WO 2014/113638 Al 24 July 2014 (24.07.2014) P O P C T
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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2014/113638 Al 24 July 2014 (24.07.2014) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 47/48 (2006.01) A61K 31/135 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 47/30 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, PCT/US20 14/0 11991 MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (22) International Filing Date: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 17 January 2014 (17.01 .2014) SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (25) Filing Language: English ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 61/753,743 17 January 2013 (17.01.2013) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (71) Applicant: AER DEVICES, INC. [US/US]; 2400 W. TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Coast Hwy., Suite 11-302, Newport Beach, CA 92663 EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (US). MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (72) Inventors: MILLIGAN, Joseph; 121 41st St., Newport KM, ML, MR, NE, SN, TD, TG). Beach, CA 92663 (US). SHAEFFER, Jason; 25 10 Glen- neyre St., Laguna Beach, CA 9265 1 (US). PHAM, David, Published: N.; 16772 Baruna Lane, Huntington Beach, CA 92649 — with international search report (Art. 21(3)) (US). — before the expiration of the time limit for amending the (74) Agents: FESSENMAIER, Martin et al; Fish & Associ claims and to be republished in the event of receipt of ates, PC, 2603 Main Street, Suite 1000, Irvine, CA 92614 amendments (Rule 48.2(h)) (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (54) Title: MULTI-USE ALBUTEROL MAINTENANCE THERAPY FORMULATIONS AND DEVICES THEREFOR Aer Devices versus Conventional Therapy FIG. 3 (57) Abstract: Contemplated devices, formulations, and methods allow for significant reduction of albuterol using an on-demand thermal vaporizer while maintaining bioequivalent functional response to currently known modes of administration. In particularly preferred aspects, the total administered dose is less than 4% of an administered dose of an aqueous solution given via a known nebulizer, and less than 15% of an administered dose of an aqueous/ethanolic solution given via a known metered dose inhaler. MULTI-USE ALBUTEROL MAINTENANCE THERAPY FORMULATIONS AND DEVICES THEREFOR [0001] This application claims the benefit of US Provisional Application Serial Number 61/753743, which was filed January 17, 2013, and which is incorporated by reference herein. Field of The Invention [0002] The field of the invention is devices and methods for pulmonary delivery of drugs, and especially devices and methods for multi-use pulmonary delivery of bronchodilatory drugs for maintenance treatment of a patient. Background of the Invention [0003] Chronic obstructive pulmonary disease (COPD) is a fairly common pulmonary disease in which air flow to and from the lungs is compromised. Likewise, allergen- and exercise-induced asthma are fairly common disorders that are generally characterized by airflow obstruction and bronchospasm. Among other options for treatment of COPD and asthma, albuterol (salbutamol, (RS)-4-[2-(tert-butylamino)-l-hydroxyethyl]-2-(hydroxymeth- yl)phenol) is fairly effective in treatment of symptoms associated with COPD and asthma. [0004] For example, COPD patients are often on a maintenance treatment with inhaled albuterol in which a mechanical (e.g., ultrasonic or impact) nebulizer generates a mist that carries the albuterol to the lungs. While such nebulizer maintenance treatment is conceptually very simple, patients will typically be restricted to home treatment as the nebulizer is relatively bulky and often dependent on line voltage. Alternatively, albuterol can also be administered as a highly concentrated spray from a hand-held metered dose inhaler (MDI). However, use of an MDI for delivery is typically limited to use as a rescue inhaler due to the high drug concentration and so not suitable for maintenance therapy. [0005] In addition, and particularly where an ultrasonic or impact nebulizer is used, the albuterol containing liquid that is placed into the vaporization chamber must be completely used or the remaining liquid must be discarded. Moreover, due to the constant concentration of albuterol in the mist from a nebulizer, the patient can typically not modify the amount of albuterol taken per inhalation. Similarly, MDI delivery is limited to a constant dose of albuterol taken per inhalation. Moreover, and regardless of the mode of administration (i.e., nebulizer or MDI), pediatric use is often difficult as children tend to have difficulty with the operation of a nebulizer mask or MDI. In addition, the recently revised guidelines for asthma treatment by the National Institutes of Health recommended that pediatric patients use the lowest beta-agonist doses needed to control symptoms. However, lowest beta-agonist doses are typically achieved by dilution of the treatment solution, which is potentially dangerous due to calculation errors and/or contamination of residual medication. [0006] Regardless of the above difficulties, side effects of albuterol are fairly common and include tachycardia, uncontrollable shaking of a part of the body, nervousness, headache, nausea, vomiting, cough, throat irritation, muscle, bone, or back pain, and in severe cases chest pain, difficulties breathing, difficulty swallowing, and swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs, all of which tend to increase in frequency and/or severity with increasing administered dosage. Therefore, it would be highly desirable to have compositions and methods that would allow administration of a reduced dosage of albuterol (and other beta receptor agonists) while having bioequivalent functional response/therapeutic effect as it is thought that such reduced dosages will significantly reduce side effects. Viewed from a different angle, it would be also highly advantageous to have compositions and methods that increase potency of albuterol and other beta receptor agonists when administered via pulmonary route. [0007] Thus, even though various uses, devices, and methods for pulmonary administration of albuterol and other beta2-receptor agonist bronchodilators are known, there is still a need to provide improved compositions, methods and devices, especially where administration is for maintenance therapy. Summary of The Invention [0008] The present invention is directed to various compositions, methods, uses, devices and formulations for pulmonary administration of a therapeutically effective amount of a drug, and especially a beta2-receptor agonist bronchodilator and/or corticosteroid to a patient in need thereof. Among other advantages, the compositions, methods, and uses according to the inventive subject matter unexpectedly allow for substantial reduction of total administered dose of the drug using an on-demand thermal vaporizer while maintaining a bioequivalent functional response to currently known modes of administration. Viewed from a different perspective, using inventive compositions and methods significantly increases potency of the beta2-receptor agonist bronchodilator and/or corticosteroid, and thus allows for a substantial reduction in the required administered dose, which in turn will reduce the incidence and/or severity of side effects associated with the drugs. [0009] In one aspect of the inventive subject matter, the inventors contemplate compositions, methods, and use of a low-molecular weight polyol as thermo-nebulizable carrier for a beta2- receptor agonist bronchodilator (and/or corticosteroid) to reduce the administered dosage of the beta2-receptor agonist bronchodilator formulation while maintaining a desired functional response for the beta2-receptor agonist bronchodilator. [0010] In particularly preferred compositions, methods, and uses, the thermo-nebulizable carrier is or comprises a low-molecular weight polyol, most preferably in an amount of between 80-92 vol% of the formulation. For example, suitable thermo-nebulizable carrier are or comprise propylene glycol, glycerol, and/or PEG400 (polyethylene glycol) in a total amount of between 80-92 vol% of the formulation. Where the beta2-receptor agonist bronchodilator is a short-acting agonist, especially contemplated agonists include albuterol, albuterol sulfate, levalbuterol, terbutaline, pirbuterol, procaterol, clenbuterol, metaproterenol, fenoterol, bitolterol mesylate, ritodrine, and isoprenaline, and where the beta2-receptor agonist bronchodilator is a long-acting agonist, preferred agonists include salmeterol, formoterol, bambuterol, clenbuterol, olodaterol, and indacaterol. Especially preferred beta2- receptor agonist bronchodilator include albuterol, and albuterol sulfate or other short-acting antimuscarinic agonist such as ipratropium bromide.