1. “Tobramycin” (pdf). Toku-E. 2010-01-12. Retrieved 2012-06-11.
2.  “Nebulized Tobramycin in treating bacterial Sinusitis” (Press release). July 22, 2008. Retrieved 2009-12-06.

A widely accepted therapy for treating respiratory infections caused by Gram- negative bacteria involves intravenous administration of a single antibiotic or combinations of antibiotics. Gibson et al., 2003 Am. J. Respir. Crit. Care. Med.

168(8):918-951 ; Ramsey, 1996 N. Engl. J. Med. 335(3): 179-188. However, this method of treatment has several significant limitations including: (1 ) narrow spectrum of activity of existing antibiotics, (2) insufficient concentrations of antibiotic reaching the respiratory tract to ensure rapid onset and high rates of bacterial killing, and (3) development of adverse side effects due to high systemic concentrations of drug.

Aerosol administration of antibiotics (Conway, 2005 Chronic Repir. Dis. 2:35- 41 ; O’Riordan, 2000 Respir. Care 45(7):836-845) addresses several of the limitations of parenteral administration (Flume and Klepser, 2002 Pharmacotherapy 22(3 Pt 2):71 S-79S; Kuhn, 2001 Chest. 120:94S-98S). It enables topical delivery of high concentrations of drug to the endobronchial spaces and reduces side effects by lowering systemic exposure to antibiotic. However, patients having chronic respiratory conditions, such as chronic obstructive pulmonary disease, cystic fibrosis and bronchiestasis, may receive prolonged and repeated antibiotic therapies over the entire duration of their adult lives. Gibson et al., 2003 Am. J. Respir. Crit. Care. Med. 168(8):918-951 ; Ramsey, 1996 N. Engi. J. Med. 335(3): 179-188. Therefore, cumulative antibiotic toxicity and development of resistance remains a significant problem. Chronic obstructive pulmonary disease (COPD), a smoking-related condition characterized by progressive and poorly reversible airflow obstruction and airway inflammation, is the fourth most common cause of death in developed countries. COPD is projected to be the third leading cause of global deaths in 2020 and is the only one of the four most common causes of death with an increasing mortality rate. In 2008 in the United States, there were an estimated 10 million patients diagnosed with chronic obstructive pulmonary disease (COPD). SDI COPD Claims Analysis, May 2009. Murray et at., 1997 Lancer 349: 1269-76. Approximately 7 million U.S. patients receive treatment for COPD. Mannino et al; The Epidemiology and

Economics of COPD, Proc Am Tho e Soc 2007. In the US, direct COPD costs in 2002 were approximately $18.0 billion. Statistics from National Center for Health Statistics, National Health Interview Survey: Research for the 1995-2004 redesign, Hyattsville, Maryland: U.S. Department of Health and Human Services, CDC, NCHS. Vital and Health Stat 2( 26), 1999.

The clinical course of COPD is characterized by chronic disability, with intermittent, acute exacerbations which may be triggered by a variety of stimuli including exposure to pathogens, inhaled irritants (e.g., cigarette smoke), allergens, or pollutants. “Acute exacerbation” refers to worsening of a patient’s COPD symptoms from his or her usual state that is beyond normal day-to-day variations, and is acute in onset. See, Rabe et al., 2007 Am J Res Crit Care Med, 176: 532- 555. Acute exacerbations of COPD greatly affect the health and quality of life of patients with COPD. Bathoorn, E, Int J Chron Obstruct Pulmon Dis. 2008 3(2):217- 229. Acute exacerbation of COPD is a key driver of the associated substantial socioeconomic costs of the disease. Approximately 73% ($13 billion) of direct COPD costs in 2002 were due to hospitalizations related to acute exacerbations of COPD. Investigators from the Burden of Obstructive Lung Disease (BOLD) Initiative have estimated the cumulative discounted cost of COPD care in the US to be $880 billion by 2020 – an average of more than $44 billion per year over two decades. Lee et al., 2006 ATS Proceedings, 3:A598. Multiple studies have also shown that prior exacerbation is an independent risk factor for future hospitalization for COPD.

Garcia-Aymerich et al., 2003, Thorax, 58:100-105. Hospitalization consumes roughly 70% of COPD healthcare expenditure in the US. McGhan et al., 2007, Chest, 132(6): 1748-1755. Accordingly, for a new drug therapy to significantly reduce the health and economic costs of COPD, it must address acute exacerbations of COPD.

It is clear that there is a continued need for an improved method of treatment for acute and chronic respiratory infections caused by Gram-negative and Gram- positive bacteria, particularly multidrug resistant bacteria, such as P. aeruginosa. This is particularly evident in patients having chronic respiratory conditions where current therapies are limited by problems with development of resistance and toxicity. Such method of treatment would preferably comprise inhalation of an aerosolized antibiotic composition that delivers a therapeutically effective amount of the active pharmaceutical ingredients directly to the endobronchial space of the airways or to the nasal passages. Such treatment would ideally be efficacious, reduce the frequency of drug resistance, and improve safety.

PCT Publication No. WO2005/1 0022 to Gilead Sciences, Inc. (formerly Corus Pharma) discloses a fosfomycin plus tobramycin combination formulation for delivery by aerosolization. The concentrated fosfomycin/tobramycin combination formulation containing an efficacious amount of fosfomycin and tobramycin is able to inhibit susceptible bacteria. Fosfomycin and tobramycin are formulated in solution such that when reconstituted, the pH is between 4.5 and 8.0 or as a dry powder. Also disclosed is a method for treatment of respiratory tract infections by a formulation delivered as an aerosol having mass medium aerodynamic diameter predominantly from 1 to 5 microns, produced by a jet or ultrasonic nebulizer (or equivalent) or dry powder inhaler.

tobramycin solution for inhalation of various formulations are described in the prior art. 例如，美国专利第5，508，269号公开了一种制剂，该制剂包括在Iml的盐水中40_100mg (毫克)的氨基糖苷被稀释成四分之一生理盐水强度，该制剂的PH值在5. 5到6. 5之间，其中该溶液以5ml浓缩形式气雾给药。 For example, U.S. Patent No. 5,508,269 discloses a preparation which is included in the brine Iml 40_100mg (mg) was diluted into a quarter normal saline aminoglycoside strength, the PH value of the preparation of 5 . 5 to 6.5 between, wherein the solution in concentrated form 5ml aerosol administration. [0011] 美国专利6987094公开了一种气雾制剂，其包括75mg/ml妥布霉素的水性溶液，该溶液包括O. 45%w/v (质量/体积百分比）的氯化钠，该制剂的pH值在4. O到5. 5之间，而渗透压在250到450m0sm/l (毫渗透克分子/毫升)。[0011] U.S. Patent 6,987,094 discloses an aerosol formulation which comprises an aqueous solution of 75mg/ml tobramycin, the solution comprises O. 45% w / v (mass / volume) of sodium chloride, the preparation the pH value of 4. O to 5.5, between the osmotic pressure of 250 to 450m0sm / l (mg penetration mol / ml). [0012] 美国专利申请2007/0116649公开了一种气雾制剂，其包括约100mg/ml到200mg/ ml的抗革兰阴性抗生素。 [0012] U.S. Patent Application 2007/0116649 discloses an aerosol formulation comprising about 100mg/ml to 200mg / ml of antibiotics against gram-negative. 提到了妥布霉素制剂，但是没有公开有妥布霉素的实验。Tobramycin formulations mentioned, but there is no disclosure tobramycin experiment. [0013] 美国专利申请2007/0071686公开了一种妥布霉素组合物，其包括约80mg/ml到120mg/ml的妥布霉素、一酸性辅助剂和低浓度的氯化钠。[0013] U.S. Patent Application 2007/0071686 discloses a tobramycin composition comprises about 80mg/ml to 120mg/ml of tobramycin, an acidic auxiliary agents and a low concentration of sodium chloride. 所述酸性辅助剂可以是硫酸钠或磷酸钠。 The acidic auxiliary agent may be sodium or sodium phosphate. 根据US2007/0071686，活性剂的浓度不超过120mg/ml，这是因为据说妥布霉素的浓度因粘度原因对雾化有负面影响。According to US2007/0071686, the concentration of the active agent is not more than 120mg/ml, this is because the concentration of tobramycin said reasons due to the viscosity of a negative impact on atomization. 而且，根据US2007/0071686的妥布霉素组合物利用喷雾器给药给患者，即活性成分通过潮式呼吸吸入。Moreover, the composition according to US2007/0071686 of tobramycin administered to patients using the spray, that the active ingredient through the tidal breathing inhalation. [0014] 欧洲专利2186508尤其公开了一种少于4ml溶液的组合物，其包括的60 – 200mg/ ml的、在生理上可接受的载体上的氨基糖苷抗生素。 [0014] In particular, in European Patent 2,186,508 discloses a composition of the solution is less than 4ml, comprising of 60 – 200mg / ml, and in a physiologically acceptable carrier aminoglycoside antibiotics. EP2186508中的实验显示，包括120mg/ ml妥布霉素的组合物使用PARI LC PLUS®牌喷雾器(德国Starnberg的Pari Boy N压缩器公司）给药需要约10分钟。EP2186508 The experiments showed that including 120mg / ml tobramycin compositions using PARI LC PLUS ® brand spray (Starnberg, Germany The Pari Boy N compressor company) to about 10 minutes of administration. 尽管这少于商业上可获得的TOBI®给药所需的时间,但从患者配合度和患者友好角度考虑，所需的时间还是太长。 Although this is less than the commercially available TOBI ® dosing time required, but with the degree of the patient, and patient-friendly point of view, the time is too long. EP2186508提到，使用呼吸致动吸入装置对于前面提到的商业上可获得的系统可以获得更快的给药时间。 EP2186508 mentioned breath actuated inhalation device used for the previously mentioned commercially available systems can be obtained faster delivery time. 但是，EP2186508 中使用呼吸致动吸入装置（AcroDose™)所获得的给药时间的实验仅限于低浓度的妥布霉素（60mg/ml)。However, EP2186508 using the breath actuated inhaler device (AcroDose ™) obtained experimental delivery time is limited to low concentrations of tobramycin (60mg/ml). 其还指出，使用AcroDose™系统的60mg/ml组合物给药,还必须给药第二可分量。 It also noted that the use AcroDose ™ system 60mg/ml composition administered may also be administered a second component. 从患者友好和配合角度来看，需要加入和给药第二可分量代表一种缺点。 Friendship and cooperation from the patient’s point of view, and the administration need to add a second component represents a drawback can be. [0015] 妥布霉素溶液也以局部给药出名，例如治疗角膜炎，参见Davis等人在“Canad. J Ophtal. ”(加拿大眼科杂志，1978年第13期273页)的文章,Davis等人在“Arch Opthalmol” (眼科杂志，1978年第96卷123-125页)的文章和Unter man等人在“ J. Cataract Refract. Surg. ”（白内障手术杂志，1988年第14卷500-504页）的文章。[0015] tobramycin solution is also famous for topical administration, such as treatment keratitis, see Davis et al in “Canad. J Ophtal.” (Canadian Journal of Ophthalmology, 1978 13 273) of the article, Davis, etc. in “Arch Opthalmol” (Ophthalmology 1978 Volume 96 pages 123-125) of articles and Unter man and others in “J. Cataract Refract. Surg.” (cataract surgery magazine, Volume 14, 500-504, 1988 pages) of the article. [0016] 现有给药手段和治疗方案的公知缺点是给药所需的时间，尤其影响患者的配合度和患者的生活质量。  Existing methods of administration and treatment programs known