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(12) United States Patent (10) Patent No.: US 8431,553 B2 FOX Et Al

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(12) United States Patent (10) Patent No.: US 8431,553 B2 FOX Et Al USOO843 1553B2 (12) United States Patent (10) Patent No.: US 8431,553 B2 FOX et al. (45) Date of Patent: Apr. 30, 2013 (54) COMBINATION OF METHYLXANTHINE OTHER PUBLICATIONS COMPOUNDS AND STEROIDS TO TREAT CHRONIC RESPRATORY DISEASES Giembycz (Expert Opinion on Investigational Drugs (2001) 10:1361-1379).* Evans et al. (The New England Journal of Medicine (1997) (75) Inventors: Justian Craig Fox, Harlow (GB); Mary 337: 1412-1418).* Frances Fitzgerald, Harlow (GB); Lim et al., Comparison of high dose inhaled steroids, low dose Harry Finch, Harlow (GB) inhaled steroids plus low dose theophylline, and low dose inhaled Steroids alone in chronic asthma in general practice, Thorax 55:837 (73) Assignee: Pulmagen Therapeutics (Synergy) 841 (2000). Limited, Burnham (GB) Eyles et al., “Immunological responses to nasal delivery of free and encapsulated tetanus toxoid: studies on the effect of vehicle volume'. Int. J. Pharm., 189(1): 75-79 (1999). (Abstract). (*) Notice: Subject to any disclaimer, the term of this Geelhaar et al., “Morphometric estimation of pulmonary diffusion patent is extended or adjusted under 35 capacity. 3. The effect of increased oxygen consumption in Japanese U.S.C. 154(b) by 233 days. Waltzing mice”, Respir. Physiol., 11(3): 354-366 (1971). Guidance for Industry: Estimating the Maximum Safe Starting Dose (21) Appl. No.: 11/883,635 in Intial Clinical Trials for Therapeutics in Adult Healthy Volunteers, U.S. Food and Drug Administration (FDA) (2005), http://www.fda. (22) PCT Filed: Feb. 13, 2006 gov/Cder/Guidance/5541 finlpdf. Karrer, “The ultrastructure of mouse lung: the alveolar macrophage'. J Biophys. Biochem. Cytol., 4(6): 693-700 (1958). (86). PCT No.: PCT/GB2OO6/OOO482 Shen, et al., “The effects of intranasal budesonide on allergen-in duced production of interleukin-5 and eotaxin, airways, blood, and S371 (c)(1), bone marrow eosinophilia, and eosinophil progenitor expansion in (2), (4) Date: Apr. 4, 2008 sensitized mice'. Am. J. Respir. Crit. Care Med., 166(2): 146-153 (2002). (87) PCT Pub. No.: WO2006/085102 Bel, E.H. (2006) Severe Asthma. Breathe 3: 128-139. Napp Pharmaceuticals Limited, Uniphyllin Continus tablets, Sum PCT Pub. Date: Aug. 17, 2006 mary of Product Characteristics last updated Jan. 18, 2008 print out of http://emc.medicines.org.uk/medicine/1233/SPC/ (65) Prior Publication Data Uniphyllin+Continus+tablets, last visited Apr. 28, 2009. Evans et al. (1997) A comparison of low-dose inhaled budesonide US 2008/0318913 A1 Dec. 25, 2008 plus theophylline and high-dose inhaled budesonide for moderate asthma, N. Engl. J. Med. 337:1412-1418. (30) Foreign Application Priority Data Lim et al. (1998) A randomised, double blind placebo-controlled comparison of low dose theophylline plus low dose inhaled Steroids Feb. 11, 2005 (GB) ................................... O5O2949.1 vs. high dose inhaled Steroids in the management of asthma, Am. J. Dec. 22, 2005 (GB) ................................... O526.124.3 Respir. Crit. Care Med. 157: A415. Morali et al. (2001) Efficacy of Inhaled Budesonide and Oral (51) Int. Cl. Theophylline in Asthmatic Subjects, J. Asthma 38:673-679. AOIN 45/00 (2006.01) Rivington et al. (1995) Efficacy of Uniphyl, Salbutamol, and Their Combination in Asthmatic Patients on High-dose inhaled steroids, A6 IK3I/56 (2006.01) Am. J. Respir. Crit. Care Med. 151:325-32. Suessmuth etal. (2003) Low-dose theophylline in childhood asthma. (52) U.S. Cl. a placebo-controlled, double-blind study, Pediatr. Allergy Immunol. USPC .......................................................... S14/171 14:394-400. Ukena et al. (1997) Comparison of addition of theophylline to (58) Field of Classification Search ................... 514/171 inhaled steroid with doubling dose of inhaled steroid in asthma, Eur, See application file for complete search history. Respir. J. 10:2754-2760. Wrenn et al. (1991) Aminophylline Therapy for Acute Bronchospastic Disease in the Emergency Room, Annals Intern. (56) References Cited Med. 115:241-247. Barnes (2003) Theophylline, New Perspectives for an Old Drug, Am. U.S. PATENT DOCUMENTS J. Respir. Crit. Care Med. 167:813-818. 6,025,360 A 2, 2000 Miller et al. .................. 514,263 Ouagued et al. (2004) The Novel Phosphodiesterase 4 Inhibitor, 2003/0134865 A1 7/2003 Adcock et al. C1-1044, Inhibits LPS-Induced TNF-O. Production in Whole Blood 2004/O105819 A1 6, 2004 Hale et al. From COPD Patients, Pulm. Pharmacol. Ther., 18:49-54. 2005, 0026848 A1 2/2005 Robinson et al. FOREIGN PATENT DOCUMENTS (Continued) EP O 421 587 * 4f1991 Primary Examiner — Marcos SZnaidman EP O421587 4f1991 (74) Attorney, Agent, or Firm — Morgan, Lewis & Bockius EP 1080720 3, 2001 LLP FR 3622 M 10, 1965 WO 93, 15741 8, 1993 (57) ABSTRACT WO 2005/O11594 A2 2, 2005 WO 2005/O11595 A3 2, 2005 There is provided the use of a methylxanthine derivative such WO 2005/011602 A3 2, 2005 as theophylline and a steroid in a synergistic combination for WO 2005/011604 A2 2, 2005 the treatment of chronic obstructive pulmonary disease, WO 2005/011608 A2 2, 2005 wherein the combination is administered by the inhaled route WO 2005/011613 A2 2, 2005 for pulmonary delivery. WO 2005/011615 A2 2, 2005 WO WO 2006/O13359 2, 2006 23 Claims, 5 Drawing Sheets US 8431553 B2 Page 2 OTHER PUBLICATIONS Bone et al. (1994) In chronic pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone, Barnes et al., “Theophylline in the management of asthma: time for Chest, 105:14 11-1419. reappraisal?” Eur, Respir. J., 1994, 7(3):579-591. CaZZola et al. (2004) Salmeterol/fluticaSone propionate in a single Markham et al., “Theophylline. A review of its potential steroid inhaler device versus theophylline + fluticaSone propionate in sparing effects in asthma.” Drugs, 1998, 56(6):1081-1091. patients with COPD, Pulm. Pharmacol. Ther. 17:141-145. Fontana et al., “Effect of aminophylline aerosol on the bronchial Dal Negro et al. (2004 Salmeterol & fluticasone 50 microg/250 response to ultrasonic mist of distilled water in asthmatic patients.” microg bid in combination provides a better long-term control than Respiration, 1988, 54(4):241-246. salmeterol 50 microg bid alone and placebo in COPD patients already Thompson et al., “The use of aminophylline by inhalation.” Br. J. treated with theophylline, Pulm. Pharmacol. Ther. 16:241-246. Clin. Pharmacol., 1982, 14(3):463-464. Kokubu (1995) Bronchodilating effect of inhalation of aeroslized Cushley et al., “Bronchodilator actions of Xanthine derivatives aminphylline in asthmatic patients, Allergy, 44:1379-1386. administered by inhalation in asthma.” Thorax, 1985, 40(3):176-179. Stewartet al. (1976) A trial of Aerosolized Theophyline in Relieving Cosio et al., “Theophylline restores histone deacetylase activity and Brochospasm, Chest, 69:718-721. steroid responses in COPD macrophages.” J. Exp. Med., 2004, Yaeger et al. (1995) Protective effects of inhaled aminophylline on 200(5):689-695. methacoline-induced airway responses in greyhound dogs, Current Bohadana et al. (1980) The bronchodilator action of theophylline Therapeutic Research, 56:47-56. earosol in subjects with chronic airflow obstruction, Bull. Eur, Physiopathol Respir, 16:13-24. * cited by examiner U.S. Patent Apr. 30, 2013 Sheet 1 of 5 US 8431,553 B2 Figure 1. Total BA cells 00 75 50 25 -25 3. 0.3 31 O.3 110.3 O.S 0.1 0.510.1 0.25 O, O. 10.1 1-a- Oral -a-b- -- intranasal -o- Dose (mg/kg) Oral Theo Oral Theo + Dex Dntranasal Theo man intranasal Theo + Dex Es Oral Dex intranasal Dex U.S. Patent Apr. 30, 2013 Sheet 2 of 5 US 8431,553 B2 Figure 2 1.75 Intranasal Theo + DeX 31 O.3 1 1 0.3 0.5 / 0.1 0.25 / 0.1 0.1 1 0.1 Dose (mg/kg) U.S. Patent Apr. 30, 2013 Sheet 3 of 5 US 8431,553 B2 Figure 3 Total BAL. Macrophages O p < 0.001 p < 0.001 3. O3 310,3 0.3 0.5 O. 0.5 O, O,251 01 01 0.1 -CH- Oral -o -CH- intranasal -o- Dose (mg/kg) Oral Theo Oral Theo + Dex D Intranasal Theo Mentranasal Theo + Dex E Ora Dex intranasal Dex U.S. Patent Apr. 30, 2013 Sheet 4 of 5 US 8431,553 B2 Figure 4 Total BAL. Neutrophils 100 p <0.001 p < 0.001 p < 0.05 p < 0.05 75 3 0.3 31 O.3 103 0.5 O 0.50, 0.25 O. O. O. -- Oral -u-D -- intranasal -b- Dose (mg/kg) TOral Theo Oral Theo + Dex Dntranasal Theo entranasal Theo - Dex Oral Dex intranasal Dex U.S. Patent Apr. 30, 2013 Sheet 5 of 5 US 8431,553 B2 Figure 5 Total BAL Lymphocytes 100 75 50 25 25 3 O3 303 110.3 0.5 O O.5.0.1 .250. O. O. -C- Ora -o 1- intranasal -o- Dose (mg/kg) Oral Theo Ora Theo + Dex intranasal Theo Ontranasal Theo + Dex EOral Dex Intranasal Dex US 8,431,553 B2 1. 2 COMBINATION OF METHYLXANTHINE Theophylline prevents the translocation of the proinflam COMPOUNDS AND STEROIDS TO TREAT matory transcription factor nuclear factor-KB (NF-kB) into CHRONIC RESPRATORY DISEASES the nucleus, thus potentially reducing the expression of inflammatory genes in asthma and COPD (Tomita, et al. Arch The present invention provides the inhaled use of methylx Pharmacol 1999, 359:249-55). These effects are seen at high anthine derivatives such as theophylline and steroid drugs in concentrations and may also be mediated by inhibition of a synergistic combination for manufacture of a medicament PDE. It is likely therefore, that PDE inhibition is not a mecha in the treatment of chronic respiratory diseases such as nism of action of theophylline when administered at low oral chronic obstructive pulmonary disease (COPD).
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