution of claim 15, wherein the albuterol is in the form of an acid addition salt thereof.

19. The method of claim 18, wherein the acid addition salt of albuterol is albuterol sulfate. The method solution of claim 15, wherein the albuterol is in the form of a racemic 00 Smixture.

21. The method solution of claim 15, wherein the amount of albuterol in the inhalation solution ranges from about 0.63 mg to about 1.25 mg.

22. The method solution of claim 15, wherein the amount of albuterol in the inhalation Ssolution is about 0.63 mg or about 1.25 mg.

23. The method of claim 15, wherein the pediatric inhalation solution is administered to the child by nebulization.

24. A method of inducing bronchodilation or providing relief of bronchospasm in a child suffering from asthma, said method comprising the step: administering to the child the pediatric inhalation solution of claim 14 by nebulization. A method of inducing bronchodilation or providing relief of bronchospasm in a child suffering from asthma, said method comprising the steps: a) placing the inhalation solution into a chamber of a nebulizer, said nebulizer having a mouthpiece or facemask associated with the chamber of the nebulizer; b) positioning the mouthpiece or facemask in close proximity to the child's mouth or face; c) passing the inhalation solution in a mist form from the nebulizer chamber through the mouthpiece or facemask to the child while the child breathes into the mouthpiece or facemask; and d) the child breathing into the mouthpiece or facemask until at least substantially all the mist is removed from the nebulizer chamber.

26. A method of inducing bronchodilation or providing relief of bronchospasm in a child suffering from asthma, said method comprising the steps of: providing instructions for administering to the child the pediatric inhalation solution of claim 1.

27. A kit for relieving bronchospasm in a child suffering from asthma, said kit comprising: one or more containers; said one or more containers each comprising a premixed, premeasured aqueous inhalation solution comprising a single unit dose of a therapeutically effective pediatric amount of albuterol; wherein the amount of albuterol in the solution ranges from about 0.08 mg to about 1.90 mg; the solution being suitable for nebulization in a nebulizer.

28. The kit according to claim 27, wherein the inhalation solution is sterile.

29. The kit according to claim 27, wherein the inhalation solution is free of antimicrobial preservative. LibC/593029speci 18 The kit according to claim 27, wherein the amount of albuterol in the inhalation solution ranges from about 0.63 mg to about 1.25 mg. CK 31. The kit according to claim 27, wherein the amount of albuterol in the inhalation solution is about 0.63 mg or about 1.25 mg.

32. The kit according to claim 27, further comprising a label which indicates that the inhalation solution can be used to relieve bronchospasm in children suffering from asthma.

33. The kit according to claim 27, further comprising instructions for using the inhalation solution to relieve bronchospasm in children. 00

34. The kit of claim 27, wherein the one or more containers are packaged in the same pouch or box. The kit of claim 34, wherein said containers comprise semi-permeable plastic and are Spackaged in an aluminum foil pouch. (N 36. A kit for treating bronchospasm in a child suffering from asthma, said kit comprising: a) one or more containers; said one or more containers each comprising a sterile, premixed, premeasured aqueous inhalation solution free of benzalkonium chloride for use in a nebulizer; said inhalation solution comprising a single unit dose of a therapeutically effective pediatric amount of albuterol, wherein said pediatric amount ranges from about 0.63 mg to about 1.25 mg; b) a label which indicates that the inhalation solution can be used to relieve bronchospasm in children suffering from asthma; and c) instructions for using the inhalation solution to relieve said bronchospasm.

37. A prepackaged therapeutic system for relieving bronchospasm in children suffering from asthma, said prepackaged therapeutic system comprising packaging material, wherein said packaging material comprises: a) one or more containers; said one or more containers each comprising a premixed, premeasured aqueous inhalation solution comprising a single unit dose of a therapeutically effective pediatric amount of albuterol; wherein said pediatric amount of albuterol ranges from 0.08 mg to about 1.90 mg; the solution being suitable for nebulization in a nebulizer.

38. The prepackaged therapeutic system of claim 37, wherein said pediatric amount of albuterol ranges from about 0.63 mg to about 1.25 mg.

39. The prepackaged therapeutic system of claim 37, wherein said pediatric amount of albuterol is about 0.63 mg or about 1.25 mg. The prepackaged therapeutic system of claim 37, wherein the inhalation solution in each of the one or more containers is sterile.

41. The prepackaged therapeutic system of claim 37, wherein the inhalation solution in each of the one or more containers is free of antimicrobial preservative.

42. The prepackaged therapeutic system of claim 37, wherein said packaging material further comprises a label which indicates that the inhalation solution can be used to relieve bronchospasm in children.

43. The prepackaged therapeutic system of claim 37, wherein said packaging material comprises instructions for using the solution to relieve bronchospasm in children. LibCIS93029spea

44. A prepackaged therapeutic system for relieving bronchospasm in children suffering from 0 asthma, said prepackaged therapeutic system comprising packaging material, wherein said packaging NC1 material comprises: a) one or more containers; the one more containers each comprising a sterile, premixed, t 5 premeasured aqueous inhalation solution free of antimicrobial preservative for nebulization in a nebulizer; the inhalation solution comprising a single unit dose of a therapeutically effective pediatric amount of albuterol, wherein the pediatric amount of albuterol ranges from about 0.63 mg to about 1.25 mg; 0o b) a label indicating that the inhalation solution can be used to relieve bronchospasm in children; and c) instructions for using the inhalation solution to relieve bronchospasm in children. A method of making a premixed, premeasured inhalation solution for relieving Sbronchospasm in children suffering from asthma; said method comprising the steps: a) placing a unit dose of a therapeutically effective pediatric amount of albuterol in a pharmaceutically acceptable vehicle, wherein the amount of albuterol in the vehicle ranges from about 0.08 mg to about 1.90 mg; b) providing the inhalation solution in a single container.

46. The method of claim 45, further comprising the step of adding sulfuric acid to adjust the pH of the inhalation solution to a level ranging from about 3.0 to about

47. The method of claim 45, further comprising the step of adding an osmotic agent to adjust the isotonicity of the inhalation solution; 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 according to claim 45, further comprising the step: a) sterilizing the inhalation solution by passing it through a filter or by steam sterilization.

49. The method of claim 45, further comprising the step of adding sulfuric acid to adjust the pH of the inhalation solution to a level ranging from about 3,0 to about A method of making a premixed, premeasured inhalation solution for relieving bronchospasm in a child suffering from asthma; said method comprising the steps: a) placing a unit dose of a therapeutically effective pediatric amount of albuterol in a pharmaceutically acceptable vehicle, wherein the amount of albuterol in the vehicle ranges from about 0.002 weight percent to about 0.075 weight percent; b) providing the inhalation solution in a single container.

51. A device for use in the relieving bronchospasm in a child suffering from asthma, the device having indicia; the indicia providing instructions for utilizing a premixed, premeasured inhalation solution comprising a single unit dose of a therapeutically effective pediatric amount of albuterol to relieve said bronchospasm; wherein said pediatric amount of albuterol ranges from about 0.63 mg to about 1.25 mg albuterol; said solution being suitable for nebulization in a nebulizer.

52. A pediatric inhalation solution substantially as hereinbefore described with reference to any one of the examples. LibC/593029speci

53. A kit for relieving bronchospasm in a child suffering from asthma, said kit being I substantially as hereinbefore described with reference to any one of the examples.

54. A kit for treating bronchospasm in a child suffering from asthma, said kit being substantially as hereinbefore described with reference to any one of the examples. n. 5 55. A prepackaged therapeutic system for relieving bronchospasm in children suffering from IND asthma, said prepackaged therapeutic system being substantially as hereinbefore described with reference to any one of the examples.

56. A method of making a premixed, premeasured inhalation solution for relieving 00 bronchospasm in children suffering from asthma; said method being substantially as hereinbefore 1 10 described with reference to any one of the examples. Dated 16 June, 2006 DEY, L.P. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON LibC/593029spedc