+

WO2003037317A1 - Solution d'inhalation a base d'albuterol, et systeme, kit et methode permettant de soulager les symptomes de l'asthme pediatrique - Google Patents

Solution d'inhalation a base d'albuterol, et systeme, kit et methode permettant de soulager les symptomes de l'asthme pediatrique Download PDF

Info

Publication number
WO2003037317A1
WO2003037317A1 PCT/US2002/033352 US0233352W WO03037317A1 WO 2003037317 A1 WO2003037317 A1 WO 2003037317A1 US 0233352 W US0233352 W US 0233352W WO 03037317 A1 WO03037317 A1 WO 03037317A1
Authority
WO
WIPO (PCT)
Prior art keywords
inhalation solution
albuterol
containers
pediatric
asthma
Prior art date
Application number
PCT/US2002/033352
Other languages
English (en)
Inventor
Imtiaz Chaudry
Partha Banerjee
Original Assignee
Dey, L.P.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/034,829 external-priority patent/US6702997B2/en
Application filed by Dey, L.P. filed Critical Dey, L.P.
Priority to JP2003539661A priority Critical patent/JP2006513129A/ja
Priority to CA2464660A priority patent/CA2464660C/fr
Priority to AU2002347948A priority patent/AU2002347948B2/en
Priority to EP02784157A priority patent/EP1441709A1/fr
Priority to MXPA04003928A priority patent/MXPA04003928A/es
Publication of WO2003037317A1 publication Critical patent/WO2003037317A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators

Definitions

  • the present invention relates to an albuterol inhalation solution, system, kit and method for relieving symptoms associated with asthma in children.
  • Asthma is a pulmonary disease marked by (1) labored breathing; (2) wheezing; and (3) coughing. Asthma is characterized by: (1) airway inflammation; (2) airway hyperresponsiveness; 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 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.
  • Short-acting inhaled beta-agonists such as albuterol
  • 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.
  • antimicrobial preservatives such as benzalkonium chloride (BAC)
  • BAC benzalkonium chloride
  • COPD chronic obstructive pulmonary disease
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the preferred salt of albuterol is sulfate.
  • 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 C ⁇ 3 H 2 ⁇ NO 3 .
  • the chemical name for albuterol sulfate is ⁇ 1 - [(tert- butylamino)methyl]-4-hydroxy-m-xylene- ⁇ , ⁇ '-diol sulfate (2:l)(salt), and its established chemical structure is as follows:
  • 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.
  • the inhalation solution of the present invention comprises a therapeutically effective pediatric amount of albuterol.
  • 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.
  • a therapeutically effective pediatric amount of albuterol may include about 0.63 mg or about 1.25 mg albuterol.
  • the potency of the albuterol is equivalent to about 0.75 mg and about 1.50 mg of albuterol sulfate, respectively.
  • a therapeutically effective pediatric amount of albuterol may include from about 0.63 mg to about 1.25 mg of albuterol.
  • such pediatric amount comprises no more than about 1.25 mg of albuterol, or it comprises 1.25 mg of albuterol or less.
  • 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 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 mgto 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
  • 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 mg to 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.
  • 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 %.
  • 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.
  • BAC-containing solutions contain an antimicrobial preservative such as BAC or EDTA.
  • 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.
  • 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.
  • the formulation of the present invention which comprises a therapeutically effective pediatric amount of albuterol
  • 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.
  • compositions provided herein are stable.
  • the compositions provided herein are stored between about 15°C and about 30°C, and remain stable for a relatively long period of time.
  • the compositions are stored at 25°C.
  • 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.
  • 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.
  • 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.
  • a length of time i.e., shelf-life
  • >80% or >85% or >90% or >95% estimated bronchodilating agent remains after such storage, for example.
  • compositions produced herein are at least substantially clear, based on color measurement tests set forth by the America Public Health Association ("APHA").
  • APHA America Public Health Association
  • 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.
  • the process of the present invention provides compositions having an albuterol content of about 0.021% or 0.042% per vial.
  • 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.
  • the process of the present invention provides an average fill volume of about 2.80 ml to about 3.30 ml into each vial.
  • compositions that may contain minimal amounts of contaminants including, but not limited to the following:
  • compositions may also contain minimal amounts of particulate matter, including, but not limited to the following: about NMT 1000 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.
  • 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.
  • the present invention overcomes the aforementioned problems by providing therapeutically effective pediatric amounts of albuterol in prepackaged, premixed, premeasured and/or unit dose amounts.
  • 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 risk of cross- contamination, and less waste of medication when providing an inhalation solution in a premixed, ready to use form.
  • 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.
  • 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 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.
  • 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 mgto about 1.25 mg of albuterol, respectively).
  • the nebulizer solution is contained in a unit-dose, low-density polyethylene (LDPE) container.
  • LDPE low-density polyethylene
  • 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.
  • 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.
  • 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.
  • the inhalation solution of the present invention provides relief of bronchospasm in patients 2 to 12 years of age.
  • 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.
  • the albuterol inhalation solution of the present invention may be administered together with one or more other drugs.
  • an antiasthmatic drug such as theophylline or terbutaline, or an antihistamine or analgesic such as aspirin, acetaminophen or ibuprofen
  • an antiasthmatic drug such as theophylline or terbutaline
  • an antihistamine or analgesic such as aspirin, acetaminophen or ibuprofen
  • the albuterol and the one or more drugs may be administered in one formulation or as two separate entities.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • nebulizer such nebulizer including, but not limited to, a jet nebulizer, ultrasonic nebulizer and breath-actuated nebulizer.
  • the nebulizer is a jet nebulizer connected to an air compressor with adequate air flow.
  • the nebulizer being equipped with a mouthpiece or suitable face mask.
  • 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.
  • 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-FlexTM top is advantageous in that it allows for easy dispensing of the solution, prevents spillage and eliminates the need to open the container by cutting off the top, or the like, thereby reducing cross-contamination.
  • One or more of the semi-permeable single unit dose containers may be 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.
  • the present invention comprises a prepackaged inhalation system and/or kit suitable for pediatric patients suffering from asthma.
  • a 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.
  • 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 vials.
  • a box containing one or more prepackaged, unit dose vials or a box containing individual packages or pouches comprising one or more unit dose vials is depicted in Figure 5.
  • 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.
  • 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.
  • a system and/or kit of the present invention may also include a label and/or instructions designed to facilitate user compliance.
  • 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 directed to a prepackaged therapeutic system and/a kit for inducing bronchodilation in a child suffering from asthma, the prepackaged therapeutic system comprising:
  • indicia comprising indication, adverse reaction, dosage and administration data pertaining to the inhalation solution in each of the one or more containers;
  • 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.
  • 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.
  • 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.
  • the prepackaged therapeutic system and/a kit is adapted to induce bronchodilation in a child suffering from asthma
  • the prepackaged therapeutic system may comprise:
  • indicia comprising indication, adverse reaction, and dosage and administration data pertaining to the inhalation solution in each of the one or more containers;
  • 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;
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the method of the present invention 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.
  • 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.
  • the entire contents of a one unit- dose vial e.g., 1.50 mg/3 ml or 0.75 mg/3 ml albuterol sulfate
  • 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 FEVi 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.
  • the method of the present invention 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.
  • the present invention is directed to 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;
  • 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;
  • the adverse reaction data informs the patient or prescriber that otitis media and skin-appendage infection might occur after administering the inhalation solution in the one or more containers.
  • 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 1.25 mg of albuterol administered 3 to 4 times daily by nebulization over 5 to 15 minutes.
  • 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.
  • the method of the present invention 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; (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;
  • 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;
  • the dosage and administration data comprises data that informs the patient or prescriber 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.
  • 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.
  • the method 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.
  • 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.
  • an acid e.g., sulfuric acid
  • an 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.
  • 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.
  • 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.
  • 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.
  • 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 effective pediatric amount of Albuterol Sulfate 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.
  • HDPE high density polyethylene
  • HDPE high density polyethylene
  • tri- blender for stainless steel
  • 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).
  • LDPE low density polyethylene
  • 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.
  • cards of five filled vials 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.
  • the present invention also comprises a device for use in the relief of bronchospasm associated with pediatric asthma.
  • 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.
  • 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 PlusTM nebulizer and a Pari PRONEBTM compressor. Both of these products are commercially available.
  • 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.
  • 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).
  • 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 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.
  • 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.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pulmonology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Otolaryngology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

Solution d'inhalation à base d'albutérol, et système, kit et méthode permettant de soulager le bronchospasme chez les enfants souffrant d'asthme. Dans un mode de réalisation, la solution selon la présente invention est une dose unitaire stérile, prémélangée et prémesurée d'albutérol pour des patients asthmatiques ayant de 2 à 12 ans. Cette solution peut être exempte de produits chimiques anti-microbiens tels que le chlorure de benzalconium. Dans un autre mode de réalisation, la solution selon la présente invention contient environ 0,63 mg ou environ 1,25 mg d'albutérol.
PCT/US2002/033352 2001-10-26 2002-10-18 Solution d'inhalation a base d'albuterol, et systeme, kit et methode permettant de soulager les symptomes de l'asthme pediatrique WO2003037317A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2003539661A JP2006513129A (ja) 2001-10-26 2002-10-18 小児喘息の症状を緩和するためのアルブテロール吸入溶液、システム、キット及び方法
CA2464660A CA2464660C (fr) 2001-10-26 2002-10-18 Solution d'inhalation a base d'albuterol, et systeme, kit et methode permettant de soulager les symptomes de l'asthme pediatrique
AU2002347948A AU2002347948B2 (en) 2001-10-26 2002-10-18 Albuterol inhalation solution, system, kit and method for relieving symptoms of pediatric asthma
EP02784157A EP1441709A1 (fr) 2001-10-26 2002-10-18 Solution d'inhalation a base d'albuterol, et systeme, kit et methode permettant de soulager les symptomes de l'asthme pediatrique
MXPA04003928A MXPA04003928A (es) 2001-10-26 2002-10-18 Solucion para inhalacion de albuterol, sistema, equipo y metodo para aliviar sintomas de asma pediatrica.

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US34820301P 2001-10-26 2001-10-26
US60/348,203 2001-10-26
US10/034,829 US6702997B2 (en) 2001-10-26 2001-12-27 Albuterol inhalation solution, system, kit and method for relieving symptoms of pediatric asthma
US10/034,829 2001-12-28
AU32975/02A AU3297502A (en) 2001-10-26 2002-04-05 An albuterol inhalation solution, system, kit and method for relieving symptoms of pediatric asthma
AU32975/02 2002-04-05
JP2002-145456 2002-04-11
JP2002145456A JP2003212764A (ja) 2001-10-26 2002-04-11 小児喘息の症状を緩和するためのアルブテロール吸入溶液、システム、キット及び方法

Publications (1)

Publication Number Publication Date
WO2003037317A1 true WO2003037317A1 (fr) 2003-05-08

Family

ID=27422969

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/033352 WO2003037317A1 (fr) 2001-10-26 2002-10-18 Solution d'inhalation a base d'albuterol, et systeme, kit et methode permettant de soulager les symptomes de l'asthme pediatrique

Country Status (6)

Country Link
EP (1) EP1441709A1 (fr)
JP (1) JP2006513129A (fr)
CA (1) CA2464660C (fr)
MX (1) MXPA04003928A (fr)
NZ (1) NZ550304A (fr)
WO (1) WO2003037317A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0370632A1 (fr) * 1988-11-04 1990-05-30 FISONS plc Solution pharmaceutique contenant du salbutamol et de l'acide cromoglycique
WO1994013262A1 (fr) * 1992-12-09 1994-06-23 Boehringer Ingelheim Pharmaceuticals, Inc. Formulations de solutions medicinales aerosol stabilisees
US6451289B2 (en) * 2000-03-24 2002-09-17 Sepracor Inc. Albuterol formulations

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62292719A (ja) * 1986-06-12 1987-12-19 Kaken Pharmaceut Co Ltd 外用澄明水溶性製剤
KR970701174A (ko) * 1994-02-10 1997-03-17 오노다 마사요시 신규한 카바메이트 유도체 및 이의 의약 조성물(Novel carbamate derivative and medicinal composition containing the same)
WO1997003068A1 (fr) * 1995-07-11 1997-01-30 Merck & Co., Inc. Sel de bisulfate de triazolymethyle-indole ethylamine
DE19653969A1 (de) * 1996-12-20 1998-06-25 Boehringer Ingelheim Kg Neue wässrige Arzneimittelzubereitung zur Erzeugung treibgasfreier Aerosole
US6126919A (en) * 1997-02-07 2000-10-03 3M Innovative Properties Company Biocompatible compounds for pharmaceutical drug delivery systems
AU9674398A (en) * 1997-10-09 1999-05-03 Schering Corporation Mometasone furoate suspensions for nebulization
US20030183224A1 (en) * 2000-03-01 2003-10-02 Hailey Mark Andrew Metered dose inhaler

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0370632A1 (fr) * 1988-11-04 1990-05-30 FISONS plc Solution pharmaceutique contenant du salbutamol et de l'acide cromoglycique
WO1994013262A1 (fr) * 1992-12-09 1994-06-23 Boehringer Ingelheim Pharmaceuticals, Inc. Formulations de solutions medicinales aerosol stabilisees
US6451289B2 (en) * 2000-03-24 2002-09-17 Sepracor Inc. Albuterol formulations

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Product Information VENTOLIN", INTERNET, September 1998 (1998-09-01), XP002228636, Retrieved from the Internet <URL:http://us.gsk.com/products/assets/us_ventolin.pdf> [retrieved on 20030124] *
"Summary of products characteristics Ventolin Nebules", INTERNET, June 1998 (1998-06-01), XP002228635, Retrieved from the Internet <URL:http://uk.gsk.com/products/assets/uk_ventolin_nebules.pdf> [retrieved on 20030124] *
ALDERSON S H, WARREN R H: "Pediatric Aerosol Therapy Guidelines. Indications, Techniques, and Dosages.", CLINICAL PEDIATRICS, vol. 23, no. 10, 1984, United States, pages 553 - 557, XP009004562 *

Also Published As

Publication number Publication date
JP2006513129A (ja) 2006-04-20
NZ550304A (en) 2008-05-30
CA2464660A1 (fr) 2003-05-08
EP1441709A1 (fr) 2004-08-04
MXPA04003928A (es) 2005-03-31
CA2464660C (fr) 2011-12-20

Similar Documents

Publication Publication Date Title
AU2002347948B2 (en) Albuterol inhalation solution, system, kit and method for relieving symptoms of pediatric asthma
AU2002347948A1 (en) Albuterol inhalation solution, system, kit and method for relieving symptoms of pediatric asthma
CA2464735C (fr) Solution d&#39;inhalation a base d&#39;albuterol et d&#39;ipratropium, et systeme, kit et methode permettant de soulager les symptomes de la bronchopneumopathie chronique obstructive
US6632842B2 (en) Albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease
US20030191151A1 (en) Albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease
CA2986839C (fr) Solution d&#39;inhalation de tiotropium a nebuliser
US20030203930A1 (en) Albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease
US20030140920A1 (en) Albuterol inhalation soultion, system, kit and method for relieving symptoms of pediatric asthma
US20050175544A1 (en) Albuterol inhalation solution, system, kit and method for relieving symptoms of pediatric asthma
IE890881L (en) Pharmaceutical Compositions
CA2464660C (fr) Solution d&#39;inhalation a base d&#39;albuterol, et systeme, kit et methode permettant de soulager les symptomes de l&#39;asthme pediatrique
AU2006202584B2 (en) An albuterol inhalation solution, system, kit and method for relieving symptoms of pediatric asthma
US20190290633A1 (en) Tiotropium Inhalation Solution for Nebulization
AU2006202585B2 (en) An albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease
AU2002353825B2 (en) An albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease
US8084461B2 (en) Albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease
AU2020369029A1 (en) Novel pediatric combination
AU2002353825A1 (en) An albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease
JP2010184937A (ja) 慢性閉塞性肺疾患の症状を緩和するためのアルブテロールおよびイプラトロピウム吸入溶液、キット、吸入溶液を中に有する１容器を作成する方法、および、吸入溶液を作成する方法
CA3080115A1 (fr) Solution d&#39;inhalation de tiotropium a nebuliser

Legal Events

Date Code Title Description
ENP Entry into the national phase

Ref document number: 2003539661

Country of ref document: JP

Kind code of ref document: A

Format of ref document f/p: F

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2464660

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2004/003928

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 532974

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2002347948

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2002784157

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 20028262603

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 2002784157

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载