US 20090047336A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0047336A1 Yang et al. (43) Pub. Date: Feb. 19, 2009 (54) NOVEL FORMULATION OF DEHYDRATED Publication Classification LPID VESICLES FOR CONTROLLED (51) Int. Cl. RELEASE OF ACTIVE PHARMACEUTICAL A63/37 (2006.01) INGREDIENT VLANHALATION A6II 47/06 (2006.01) A 6LX 9/27 (2006.01) (75) Inventors: Zhijun Yang, Kowloon (CN); A6IR 9/14 (2006.01) Wenhua Huang, Kowloon (CN); A6IP II/00 (2006.01) Chi Sun Wong, Hong Kong (CN); A6IP II/06 (2006.01) Zhongzhen Zhao, Kowloon (CN) (52) U.S. Cl. .......... 424/450; 424/489: 514/653: 514/772 Correspondence Address: (57) ABSTRACT LEYDIG VOIT & MAYER, LTD A new formulation of dehydrated lipid vesicles employs a 700 THIRTEENTH ST. NW, SUITE 300 vesicle preserver and permits the control of release and deliv WASHINGTON, DC 20005-3960 (US) ery of active pharmaceutical ingredients into the respiratory system for treatment in particular of asthma. The typical (73) Assignee: HONG KONG BAPTIST formulation provides controlled release of the active pharma UNIVERSITY, Kowloon (CN) ceutical ingredient from 0% to 100% from 0 to 72 hours after inhalation, changes the systemic administration to topical (21) Appl. No.: 11/840,537 administration, allows prolonged therapeutic period for one administration, increased stability, with reduced dose, (22) Filed: Aug. 17, 2007 reduced systemic side effects, reduced toxicity. S Patent Application Publication US 2009/0047336A1 60 T. 50 40 30 20 O O Time (hours) --DOPC+1% gly cerin w8m DOTAP+1% glycerin FIG. 2 US 2009/0047336A1 Feb. 19, 2009 NOVEL FORMULATION OF DEHYDRATED blood pressure. With the advent of selective agents, these side LPD VESCLES FOR CONTROLLED effects have become less common. Patients must becautioned RELEASE OF ACTIVE PHARMACEUTICAL against using these medicines too frequently, as with Such use INGREDIENT VLANHALATION their efficacy may decline, producing desensitization result ing in an exacerbation of symptoms which may lead to refrac FIELD OF THE INVENTION tory asthma and death. Older, less selective adrenergic recep tor agonist, such as inhaled ephedrine and epinephrine 0001. The present invention relates to lipid vesicles, and in tablets, have also been used. Cardiac side effects occur with particular to the treatment of asthma and other conditions. these agents at similar rate to albuterol, Hendeles L., Marshik PL, et al. et al. Response to nonprescription epinephrine BACKGROUND OF THE INVENTION inhaler during nocturnal asthma. Ann Allergy Asthma Immu 0002 Asthma is a chronic disease of the respiratory sys mol. December 2005:95(6):530-4, and Rodrigo GJ, Nannini tem in which the airway discontinuously constricts, with L. J. Comparison between nebulized adrenaline and B-2 ago associated inflammation. This causes symptoms such as nists for the treatment of acute asthma. A meta-analysis of coughing, wheezing, and shortness of breath with chest tight randomized trials. Am J Emerg Med. March 2006: 24(2):217 ness. The symptoms of asthma, which range from mild to life 22. Their use via injection has declined due to related adverse threatening, respond to bronchodilators and can usually be effects. These are typically provided in pocket-sized, controlled with a combination of medication. In the devel metered-dose inhaler or asthma spacer or nebulizer. oped countries, asthma has been focused upon because of its 0006 Attempts to formulate active pharmaceutical ingre rapidly increasing prevalence, affecting up to one in every dient in appropriate vehicles for targeted use have often been four urban children, see Lilly CM. Diversity of asthma: unsuccessful. Active pharmaceutical ingredient formulated Evolving concepts of pathophysiology and lessons from for inhalation seems to be rapidly absorbed, necessitating genetics. JAllergy Clin Immunol. 2005; 115 (4 Suppl): S526 frequent dosing, which heightens systemic side effects. It 31. may also lead to the mucosal of respiratory tissue damage 0003. Animal models have confirmed a role for A2B caused by a repeated use of fluorocarbon propellants, Sol antagonists in respiratory inflammation, fibrosis and airway vents, or other additives necessary for nasal or oral inhalation remodelling, as in D. Zeng & R. Polosa (2006) European administration. The aerosol droplets carrying the active phar Respiratory Disease. 2006; 26-27, and the causes of asthma maceutical ingredient should avoid multiple dosing while lies in a special type of natural killer cell. That means that providing a maximum therapeutic benefit. It should also pro asthma is often not treated with the right kind of active phar vide a controlled-release of the active pharmaceutical ingre maceutical ingredient. For example, natural killer T cells dient in the respiratory system, while the active pharmaceu seem to be resistant to the corticosteroids in widely used tical ingredient should be released continually over an inhalers, see Cromie, William J. Harvard University Gazette, extended period, providing an effective dose on B-2 agonist in Harvard News Office, Mar. 16, 2006, Retrieved on Sep. 23, the Smooth muscle with the minimum amount of active phar 2006. maceutical ingredient. By developing an appropriate formu 0004 Glucocorticoids are the most widely used of the lation vehicle for such therapy, the undesirable side effects preventive active pharmaceutical ingredients, such as accompanying active pharmaceutical ingredient therapy of ciclesonide, beclomethasone, budesonide, flunisolide, fluti asthma would be diminished. casone, mometasone, triamcinolone, etc. Using corticoster 0007 Bystrom, K., Nilsson, P. in U.S. RE38407 (2001) oids long-term has many side effects, in particular high doses describe pain management with liposome-encapsulated anal of steroids may cause osteoporosis. Currently long acting gesic drugs delivered by the pulmonary route to provide local B-adrenoceptor agonists, including Sustained-release oral or systemic analgesia. Waldrep, J. C., Knight, V., Black, M. B. albuterol, sameterol, formoterol, and, bambuterol are avail in U.S. Pat. No. 5,958,378 (1999) employ about 130-375 able. However, the US Food and Drug Administration (FDA) mg/ml of phospholipids for the liposomal aerosol delivery of released a health advisory in November 2005; alerting that the about 12-30 mg/ml of a active pharmaceutical ingredient via use of long-acting B-2 agonists could lead to a worsening of respiratory system for treatment of diseases. Examples of symptoms, indeed to death in some cases. A study says that further liposomal treatments include those for respiratory three common asthma inhalers containing the active pharma influenza Edwards, D.A., Stone, H.A.: US 200502.20720A1 ceutical ingredient Salmeterol or formoterol may be causing (2005), tumor Jin, T., Zarif, L., Mannino, R.: US four out of five US asthma-related deaths per year and should 2006153217 (2000), local respiratory infections and cystic be taken off the market, Ramanujan, Krishna (Jun. 9, 2006). fibrosis Hersch, E. M., Petersen, E. A., Profitt, R. T., Cornell Chronicle Online. Cornell News Service. Retrieved Bracken, K.R., Chiang, S-M.: U.S. Pat. No. 5,958,449 (1999) on Sep. 23, 2006. }. Liposome-containing two-phase polymer solution, treated 0005 Bronchodilators are recommended for short-term with Ca" or Zn" etc. cochleate is described in Parmar, M.: relief in all patients with asthma. A higher dose of glucocor US2006 0051406A1 (2006) to achieved efficient delivery of ticoid may be prescribed with a long-acting B-2 agonist, theo pharmaceutical agents. However, the lipids vesicles are not phylline, leukotriene modifier, or mast-cell stabilizer, for per very stable for storage and producing in a great amount sistent disease. Symptomatic control of wheezing and because most of the lipids are easy to disassemble, and the shortness of breath is generally achieved with a fast-acting lipids vesicles are in the hundreds nanometer size, which bronchodilator. The active pharmaceutical ingredients when dispersed in buffer solution must experience Brownian include selective B-2 adrenergic receptor agonists, such as motion, that may lead to the congregation of the liposome salbutamol (albuterol), terbutaline, levalbuterol, and vesicle and leakage of the active pharmaceutical ingredient. bitolterol. There may also be cardiac side effects at higher 0008 Bystrom, K., Nilsson, P., U.S. Pat. No. 6,045,828 doses due to B-1 agonist activity, such as elevated heart rate or (1996) describes a simple mixed powder of lipids and active US 2009/0047336A1 Feb. 19, 2009 pharmaceutical ingredient developed for inhalation, which is is particularly useful in formulating active pharmaceutical capable of hydration to form liposomes. In that sense the ingredient for inhaled and nebulized inhalation of small aero powder is anhydrous. The manufacturing process of the lipid Sol particles. vesicle powder employs lipids that have a phase transition 0013 The first aspect of this invention is to provide the temperature of below 37° C. Disclosure of phospholipids formulation to form the dehydrated lipids vesicles for deliv powders for rapid absorption of the active pharmaceutical ery of various active pharmaceutical ingredient by nebulizer ingredient is in Weers, J. G., Tarara, T., Clark, A.: US or inhaler into the respiratory system tissue. The dehydrated 20040105820A1 (2004) and in Mezei, M., Hung, O.: U.S. lipids vesicles formed with uniform and controllable particle size enable the active pharmaceutical ingredient to be RE38407