Method of treating pulmonary diseases with liposomal amikacin formulations

FIELD: medicine.

SUBSTANCE: inventions refers to medicine, namely to pulmonology, and can be used for treating a pulmonary disorder in a patient. That is ensured by administering an effective dose of the nebulised liposomal amikacin formulation of 100 to 2,500 mg daily within the cycle of treatment, which involves the period of administration from 15 to 75 days and the following withdrawal period from 15 to 75 days. The cycle of treatment repeats at least twice.

EFFECT: invention provides improving the pulmonary function, which is supported for at least 15 days after the termination of treatment, and increasing the one-second forced expiratory volume (FEV1).

28 cl, 16 tbl, 11 dwg, 3 ex

 

This application claims provisional priority application U.S. No. 12/250412, filed October 13, 2008, the contents of which are incorporated by the reference in full.

Prior art

Cystic fibrosis (CF), also called mucoviscidosis, is an autosomal, recessive, hereditary disease of the exocrine glands. It affects the lungs, sweat glands and digestive system, causing chronic disorders of the respiratory and digestive systems. It is called as the result of mutations of the protein transmembrane conductance regulator cystic fibrosis (CFTR). This is the most common lethal autosomal recessive disease among the white race.

The first manifestation of CF is sometimes Makarieva bowel obstruction in 16% of infants who develop CF. Other symptoms of CF are manifested in the period of early childhood. Both the lungs and the pancreas produce abnormally viscous mucus. This mucus starts to grow and starts to clog the passages in the pancreas and lungs. Pulmonary problems begin with the constant presence of thick, viscous mucus, and represent one of the most serious complications of CF. Mucus in the lungs can become a growth medium for bacteria, resulting in chronic respiratory infections and end-Kee is the resultant damage to the lung tissue. During the final stage of the CF patient is experiencing increased congestion in the chest, activity intolerance, increased wheezing and reinforced cough, highlighting which often contains sputum mixed with blood (hemoptysis), caused by bleeding from the pulmonary arteries of the bronchioles. Chronic cough and cough with a firearm sounds normal in people with CF. These thick secrets also cause obstruction of the pancreas, preventing the flow in the intestinal digestive enzymes that help digestion and absorption of food. The frequency of stools with a foul odor is often an early symptom of CF along with fatty oils, which are visible in the stool. It can disrupt the growth and nutrition in General, if a suitable treatment to support digestion is not used in the early period of life. As lung function deteriorates in patients with CF may develop pulmonary hypertension, chronic bronchitis and chronic dilation of the bronchioles (bronchiectasis). Quite common is lung abscess. Death usually occurs from severe infections, pneumonia or heart failure.

Cystic fibrosis is exclusively inherited, because both parents must carry the recessive genes that the child has acquired the disease. At the genetic level cystic fibrosis is the most frequent result of de is ecii in the frame of three base pairs in DNA. Cystic fibrosis occurs in the production of abnormal forms of the protein, called transmembrane regulator conductivity cystic fibrosis (CFTR). CFTR is involved in the transport of chloride ions across epithelial cells found in the lung and intestinal tract. In patients with CF CFTR works poorly, causing the accumulation of ions in epithelial cells. As the water follows the ions in the osmotic process, this leads to the depletion of water and viscous mucus on the surface of the alveoli. The most common anomaly of the protein CFTR mutation is denoted as ∆F508, which is characterized by a deletion of the 3 p. O. in the sequence of DNA base-pairs are localized in chromosome 7q31.1-31.2, which encodes the amino acid phenylalanine.

In addition to lung infections, most people with CF also suffer from problems with digestion, especially the digestion of fats. This leads to malabsorption and difficulties in adding and maintaining weight, which in turn affects overall health. This is due to abnormally viscous mucus, which blocks the release of digestive enzymes from the pancreas. Failure of the pancreas treated with additional enzymes. Usually necessary mixed with water forms of fat-soluble vitamins A, D, E and K, as reduced absorption of fats may lead to deficit of these vitamins.

Patients CF also characterized by a high incidence of diabetes due to blockade of the pancreas. Chronic blockade causes over time the degradation of the islets of Langerhans and reduced production of insulin causes hyperglycemia. There is also evidence that CF patients become more resistant to the produced insulin that can be initiated by infection or treatment with corticosteroids. Diabetes in CF patients is usually referred to as CFRD, diabetes associated with cystic fibrosis. A normal diet for diabetics is not possible and, therefore, the dose of insulin instead adjust to the typical high-calorie/high-fat diet CF.

Many patients with CF expansion occurs to some extent their toes, known as "drumsticks". The condition affects the fingers and toes and lead to rounding and increase your fingertips. It can also be observed in people with COPD or severe heart disease. As people with CF are prone to poor absorption of nutrients, osteoporosis can occur early puberty due to low bone density. For people with CF is critical to regularly scan by measuring the absorption of x-rays of two different energies (DEXA) to measure bone density and begin treatment if necessary. With early diagnosis, the treatment can help prevent more serious complications.

Some CF patients are characterized by hearing loss as a result of side effect of prolonged use of medicines group-streptomycin/-streptomycin, such as tobramycin, which is used to fight lung infections. Although this side effect is well known and understood, these specific antibiotics are extremely valuable for the treatment of CF patients, and often hearing loss can be considered as a necessary compromise to preserve life and health. CF occurs primarily in individuals originating from Central and Western Europe. In the United States the median age of death increased with age of 8.4 years in 1969 until the age of 14.3 years in 1998 the Average age of death has increased from 14 years in 1969 until the age of 32, 4 years in 2003 (cystic fibrosis Foundation). The main contribution to a significant increase in life expectancy is improved antibiotic treatment of chronic infections of the respiratory tract of individuals with CF (Goss and Rosenfeld 2004), as well as improved nutrition and earlier diagnosis.

The main factor in the health of the respiratory tract in individuals with CF is susceptibility to chronic infection with Pseudomonas aeruginosa. The rate of P. aeruginosa infection increases with age and the age of 18 years, 80% of individuals with CF in the United States are infected. Difficulties in the treatment of this infection are multifactorial, including poor penetration of antibiotics in place of the infection, including mucosal tube, inactivation of antibiotics sputum in CF, the growth of bacteria in the biofilm, changes in phenotype, including turning in mulinuu form of P. Aeruginosa, and the emergence of multiple drug resistance (Chmiel and Davis 2003; Gibson, Burns et al. 2003). The cornerstone of treatment of the lungs is to optimize the treatment of P. Aeruginosa, because infection with this pathogen is associated with poor clinical outcome (Doring, Conway et al. 2000; Chmiel and Davis 2003; Gibson, Burns et al. 2003; Gibson, Emerson et al. 2003).

One of the modern approaches to the management of chronic P. Aeruginosa infection in a person with CF involves the use of a suppressor therapy with inhalation of tobramycin (TOBI®). Inhalated the tobramycin 300 mg, administered twice a day with cycles of 28 days later 28-day break taking medication, as shown, reduces the number of colonies of P. Aeruginosa increases predicted % FEV1reduces hospitalization and reduces the use of antibiotics (Ramsey, Pepe et al. 1999). However, patients should receive a dose twice a day at approximately 15-20 minute periods inhalations per dose.

Daily chest physiotherapy and treatment aerosol inhalation very commonly prescribed to patients CF. Normal fizioter the Oia includes hand percussion (effleurage) chest, the methods and devices of excessive pressure or possible use of the device, such as ThAIRapy Vest or intra-lungs percussive ventilator (IPV) to achieve the same effect: release of viscous mucus. Usually given aerosol medications include albuterol, ipratropium bromide and Pulmozyme for releasing secrets and reduce inflammation. Found that those CF patients, which passed from one to another, were healthier; in subsequent some hospitals used sprayed 6%-10% saline those CF patients who did not have asthma, for the release of secrets. To combat infections sometimes give inhalated aminoglycoside antibiotics. Use a number of pharmacological agents that help in the elimination of mucus. N-acetylcysteine, which solubilities mucosal glycoprotein, however, was not approved as highly effective. Recombinant Tnkase person reduces the viscosity of sputum by destruction of concentrated amount of DNA in the sputum of patients with CF. Treatment Dnazol advantageous to increase the airway during short-term use and also prolongs the interval between episodes of pulmonary exacerbations.

Patients CF usually hospitalized somewhat regularly, often every 6 months depending on the severity of injury. the Aulnay often receive intravenous antibiotics through catheters PICC line, the Central line or Port-a-Caths.

Cystic fibrosis can also lead to bronchiectasia. Bronchiectasis is an abnormal stretching and expansion of the respiratory tract caused by the blockage of mucus. When the body cannot get rid of mucus, the mucus becomes sticky and is accumulated in the respiratory tract. Blockade and followed the infection causes inflammation, leading to weakening and expansion paths. Weakened paths can be covered with scars and deform, allowing mucus and bacteria to accumulate to a greater extent, resulting in fatigued infection and blockage of the respiratory tract. Bronchiectasis is a disease that causes localized irreversible expansion of part of the bronchial tree. Involved bronchi dilate, become inflamed and easy to tear, leading to obstruction of the airway and disturbance of breeding secrets. Bronchiectasis is associated with a wide range of disorders, but it usually results necrotizing bacterial infections, such as infections caused by Staphylococcus or Klebsiella or Bordatella pertussis.

Bronchiectasis is one of the chronic obstructive pulmonary diseases (COPD) and it may be complicated by emphysema and bronchitis. The disease is usually wrongly diagnosed as asthma or pneumonia.Bronchiectasis can develop at any age, most often starts in childhood, but symptoms may not be evident for a long time. Bronchiectasis may occur as part of a congenital defect, such as primary ciliary dyskinesia, or cystic fibrosis. Approximately 50% of all cases of bronchiectasia in the United States occurs due to cystic fibrosis. It may also develop after birth as a result of trauma or other diseases, such as tuberculosis, pneumonia and influenza.

The expansion of the bronchial walls leads to obstruction of the airway and impaired excretion of secrets, because the extended region impede the normal pressure of air in the bronchial tubes, causing stagnation of phlegm in the enhanced areas instead of push it up. Stagnant mucus creates an environment that leads to the growth of infectious pathogens, and these areas of the lungs become so very sensitive to infection. The more experience mild infections, the more become damaged lung tissue and alveoli. When this happens, the bronchioles become more stiff and extended, which creates endless destructive cycle of this disease.

There are three types of bronchiectasia, varying in severity. Spindle-shaped (cylindrical) bronchiectasis (most common type) refers to moderately inflamed the output bronchi, who lose the ability to narrow distally. When varicose bronchiectasia bronchial wall look setcoursename as expanding interspersed with areas of konstruktsii. Saccular (cystic) bronchiectasis is characterized by severe, irreversible swelling of the peripheral bronchi with or without levels of air-liquid. Noticeable chronic productive cough, which occurs in up to 90% of patients with bronchiectasis. Sputum is produced daily in 76% of patients.

In addition to CF other genetic causes or factors contributing to the bronchiectasis include syndrome Addition, the syndrome Jung, deficiency of alpha-1-antitrypsin deficiency and variants of primary immunodeficiency. Acquired bronchiectasis occurs more frequently, and one of the most important reasons is tuberculosis. Especially the typical cause of the disease in children is acquired immunodeficiency syndrome resulting from actions of the human immunodeficiency virus. Other causes of bronchiectasia include respiratory tract infections, obstruction, inhalation and aspiration of ammonia and other toxic gases, pulmonary aspiration, alcoholism, heroin and allergies. Cigarette Smoking can also contribute to bronchiectasis.

The diagnosis of bronchiectasia is based on the study of the history and characteristic putt is RNAV data CT scan with high resolution. Such patterns include anomalies tree with the kidneys and cysts with definable boundaries. Bronchiectasis may also be diagnosed without confirmation by CT scan, if history is clearly detected frequent respiratory tract infections, as well as proof of the underlying problems with the blood and culturing sputum samples.

Symptoms include cough (downward when moving in the horizontal position), shortness of breath, abnormal sounds in the chest, weakness, weight loss and fatigue. For infections of the mucus may be discolored, with an unpleasant odor and may contain blood. The severity of symptoms varies widely from patient to patient and from time to time, until asymptomatic patient.

The goal of treatment of bronchiectasia is controlling infections and bronchial secretions, relieving airway obstruction and prevention of complications. This includes continued use of antibiotics to prevent harmful infections and remove akkumulirovalasj fluid with postural drainage and chest physiotherapy. Can also be used as a surgical intervention for the treatment of local bronchiectasia, with the removal of the obstructive areas that may cause disease progression.

Inhalation strainatate, which firmly adhere to reduce sputum production and decrease konstruktsii respiratory tract, during a period of time should prevent the progression of bronchiectasia. One of the commonly used treatment options is beclomethasone dipropionate, also used in the treatment of asthma. Use of inhalers, such as albuterol (salbutamol), fluticasone (flovent/flixotide) and ipratropium (atrovent), can reduce the likelihood of infection by clearing the Airways and reduce inflammation.

Inhaled dry powder mannitol called bronchitol approved by the FDA for use in patients with cystic fibrosis with bronchiectasis. The original indication for orphan drugs approved in February 2005, allowed its use for the treatment of bronchiectasia. The original approval was based on results of phase 2 clinical trials, which demonstrated that the product is safe, well-tolerated and effective for the stimulation of hydration/remove the mucus, thereby improving the quality of life in patients with chronic obstructive lung diseases such as bronchiectasis. Continued to develop long-term studies up to 2007, with the guarantee of the safety and efficacy of treatment.

Patients with bronchiectasis often give antibi the ticks for infection control and bronchodilators to open ways. Sometimes antibiotics are prescribed for a long period to prevent recurrent infections, especially in people who suffer from cystic fibrosis. There are also methods of physiotherapy to aid in the removal of mucus. Lung transplantation is also an option in severe cases. Death is not common, but may occur due to massive hemorrhage. If pulmonary infection is treated immediately, there was less likelihood of bronchiectasia.

Pneumonia is a disease of the lungs and respiratory system in which the alveoli (microscopic air-filled sacs of the lung responsible for absorbing oxygen from the atmosphere) become inflamed and filled with fluid. Pneumonia can result from various causes, including infection with bacteria, viruses, fungi or parasites, and chemical or physical damage to the lungs. Typical symptoms associated with pneumonia include cough, chest pain, fever, and shortness of breath. Diagnostic tools include x-ray and sputum examination.

Therefore, there is a need for drugs to treat pulmonary disorders, including CF, pulmonary infection, COPD, bronchiectasis, and others. In addition, there is a need to improve lung is uncle patients with such violations.

Summary of the invention

The present invention partially relates to a method for treatment of pulmonary disorders in a patient, comprising an introduction to the patient an effective dose of the powdered composition of liposomal amikacin for at least one treatment cycle, where:

the treatment cycle includes a period of introduction from 15 to 75 days, with a subsequent period of cancellation within 15 to 75 days;

and effective dose ranges from 100 to 2500 mg of amikacin daily during the period of introduction.

In some embodiments, implementation of the treatment cycle with the introduction of the patient is repeated at least twice. In some embodiments, the implementation period is from 15 to 35 days, or from 20 to 35 days. In other embodiments, the implementation period is 28 days. In some embodiments, the implementation of the cancellation period is from 15 to 35 days, or from 20 to 35 days. In other embodiments, implementation of the cancellation period is 28 days. In some embodiments, the implementation of the cancellation period is from 25 to 75 days, from 35 to 75 days, or from 45 to 75 days. In other embodiments, implementation of the cancellation period is approximately 56 days.

In some embodiments, the implementation period is about 28 days, and the cancellation period is about 28 days, whereas the other variants of the implementation period is about 28 days and the cancellation period is approximately 56 days.

In some embodiments, the effective dose ranges from 250 to 1500 mg of amikacin, from 250 to 1000 mg of amikacin or from about 280 to about 560 mg of amikacin. In other embodiments, the effective dose is about 280, or about 560 mg of amikacin.

In some embodiments, the implementation of the pulmonary breach selected from the group consisting of chronic obstructive pulmonary disease, bronchiectasia, pulmonary infection, cystic fibrosis, deficiency of the enzyme alpha-1-antitrypsin deficiency, and combinations thereof. In other embodiments, implementation of the lung condition is a bacterial infection of the lungs, such as infection with P. aeruginosa. In some embodiments, the implementation status light represents the bronchiectasis.

In some embodiments, the implementation of the patient has a Cmaxamikacin in serum of less than approximately 10 μg/ml during the period of introduction. In other embodiments, implementation of the patient has a Cmaxamikacin in sputum at least 1000 μg per gram of sputum or during the injection or within at least 15 days after injection.

In some embodiments, the implementation of the patient is characterized by a decrease in log10SOME bacterial infection in the lungs of at least 0.5 for at least 15 days after the end of the period is Yes introduction. In other embodiments, implementation of the reduced log10SOME is at least 1,0.

In some embodiments, the implementation of the patient is experiencing improvement in lung function for at least 15 days after the end of the introduction. For example, the patient may experience an increase in FEV1the growth of blood oxygen saturation, or both effects. In some embodiments, the implementation of the patient has FEV1that is increased at least 5% above FEV1before the treatment cycle. In other embodiments, the implementation of FEV1increased by from 5 to 50%. In other embodiments, the implementation of FEV1increased by 25 to 500 ml over FEV1before the treatment cycle. In some embodiments, the implementation of the oxygen saturation is increased at least 1% above the oxygen saturation before treatment cycle.

In some embodiments, the implementation of the length of time to exacerbation of pulmonary disease is at least 20 days from the last day of introduction. In other embodiments, implementation of the duration of time before relieving treatment is at least 25 days from the last day of the injection.

In some embodiments, the implementation of the composition of the liposomal amikacin comprises a lipid selected from the group consisting of egg phosphatidylcholine (EPC), phosphatidylglycerol eggs (EPG), phosphatidylinositol eggs (EPI), statitician eggs (EPS), phosphatidylethanolamine (EPE), phosphatidic acid (EPA), soy phosphatidylcholine (SPC), phosphatidylglycerol soybean (SPG), phosphatidylserine soy (SPS), phosphatidylinositol soy (SPI), soy phosphatidylethanolamine (SPE), phosphatidic acid soybean (SPA), hydrogenated egg phosphatidylcholine (HEPC), hydrogenated phosphatidylserine eggs (HEPG), hydrogenated phosphatidylinositol eggs (HEPI), hydrogenated phosphatidylserine eggs (HEPS), hydrogenated phosphatidylethanolamine (HEPE), hydrogenated phosphatidic acid (HEPA), hydrogenated soy phosphatidylcholine (HSPC), hydrogenated phosphatidylserine soybean (HSPG), hydrogenated phosphatidylserine soy (HSPS), hydrogenated phosphatidylinositol soybean (run inline with the blow), hydrogenated soybean phosphatidylethanolamine (HSPE), hydrogenated phosphatidic acid soybean (HSPA), dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylcholine (DMPG), dipalmitoylphosphatidylcholine (DPPG), distearoylphosphatidylcholine (DSPC), distearoylphosphatidylglycerol (DSPG), dioleoylphosphatidylcholine (DOPE), palmitoyloleoylphosphatidylcholine (PSPC), palmitoyloleoylphosphatidylglycerol (PSPG), manualearphonesinstallation (MOPE), cholesterol, ergosterol, larosterna, tocopherol, ammonium salts of fatty acids, ammonium salts FOS is olpidem, ammonium salts of glycerides, myristamine, polymethylene, laurylamine, stearylamine, dilauroylglycerophosphocholine (DLEP), dimyristoylphosphatidylcholine (DMEP), dipalmitoylphosphatidylcholine (DPEP) and distearoylphosphatidylcholine (DSEP), N-(2,3-di-(9-(Z)-octadecanoyloxy))-prop-l-yl-N,N,N-trimethylammonium chloride (DOTMA), 1,2-bis(oleolux)-3-(trimethylammonio)propane (DOTAP), phosphatidylglycerols (PGs), phosphatidic acids (PAs), synthesised (PIs), phosphatidylserines (PSs), distearoylphosphatidylglycerol (DSPG), dimyristoylphosphatidylcholine acid (DMPA), dipalmitoylphosphatidyl acid (DPPA), distearoylphosphatidylcholine acid (DSPA), dimyristoylphosphatidylcholine (DMPI), dipalmitoylphosphatidylcholine (DPPI), distearoylphosphatidylglycerol (DSPI), dimyristoylphosphatidylcholine (DMPS), dipalmitoylphosphatidylcholine (DPPS), distearoylphosphatidylcholine (DSPS) and their mixtures. In other embodiments, implementation of the composition of the liposomal amikacin comprises a phospholipid and a Sterol, such as DPPC and cholesterol. In other embodiments, implementation of the composition of the liposomal amikacin comprises DPPC and cholesterol in a ratio of approximately 2: 1 by weight. In some embodiments, the implementation of the composition of the liposomal amikacin has the ratio of lipid to the drug from approximately 0.5 to approximately 1.0, from about 0.5 to 0.7, or approximately 0.6 by weight.

Brief description of the of figures

The figure 1 shows the mass distribution of sputtered particles liposomal amikacin gathered speed impactor, as a function of the limiting diameter. Used three lots of liposomal amikacin from caption to table 15 (labeled 1, 2 and 3) with eFlow nebulizer system ACI (filled symbols) or with a nebulizer LDC Star and the NGI system (unfilled symbols).

The figure 2 shows the decrease in Log10CFU/lungs of rats after inhalation of liposomal amikacin 75 mg/ml or tobramycin. Symbols represent Log10CFU/lungs each rats 18 days after drip PA3064 in agar beads and 3 days after the last session of the inhalation of saline or one of the above antibiotics. Values of 2.0 Log10SOME represent the lower limit of the method of determination of bacteria in the lung. The segments represent the average in each group. Results mean and standard deviations and bilateral t-test was calculated using the Excel program from Microsoft.

The figure 3 shows the decrease in Log10CFU/lungs of rats after inhalation of liposomal amikacin and tobramycin within 28 days. Equivalent dose to the above antibiotics were given via inhalation, but on different circuits. The tobramycin were given two times per day E. dnevno total within 104 minutes a day for 28 days. Liposomal amikacin given once a day for 80 min for 28 days (Q1Dx28), as well as saline. Liposomal amikacin was also given once daily for 160 min each day for 28 days (Q2Dx14), as well as saline or once a day for 160 min 14 consecutive days (Q1DX14), then objectively observed up until the rats were subjected to euthanasia. Symbols represent Log10CFU/lungs each rat 35 days after drip P. aeruginosa 3064 in agar beads. Averages and standard deviations, as well as bilateral t-test was calculated using the Excel program from Microsoft.

The figure 4 shows the scheme of studies for research 4, where patients received liposomal amikacin daily for 28 days with subsequent monitoring during the 28-day period after the last day of the injection.

Figure 5 depicts a graph showing the percentage increase in oxygen saturation over baseline in patients receiving a dose of 280 mg of amikacin compared with placebo.

Figure 6 depicts a graph showing the oxygen saturation in patients receiving a dose of 560 mg of amikacin compared with placebo.

Figure 7a shows a graph of lung function with age on the measurement of FEV1 in the group with PLA is ebo. Data on placebo for options as to 280 and 560 mg of amikacin, were combined and divided by age. Data for Arikace™ for options 280 and 560 mg of amikacin were combined and divided by age.

Figure 7b shows the change in lung function with age in patients treated with inhalation of liposomal amikacin.

The figure 8 shows a graph comparing the change in FEV1 (measured in ml) in groups with 560 mg and 280 mg of amikacin and the placebo group.

Figure 9 depicts a graph showing the change in FEV1 as percent relative to the baseline among the groups with 560 mg of amikacin, 280 mg of amikacin and placebo.

The figure 10 shows a graph of Log CFU in all patients.

The figure 11 shows a graph of Log CFU for Mokoena strains.

Detailed description of the invention

I. Definitions

For convenience, before further description of the present invention in this section certain terms used in the description, examples and appended claims. These descriptions should be read in light of the remainder of the disclosure and to be understood by a person skilled in the art. Unless otherwise noted, all methodical and scientific terms used in this description have the same meaning as commonly understood by a person skilled in the technical field.

The term "levocetirizine" refers to any disease, ailment or another painful condition related to the respiratory tract of the individual, especially to the lungs of the individual. Usually a pathological condition of the lungs leads to difficulty breathing.

The term "treatment" is known in the art and refers to the treatment and to alleviate at least one symptom of any condition or disease.

The term "prophylactic" or "therapeutic" treatment is known in the art and refers to the introduction to the recipient one or more appropriate compositions. If it is entered before the clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the animal-recipient), then the treatment is prophylactic, i.e., it protects the recipient against developing the unwanted condition, whereas if it is entered after the manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to reduce, alleviate or retain an unwanted condition or side effects).

The terms "therapeutically effective dose" and "therapeutically effective amount" refers to the number of connections, which leads to the prevention or relief of symptoms in a patient or a desired biological outcome, e.g., improvement in clinical signs is s, delayed the onset of disease, reduced levels of bacteria and so on

The term "FEV1" well known in the art as a criterion of lung function and denotes forced expiratory volume in one second. Values of FEV1used in the present description, measured in ml, as well as the percentage change from baseline, for example, change from the value before treatment.

"Patient", "individual" or "recipient" subjected to treatment using the presented method, can mean either human or animal, not a person.

The term "mammal" is well known in the art and examples of mammals include humans, primates, cows, pigs, dogs, cats and rodents (e.g. mice and rats).

The term "bioavailable" is known in the art and refers to the shape of the present invention, which takes into account that the quantity entered or part of it should be absorbed, incorporated into or otherwise be physiologically available for individual or patient, which it is entered.

The term "pharmaceutically acceptable salt" is known in the art and refers to a relatively non-toxic, additive salts of the compounds with inorganic and organic acids, including, for example, salt is contained in the compositions of the present invention.

The term "pharmaceutically acceptable carrier" is known in the art and refers to a pharmaceutically acceptable substance, composition or filler, such as a liquid or solid filler, diluent, forming agent, solvent or encapsulating substance involved in the transfer or transportation of any of this song or its component from one organ or body part to another body or body part. Each carrier must be "acceptable" in the sense of being compatible with the particular composition and its components and do not harm the patient. Some examples of substances which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; (4) powder tragakant; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and waxes suppositories; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, lures, and polyethylene glycol; (12) esters, such as Achillea and tillaart; (13) agar; (14) tabularasa agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical compositions.

II. Liposomal amikacin

Formulations of liposomal amikacin suitable in the methods disclosed in the present description, can be obtained as described, for example, in the publication U.S. No. 20060073198 or 20080089927, both of which are included in the present description by reference. Usually amikacin is used in the form of a pharmaceutically acceptable salt, for example, amikacin sulfate salt.

The lipids used in the compositions of the present invention can be synthetic, semi-synthetic or natural lipids, including phospholipids, Tocopherols, steroids, fatty acids, glycoproteins, such as albumin, anionic lipids and cationic lipids. Lipids can be anionic, cationic or neutral. In one embodiment, the lipid composition is essentially free of anionic lipids, essentially free of cationic lipids or both. In one embodiment, the lipid composition includes only the neutral lipids. In another embodiment, the lipid with the Tav is free from anionic lipids or cationic lipids or both. In another embodiment, the lipid is a phospholipid. Phospholipids include egg phosphatidylcholine (EPC), phosphatidylglycerol eggs (EPG), phosphatidylinositol eggs (EPI), phosphatidylserine eggs (EPS), phosphatidylethanolamine (EPE) and phosphatidic acid eggs (EPA); duplicates soybeans, soy phosphatidylcholine (SPC); SPG, SPS, SPI, SPE and SPA; hydrogenated duplicates eggs and soybeans (for example, HEPC, HSPC), other phospholipids, artificially created through ester bonds of fatty acids in positions 2 and 3 of glycerol, containing a chain of from 12 to 26 carbon atoms and different head groups in position 1 of glycerol, which include choline, glycerol, Inositol, serine, ethanolamine and the corresponding phosphatidic acid. Chain these fatty acids can be saturated or unsaturated, and the phospholipid may be formed from fatty acids with different lengths of chains and varying degrees of saturation. In particular, compositions compositions may include dipalmitoylphosphatidylcholine (DPPC), the main component of natural lung surfactant, and dioleoylphosphatidylcholine (DOPC). Other examples include dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylcholine (DMPG), dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylcholine (DPPG), distearoylphosphatidylcholine (DSPC) and distearoylphosphatidylglycerol (DSPG), dioleoylphosphatidylcholine is n (DOPE) and mixed phospholipids, such as palmitoyloleoylphosphatidylcholine (PSPC) and palmitoyloleoylphosphatidylglycerol (PSPG), triacylglycerol, diacylglycerol, ceranic, sphingosine, sphingomyelin and monosilane phospholipids, such as manualearphonesinstallation (MOPE).

Used lipids may include ammonium salts of fatty acids of phospholipids and glycerides, phosphatidylglycerols (PGs), phosphatidic acids (PAs), phosphatidylcholines (PCs), synthesised (PIs) and phosphatidylserines (PSs). Fatty acids include fatty acids with lengths of carbon chains of from 12 to 26 carbon atoms, which are either saturated or unsaturated. Some specific examples include: militiamen, palmitylated, laurylamine and stearylamine, dilauroylglycerophosphocholine (DLEP), dimyristoylphosphatidylcholine (DMEP), dipalmitoylphosphatidylcholine (DPEP) and distearyldimethyl (DSEP), N-(2,3-di-(9(Z)-octadecanoyloxy))-prop-l-yl-N,N,N-trimethylammonium chloride (DOTMA), 1,2-bis(oleolux)-3-(trimethylammonio)propane (DOTAP). Examples PGs, PAs, PIs, PCs and PSs include DMPG, DPPG, DSPG, DMPA, DPPA, (DSPA, DMPI, DPPI, DSPI, DMPS, DPPS and DSPS, DSPC, DPPG, DMPC, DOPC, PC eggs.

In another embodiment, the liposome comprises a lipid selected from the group consisting of phosphatidylcholines (PCs), phosphatidylglycerols (PGs), phosphatidic acids (PAs), synthesised (PIs) and phosphatidylserines (PSs).

In another embodiment, lip which d is selected from the group consisting of: egg phosphatidylcholine (EPC), phosphatidylglycerol eggs (EPG), phosphatidylinositol eggs (EPI), phosphatidylserine eggs (EPS), phosphatidylethanolamine (EPE), phosphatidic acid (EPA), soy phosphatidylcholine (SPC), phosphatidylglycerol soybean (SPG), phosphatidylserine soy (SPS), phosphatidylinositol soy (SPI), soy phosphatidylethanolamine (SPE), phosphatidic acid soybean (SPA), hydrogenated egg phosphatidylcholine (HEPC), hydrogenated phosphatidylserine eggs (HEPG), hydrogenated phosphatidylinositol eggs (HEPI), hydrogenated phosphatidylserine eggs (HEPS), hydrogenated phosphatidylethanolamine (HEPE), hydrogenated phosphatidic acid (HEPA), hydrogenated soy phosphatidylcholine (HSPC), hydrogenated phosphatidylserine soybean (HSPG), hydrogenated phosphatidylserine soy (HSPS), hydrogenated phosphatidylinositol soybean (run inline with the blow), hydrogenated soybean phosphatidylethanolamine (HSPE), hydrogenated phosphatidic acid soybean (HSPA), dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylcholine (DMPG), dipalmitoylphosphatidylcholine (DPPG), distearoylphosphatidylcholine (DSPC), distearoylphosphatidylglycerol (DSPG), dioleoylphosphatidylcholine (DOPE), palmitoyloleoylphosphatidylcholine (PSPC), palmitoyloleoylphosphatidylglycerol (PSPG), monooleate is telethonin (MOPE), tocopherol, ammonium salts of fatty acids, ammonium salts, phospholipids, ammonium salts, glycerides, myristamine, polymethylene, laurylamine, stearylamine, dilauroylglycerophosphocholine (DLEP), dimyristoylphosphatidylcholine (DMEP), dipalmitoylphosphatidylcholine (DPEP) and distearoylphosphatidylcholine (DSEP), N-(2,3-di-(9-(Z)-octadecanoyloxy))-prop-l-yl-N,N,N-trimethylammonium chloride (DOTMA), 1,2-bis(oleolux)-3-(trimethylammonio)propane (DOTAP), distearoylphosphatidylglycerol (DSPG), dimyristoylphosphatidylcholine acid (DMPA), dipalmitoylphosphatidyl acid (DPPA), distearoylphosphatidylcholine acid (DSPA), dimyristoylphosphatidylcholine (DMPI), dipalmitoylphosphatidylcholine (DPPI), distearoylphosphatidylglycerol (DSPI), dimyristoylphosphatidylcholine (DMPS), dipalmitoylphosphatidylcholine (DPPS), distearoylphosphatidylcholine (DSPS) and their mixtures.

In another embodiment, the liposome comprises a lipid selected from the group consisting of phosphatidylcholine. Phosphatidylcholine may be unsaturated, such as DOPC or POPC, or saturated, such as DPPC. In another embodiment, the liposome does not include the Sterol. In one embodiment, the liposome is essentially composed of phosphatidylcholine and Sterol. In another embodiment, the liposome is essentially composed of DPPC and cholesterol.

Liposomes or lipid anti-infective compounds, consisting of the of opticalchannel, such as DPPC, contribute to the capture of lung cells, such as alveolar macrophages, and help to support the release of anti-infective agent in the lung (Gonzales-Rothi et al. (1991)). Negatively charged lipids, such as PGs, PAs, PSs and PIs, in addition to the reduction of particle aggregation may play a role in the parameters supported release inhalation composition, as well as in the transport of the compound through the light (transcytosis are activated) system for the receipt.

Not limited to any particular theory, believe that when the lipid comprises a neutral lipid and does not include negatively charged or positively charged phospholipid liposomal composition characterized by improved capture of light. For example, the liposome may have improved permeability in the biofilm or in the layer of mucus, when the lipid includes only neutral lipids. Examples of neutral lipids include the above phosphatidylcholine, such as DPPC and sterols, such as cholesterol.

IV. Treatment

The present invention is directed to methods of treating lung conditions in in need thereof of an individual including an introduction to the individual an effective amount of any of the above formulations of liposomal antibiotics. In some embodiments, the implementation of the lung condition is a bacterial INF is the Ktsia. In some embodiments, the implementation of the method includes the introduction to the needy in this patient an effective amount of the composition of the liposomal amikacin (also referred to in this description as "liposomal amikacin) by daily inhalation. In some embodiments, the implementation of the introduction using inhalation includes spraying liposomal composition.

In some embodiments, the implementation of the composition of the liposomal amikacin administered daily over a period of time followed by a period of time (the cancellation period), during which the liposomal composition is applied. For example, in some embodiments implement a method of treating pulmonary disorders includes an introduction to the patient an effective dose of the powdered composition of liposomal amikacin for at least one treatment cycle, where:

the treatment cycle includes a period of introduction from 15 to 75 days, followed by a period of cancellation within 15 to 75 days;

and effective dose ranges from 100 to 2500 mg of amikacin daily during the period of introduction.

In some embodiments, the implementation of the above cycle of treatment with the introduction of the patient is conducted at least twice. In other embodiments, implementation of the treatment cycle with the introduction of the patient can be held on 3, 4, 5, 6 or more times.

During the period of introduction of liposomal Amica is entered in a daily basis. In some embodiments, the implementation of liposomal amikacin may be entered each day or every third day during the period of introduction. As illustrated above, the introduction period can range from 15 to 75 days. In some embodiments, the implementation period is from 15 to 35 days, or from 20 to 35 days. In other embodiments, the implementation period is from 20 to 30 days, from 25 to 35 days, or from 25 to 35 days. In other embodiments, the implementation period is approximately 25, 26, 27, 28, 29 or 30 days. In other embodiments, the implementation period is about 28 days.

During the cancellation period the composition of the liposomal amikacin is not administered to the patient. In some embodiments, the implementation of the cancellation period is 15 days or more, for example, from 15 to 75 days, from 15 to 35 days, or from 20 to 35 days. In other embodiments, implementation of the cancellation period is from 20 to 30 days, from 25 to 35 days, or from 25 to 30 days. In other embodiments, implementation of the cancellation period is approximately 25, 26, 27, 28, 29 or 30 days. In other embodiments, implementation of the cancellation period is about 28 days, while in still some embodiments, the implementation of the cancellation period is at least 29 days.

In some embodiments, the implementation of the cancellation period is from 25 to 75 days, from 35 to 75 days is from 45 to 75 days. In other embodiments, implementation of the cancellation period is from 50 to 75 days, from 50 to 70 days, from 50 to 65 days or 50 to 60 days. In other embodiments, implementation of the cancellation period is approximately 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 days, while in other embodiments, implementation of the cancellation period is approximately 56 days.

In some embodiments, the implementation period is about 28 days, and the cancellation period is about 28 days, while in other embodiments, the implementation period is about 28 days and the cancellation period is approximately 56 days.

In some embodiments, the effective dose ranges from 250 to 1500 mg of amikacin, from 250 to 1000 mg of amikacin, from 250 to 750 mg of amikacin or from 250 to 700 mg of amikacin each day of the period of introduction. In other embodiments, the effective dose is from about 280 to about 560 mg of amikacin. In other embodiments, the effective dose is from about 230 to about 330 mg, or from about 510 to about 610 mg. In other embodiments, the effective dose of amikacin is about 280, or about 560 mg of amikacin.

In some embodiments, the implementation period is about 28 days, and the dose costs the t from about 280 to about 560 mg of amikacin. In other embodiments, the implementation period is about 28 days, and the cancellation period is about 28 days, and the dose is from about 280 to about 560 mg. In other embodiments, the implementation period is about 28 days, and the cancellation period is approximately 56 days, and the dose is from about 280 to about 560 mg

In some embodiments, the implementation of the pulmonary breach selected from the group consisting of chronic obstructive pulmonary disease, bronchiectasia, pulmonary infection, cystic fibrosis, deficiency of the enzyme alpha-1-antitrypsin deficiency, and combinations thereof. In some embodiments, the implementation is a lung condition cystic fibrosis. In other embodiments, implementation of the lung condition is a bacterial lung infection with Pseudomonas (e.g., P. aeruginosa, P. paucimobilis, P. putida, P. fluorescens and P. acidovorans), staphylococcal methicillin-resistant Staphylococcus aureus (MRSA), strep (including Streptococcus pneumoniae), Escherichia coli, Klebsiella, Enterobacter, Serratia, Haemophilus, Yersinia pesos, Burkholderia pseudomallei, B. cepacia, B. gladioli, B. multivorans, B. vietnamiensis, Mycobacterium tuberculosis, M. avium complex (MAC)(M. avium and M. intracellulare), M. kansasii, M. xenopi, M. marinum, M. ulcerans or M. fortuitum complex (M. fortuitum and M. chelonei) infection. In some embodiments, the implementation of infection is an infection with P. aeruginosa, then it is in other variants of the implementation of the infection is not tuberculous mycobacterial infection. Pulmonary infection may be related or may not be associated with cystic fibrosis. Thus, in some embodiments, the implementation status light represents both cystic fibrosis and lung infections, such as infection with P. aeruginosa. In other embodiments, the implementation status of the lungs represent the bronchiectasis. Bronchiectasis may be associated or not associated with cystic fibrosis.

In the presented method offers good levels of amikacin in place of pulmonary disorders with limited systemic exposure to the drug and also offers a sustainable advantage for the individual for unexpectedly long periods of time. Without regard to any specific theory it is believed that the introduction of liposomal amikacin in accordance with the methods described in the present invention, leads to the effect of "depot" in the lungs of the individual. Specifically, it is believed that liposomal particles are sufficiently small and contain suitable lipid composition for penetration and diffusion through the sputum of CF and the bacterial biofilm. Liposomes protect captured cationic amikacin in neutral liposomes, minimizing electrostatic interaction with negatively charged sputum/a biofilm that otherwise would have to reduce its bioavailability is awn. In addition, there are derived from P. aeruginosa virulence factors (rhamnolipid) (Davey et al. 2003), which release amikacin from liposomes. Therefore, it is assumed that relatively high concentrations of drugs can be delivered locally in the surrounding bacterial microcolony.

In addition, it is believed that inhalation of liposomal amikacin leads to dose-dependent involvement of macrophages as an adaptive response to inhalation of the composition of the drug/lipid. The presence of alveolar macrophages (which, as shown, are functionally normal in rats treated with liposomal amikacin) may be especially beneficial in patients with CF. Patients CF are known to have in his lungs, decreased levels of macrophages and possibly with poor functional activity that can contribute to chronic lung infection by P. aeruginosa in a stronger prevalence of non-tuberculous mycobacterial infection in this population. Dose-dependent involvement of macrophages may also contribute to the maintenance of the effects observed when using methods of the present invention. Specifically, macrophages in the lung can capture liposomal amikacin and then remain in the lung for a certain period of time with subsequent release of liposomal amikacin macrophages. lynchesque study (described in the examples below) liposomal amikacin in patients with CF, chronically infected with P. aeruginosa demonstrated the safety, tolerability and dose-dependent improvement in lung function and respiratory symptoms; and the decrease in the density of bacteria in the sputum at the end of the 28-day treatment. This improvement in lung function was maintained for at least 28 days after treatment (56th day) dose of 560 mg of liposomal amikacin, which indicates that supported the treatment effect.

Thus, the methods of the present invention in some embodiments, the implementation provide the best levels of amikacin in blood and sputum. For example, the methods provide a relatively low systemic exposure with amikacin at the same time, delivering high levels supported amikacin in place of pulmonary disorders. For example, in some embodiments, the implementation of Cmaxamikacin in serum of the patient is less than about 25 μg/ml during the period of introduction. In other embodiments, the implementation of Cmaxserum is less than 20, 15, 10, 5 or 2 μg/ml during the period of introduction.

In some embodiments, the implementation of Cmaxamikacin in the sputum of the patient is at least about 500 μg per gram of sputum or during the injection or within an extended period of time, such as at least 15 days after injection. In other in which the options for the implementation of C maxamikacin sputum is at least, 750, 1000, 1500, 2000, 2500, 3000 or 3500 micrograms per gram of sputum.

When pulmonary violation includes a lung infection, the present invention also proposes the reduction of colony forming units of bacteria in the lung for an extended period of time. For example, SOME decrease in comparison with the size of the original level. In some embodiments, the implementation of the patient is characterized by a decrease in log10SOME bacterial infection in the lungs of at least approximately 0.5 for at least 15 days after the end of the introduction. In other embodiments, implementation of the reduced log10SOME is at least 1.0, 1.5, 2.0mm or 2.5. During infection with Pseudomonas, in particular, can form large colonies, known as "maloigne" Pseudomonas, especially in patients with cystic fibrosis. In some embodiments, the implementation of SOME reduced as described above, in Mokoena strain during infection with Pseudomonas.

In some embodiments, the implementation of the patient is experiencing improvement in lung function for at least 15 days after the end of the introduction. For example, the patient may experience an increase in the forced expiratory volume in one second (FEV1), increased blood oxygen saturation, or both effects. In some embodiments, the implementation of bol is Noah has FEV 1that is increased at least 5% or at least 10% above FEV1before the treatment cycle. In other embodiments, the implementation of FEV1increased by from 5 to 50%, from 5% to 25%, or from 5 to 20%. In other embodiments, the implementation of FEV1increased by 5% to 15% or from 5% to 10%. In other embodiments, the implementation of FEV1increased by from 10 to 50%, from 10 to 40% from 10% to 30% or from 10% to 20%. FEV1often measured in ml, Respectively, in some embodiments, the implementation of FEV1increases of at least 25 ml compared with FEV1before treatment. In some embodiments, the implementation of FEV1increased by 25 to 500 ml, from 25 to 400 25 to 300 or 25 to Jr. In other embodiments, the implementation of FEV1increases from 50 to 500 ml, from 50 to 400 ml, from 50 to 300 ml, 50 to 200 ml or 50 to 100 ml.

In some embodiments, the implementation of the blood oxygenation increases in an individual compared to levels of blood oxygen saturation before the introduction. In some embodiments, the implementation of the oxygen saturation is increased at least 1% or at least 2% for at least 15 days after the period of introduction. In other embodiments, the implementation levels of blood oxygen saturation increased from approximately 1 to 50%, from 1 to 25%, from 1% to 15%, from 1% to 10% or from 1% to 5%. In other embodiments, implementation of the saturation levels of the shelter is oxygen increase by approximately 2% to 10% or from 2% to 5%.

The above extended periods of time can be at least, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or 75 days after the period of introduction. In other embodiments, the implementation of a long period of time is at least 28, 35, 42, 48, or 56 days after the period of introduction. In other embodiments, the implementation of a long period ranges from 15 to 75 days, from 15 to 35 days, or from 20 to 35 days. In other embodiments, the implementation of an extended period of time ranges from 20 to 30 days, from 25 to 35 days, or from 25 to 30 days. In other embodiments, the implementation of a long period of time is about 25, about 26, about 27, about 28, about 29, or about 30 days or about 28 days, or at least 29 days. In other embodiments, the implementation of an extended period of time lasts for 25 to 75 days, from 35 to 75 days, or from 45 to 75 days. In other embodiments, the implementation of a long period ranges from 50 to 75 days, from 50 to 70 days, from 50 to 65 days or 50 to 60 days. In other embodiments, implementation of the extended period is about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, or about 60 days, then the and as in other variants of the implementation of the extended period is approximately 56 days.

In some embodiments, the implementation of the above methods advantageously provide for the reduction of pulmonary exacerbations in a patient. The method also advantageously increases the length of time to pulmonary exacerbation. For example, in some embodiments, the exercise duration time to pulmonary exacerbation is at least about 20 days. In other embodiments, implementation of the length of time varies from 20 to 100 days. In other embodiments, the exercise duration time is from 25 to 100 days, from 30 to 100 days, from 35 to 100 days, or from 40 to 100 days. In other embodiments, the exercise duration time is from 25 to 75 days, from 30 to 75 days, from 35 to 75 days, or from 40 to 75 days. In other embodiments, implementation of the length of time is 30 to 60 days.

In some embodiments, implementation of the reduced degree relieving treatment. In other embodiments, implementation of the reduced length of time, relieving treatment, for example, when a patient has a lung infection, reduced time to deliver anti-infective treatment. In some embodiments, the implementation of the length of time varies from 20 to 100 days. In other embodiments, the exercise duration time is from 25 to 100 days, from 30 to 100 days, from 35 to 100 days, or from 40 to 100 DN is th. In other embodiments, the exercise duration time is from 25 to 75 days, from 30 to 75 days, from 35 to 75 days, or from 40 to 75 days. In other embodiments, implementation of the length of time is 30 to 60 days.

In some embodiments, the implementation of the composition of the liposomal amikacin used in the above methods include amikacin, and any of the lipids described above. In some embodiments, the implementation of the composition of the liposomal amikacin comprises a phospholipid and a Sterol, such as DPPC and cholesterol. In other embodiments, implementation of the composition of the liposomal amikacin comprises DPPC and cholesterol in a ratio of approximately 2: 1 by weight. In some embodiments, the implementation of the composition of the liposomal amikacin has the ratio of lipid to the drug from approximately 0.5 to approximately 1.0, from about 0.5 to 0.7, or approximately 0.6 by weight. In other embodiments, implementation of the composition of the liposomal amikacin has the ratio of lipid to the drug from about 0.3 to about 1.0 by weight, while in other embodiments, implementation of the ratio of lipid to the drug is from about 0.5 to about 0.7 or about to 0.65 by weight. Liposomes in the composition can be adjusted diameter from 100 to 1000 nm, from 100 to 500 nm, from 200 to 500 nm or about 300 nm. In some valentinorossini total concentration of amikacin in the composition of the liposomal amikacin ranges from approximately 20 to 100 mg/ml, from 20 to 90 mg/ml, from 30 to 90 mg/ml, from 30 to 80 mg/ml or 40 to 80 mg/ml In other embodiments, the implementation of the concentration is approximately 30, 40, 50, 60, 70, 80 or 90 mg/ml

In some embodiments, the implementation of the above method includes:

introduction to the patient an effective dose of the powdered composition of liposomal amikacin for at least one treatment cycle, where:

the treatment cycle includes a period of introduction for approximately 28 days followed by a withdrawal period for about 28 days;

effective dose comprises from about 280 to about 560 mg of amikacin daily during the period of administration; and

the composition of the liposomal amikacin comprises DPPC and cholesterol in a ratio of approximately 2:1 and the ratio of lipid to amikacin is from approximately 0.5 to approximately 0.7.

In other embodiments, implementation of the method includes:

introduction to the patient an effective dose of the powdered composition of liposomal amikacin for at least one treatment cycle, where:

the treatment cycle includes a period of introduction for approximately 28 days followed by a withdrawal period for approximately 56 days;

effective dose comprises from about 280 to about 560 mg of amikacin daily during the period of administration; and

the composition of the liposomal Amica is the Qing comprises DPPC and cholesterol in a ratio of approximately 2:1 and the ratio of lipid to amikacin is from approximately 0.5 to approximately 0.7.

In other embodiments implementing the present invention relates to a method of ensuring the lasting effects of the treatment of the individual, including: introduction to the patient an effective dose of the powdered composition of liposomal amikacin for at least one treatment cycle, where a cycle includes a period of introduction from 15 to 75 days, followed by a period of cancellation within 15 to 75 days; and the effective dose ranges from 100 to 2500 mg of amikacin daily during the period of introduction.

In another embodiment, the present invention relates to a method of improving levels of blood oxygen saturation in a patient with pulmonary condition, including: introduction to the patient an effective dose of the powdered composition of liposomal amikacin for at least one treatment cycle, where a cycle includes a period of introduction from 15 to 75 days, followed by a period of cancellation within 15 to 75 days; and the effective dose ranges from 100 to 2500 mg of amikacin daily during the period of introduction.

In another embodiment, the present invention relates to a method of improving FEV1a patient with pulmonary condition, including: introduction to the patient an effective dose of the powdered composition of liposomal amikacin for at least one treatment cycle, where a cycle includes a period is doing from 15 to 75 days, followed by a period of cancellation within 15 to 75 days; and effective dose ranges from 100 to 2500 mg of amikacin daily during the period of introduction.

In another embodiment, the present invention relates to a method of reducing bacterial density in the lung or sputum in a patient with bacterial pulmonary infection, including: introduction to the patient an effective dose of the powdered composition of liposomal amikacin for at least one treatment cycle, where a cycle includes a period of introduction from 15 to 75 days, followed by a period of cancellation within 15 to 75 days; and the effective dose ranges from 100 to 2500 mg of amikacin daily during the introduction, and where the bacterial density is reduced during at least 15 days after the last day of the injection.

Examples

Introduction to materials and methods

Compositions for inhalation-based lipid or liposomal aminoglycoside such as amikacin, represent the structures of aminoglycosides with the continuous release encased in liposomal carriers nano-range, designed for administration by inhalation. The direction of high concentrations of amikacin in continuous release into the lungs and properties of these compounds to penetrate the biofilm creates a number of advantages compared to the inhalation of "free" antibiotic, for example, and galleryimage tobramycin. Amikacin may be enclosed in liposomes consisting of dipalmitoylphosphatidylcholine (DPPC) and cholesterol in the target ratio of lipid to the drug approximately 0.6 to 0.7:1 (wt./mass.). An example of a composition with ~70 mg/ml of liposomal amikacin suitable in the above-mentioned methods, is presented below:

ComponentConcentration
Amikacin1~70 mg/ml
Dipalmitoylphosphatidylcholine (DPPC)~30 mg/ml
Cholesterol~15 mg/ml
a 1.5% NaClQS
1Added to the composition in the form of amikacin sulfate, USP.

These compounds may be obtained in accordance with the methods described in the publications U.S. 20060073198 or 20080089927, both of which are hereby incorporated by reference.

These compounds have several advantages in the treatment of lung diseases, for example, individuals with CF with chronic infection caused by P. aeruginosa, including:

1. The possibility of achieving prolonged antibiotic action of amikacin in the lung by achieving high concentrations and is glinennii half-life due to continuous release.

2. The ability to direct and increase the effective concentration of amikacin in the lung with a low system-level aminoglycoside.

3. The best direction against the growth of bacteria in the biofilm due to the unique properties based on the lipid or liposomal aminoglycosides.

4. Additional drug release at the site of infection in the lungs of patients with CF through directed action Sekretareva phospholipase C and rhamnolipids of bacteria and/or phospholipase A2 or defensins from activated polymorphically leukocytes.

5. Amikacin is a semisynthetic aminoglycoside with a unique resistance to enzymes that inactivate aminoglycosides. Therefore, some strains of P. aeruginosa that are resistant to tobramycin, apparently, must remain sensitive to amikacin.

6. Amikacin has less affinity compared with other aminoglycosides to megalin, the Transporter responsible for the accumulation of aminoglycosides in the cortex of the kidney, and thus has obviously lower nephrotoxicity.

7. And increased half-life, and increased area under the concentration curve (AUC) based on lipid or liposomal aminoglycoside along with the penetration of the biofilm should provide less frequent introduction, polysensitized activity and reduced the possibility of selection of resistant organisms.

Preclinical pharmacokinetics showed that the AUC (0-48 HR) of amikacin in the lungs of rats that received a dose of 60 mg/kg aerosol liposomal amikacin was 5 times higher AUC of tobramycin in the lungs of rats that had received an equal dose of tobramycin by inhalation. In General, 10% of the injected antibiotic remains in the lungs of rats. Conversely, the AUC of the drug in the kidneys of rats that had received an equal dose of tobramycin was significantly higher than the AUC in kidney of rats treated with aerosols of liposomal amikacin. In addition, the data Toxicological studies 30-day inhalation in rats and dogs suggest that dangerous pharmacological effects through inhalation of liposomal amikacin should not be.

In studies on rat models with 14-day infection pseudomonas was observed that 60 mg/kg of liposomal amikacin (75 mg/ml), injected every other day for 14 days (Q2Dx7), which now supplies half of the total dose of aminoglycoside compared with other groups, were as effective as 60 mg/kg of liposomal amikacin entered once a day, and tobramycin, administered twice a day daily for 14 days. In this model, with 28-day dose was observed equivalent reduction in CFU in animals treated with liposomal amikacin at a daily dose of ~60 mg/kg or a dose of ~120 mg/kg every other day. Liposomal am is the discussion, enter daily dose of 120 mg/kg for 14 days, was as effective as tobramycin dose of 60 mg/kg/day (enter twice a day) for 28 days, suggesting a greater AUC and possibly prolonged post-antibiotic effect of liposomal amikacin at a dose of 120 mg/kg once a day (see example 3).

The introduction of liposomal amikacin by inhalation in animal models led to excess lung (AUC) relative to the MIC of the bacteria and demonstrated prolonged therapeutic effect at a lower frequency and duration of the dose compared to tobramycin. Importantly, preclinical data for liposomal amikacin, apparently, support the hypothesis that this particular structure may have advantages in relation to other products for inhalation, which is complicated by the rapid destruction of lung tissue that requires frequent dose (Geller, Pitlick et al. 2002), burdensome for patients and can limit the flexibility of the sick.

In addition, clinical experience has shown that sprayed liposomal amikacin 50 mg/ml, administered once daily at a dose of 500 mg for 14 days, is well tolerated, has a clinically significant effect on lung function and reduces the density of P. aeruginosa in patients with CF. In addition, the evaluation of PK data shows that systems is the first exposition of the liposomal amikacin, even at a dose of 500 mg is very low. The values of Cmax or AUC or mg of aminoglycoside detected in urine observed systemic exposure with amikacin associated with the liposomal amikacin, administered by inhalation is from about 1/5 to 1/4 of the exposure observed at 600 mg/day TOBI and less than 1/200 compared to conventional parenteral doses of amikacin. The data also show the achievement of high levels of amikacin in the sputum. The median AUC values for sputum were 290 and 980 times higher than the median AUC for serum at 1 and 14 days, respectively.

Inhalation of liposomal amikacin supports prolonged directed to light exposure and increases the flow of drugs to the site of infection. According to clinical trials Phase 1b/1a on the people, in which CF patients chronically infected with P. aeruginosa, received many doses of liposomal amikacin 50 mg/ml, the purpose of the analysis presented in the present description, were threefold: (1) the use of modeling population pharmacokinetic (PK) characteristics of systemic exposure to amikacin, including approximate systemic bioavailability; (2) to characterize the content of liposomal amikacin in sputum; and (3) to characterize the pharmacokinetic-pharmacodynamic (PK-PD) the relationship between changes in volume accelerated in the Doha per second (FEV 1) change in percent predicted forced expiratory volume in one second (FEV1% predicted), forced expiratory flow between 25-75% of forced vital capacity (FEF25-75%) and forced vital capacity (high-flow), colony-forming units (CFU) of P. aeruginosa from baseline at 7 and 14 days exposure to amikacin.

Preclinical studies with the liposomal amikacin

There have been several preclinical studies with compounds 20 and 50 mg/ml In models in vitro and in vivo was demonstrated activity of liposomal amikacin against Pseudomonas. In addition, studies have shown that virulence factors, secreted by Pseudomonas, facilitate further release of amikacin from liposomes and described the accumulation and continuous release of amikacin in the lungs of rats and dogs. Was also installed security 30-day injection of liposomal amikacin in two species.

Nonclinical pharmacokinetics showed that the AUC (0-48 HR) of amikacin in the lungs of rats that received liposomal amikacin at a dose of 60 mg/kg by sputtering, was five times higher than the AUC of tobramycin in the lungs of rats that had received an equal dose of tobramycin by inhalation. High levels of amikacin was maintained in the lungs (>250 μg/ml for 150 hours) that pre is believed the effect of the Deposit. On the contrary, the tobramycin in the lungs was at an immeasurable level within 6 hours after cessation of administration. Conversely, the AUC of the drug in the kidneys of rats that had received an equal dose of tobramycin was significantly higher than the AUC in rats that received aerosols liposomal amikacin. No significant differences in AUC of aminoglycosides in the serum and urine of animals; after 24 hours the level in serum was immeasurable. This profile confirms the desired continuous release and effect of the Deposit of amikacin in the lungs after injection spray liposomal amikacin, potentially presenting a profile with high efficiency. These data for liposomal amikacin seems to confirm the hypothesis that this particular structure may have advantages compared with other products for inhalation, which prevents rapid clearance from the lung tissue, making necessary frequent dose (Geller, Pitlick et al. 2002) and burden of patients. In addition, toxicokinetics data Toxicological studies 30-day inhalation GLP in rats and dogs showed that dogs have a 15-fold increase in accumulation of amikacin in the lungs compared with the group treated with free amikacin, at comparable levels in plasma and urine, which indicates a high concentration in the lungs at low system expos the AI.

Pharmacodynamic effect of liposomal amikacin was evaluated in vivo in a rat model of chronic lung infection with Pseudomonas (Cash, Woods et al. 1979). In the model 14-day infection Pseudomonas 60 mg/kg of liposomal amikacin (75 mg/ml) was administered every other day for 14 days (Q2Dx7). This mode was as effective as 60 mg/kg of liposomal amikacin (enter once a day for 14 days) and tobramycin (entered twice daily for 14 days). When extending a dose of up to 28 days had an equivalent decrease in SOME animals treated with liposomal amikacin at a daily dose of ~60 mg/kg or a dose every other day ~120 mg/kg in Addition, in this experiment liposomal amikacin, administered at a dose of 120 mg/kg once daily for 14 days, was as effective as tobramycin dose of 60 mg/kg/day (enter twice a day) for 28 days. This indicated a higher AUC and prolonged post-antibiotic effect of liposomal amikacin at a dose of 120 mg/kg once a day. Preclinical pharmacodynamic data, therefore, corresponded supported antimicrobial advantage, strengthen site-specific delivery of drugs to the lungs through inhalation.

Thus, the introduction of liposomal amikacin by inhalation resulted in high concentrations (AUC) in the lungs, several times previews the MIC of the bacteria, potentially provide long-lasting therapeutic effect at a reduced frequency and duration of dose, especially compared to tobramycin.

Example 1

The study phase 1b/2a

The data used for population PK analysis were obtained in two clinical trials phase 1b/2a on the person, in which CF patients chronically infected with P. aeruginosa, has introduced a total of 500 mg of liposomal amikacin on a daily basis (in the form of two 2-minute sessions with a 5 minute rest period between them) within 14 days.

Serum samples with amikacin was received before the introduction of dose and after 1, 2, 4, 6, 8, 12 and 24 hours after dose 1 and 14 days, and urine samples were collected over a 6-hour intervals for 1 and 14 days during the 24-hour period. Also collected samples of sputum for 1 and 14 days soon after a dose of between 4 and 6 hours after a dose and before the introduction of the dose on the following day, and on 14, 21 and 28 days. Samples of serum, sputum and urine were analyzed for amikacin using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS).

The pulmonary function tests (PFT) were performed during the screening -14 on day 0 and the starting point (i.e., before the introduction of dose on day 1) and on 1, 7, 14, 21, 28, 35 and day 42. In the initial point in each of those days was also collected samples of mo the company for microbiological analysis. Additional PFTs were performed in 1.5 hours and 3 hours after the dose on day 1 and day 14.

Pharmacokinetic analysis

Data were adjusted using candidate models PK, using parametric expectation maximization Monte Carlo (MC-PEM) provided by program S-ADAPT 1.53, first adjusting the concentration in the plasma, and then jointly modeling the data for serum and urine. Discrimination of the model was based on adjustment data and the change of the objective function. 24-hour area under the curve (AUC) at steady state for values of amikacin in serum was calculated using data for secondary parameter test from the final population PK model. Covariant relationship between population and individual parameters of the secondary test for the patient was evaluated first, graphically, and then through statistical models created using SYSTAT® 11 (SYSTAT Software, Inc., Richmond, CA). Values of AUC sputum from 0 to 24 hours on day 1 and day 14 was obtained using the formula of the linear trapezoid.

The dependent variables for the analysis of PK-PD included the change in PFT values for FEV1, FEV1percent predicted FEF25-75%and high-flow at 7 and 14 days from baseline (before administration of the dose on day 1) and the change log10SOME in each of these days from baseline. Estimated independent variables included and the ratio of the average 24-hour AUC for serum and sputum to the original minimum inhibitory concentration (MIC), the ratio of the AUC:MIC for P. aeruginosa. The average 24-hour AUC for serum and sputum were determined using average AUC on day 1 and day 14.

Using t-test for one sample, were assessed statistical significance of average deviations from baseline for each of the above dependent variables. Using rank correlation coefficient (rs), have assessed the direction and strength of relationship between each dependent variable and the ratio of AUC:MIC for serum and sputum. Also assessed the direction and strength of connections between the deviation of each PFT values from baseline and standard deviation of log10SOME of the initial level.

Results

In total, 24 patients completed two studies with 13 patients in trial 1 and 11 patients in trial 2. Median (min, Max) age of all patients was 23, 7 (14, 38) years with a median (range) creatinine clearance (CrCL) in the source is 126 (76,8, 173) ml/min/1.73 m2.

The best fit for the data on serum concentration was obtained using dvukhkomponentnoi model (one website suction, easy, and Central compartment) at zero order entry of medication into the lungs first order received from the lungs to the Central compartment and linear elimination. The assumption mikocheni variations for apparent total clearance (CL/F) and apparent Central volume of distribution (Vc/F) between 1 day and 14 day statistically improved objective function. Data for urine was modeled by adjusting the number of amikacin identified in the collection intervals, as a function of serum concentration and renal clearance (CLr). Table 1 summarizes the values of the fitted parameters PK.

Table 1
Structural population pharmacokinetic model for liposomal amikacin for inhalation with mikocheni variability of parameter values and standard errors
Population
average
Evidence of variability (%CV)
Final score%SEEnd
score
%SE
CLt/F 1 day (l/h)68,410,348,729,9
Vc/F day 1 (l)28612,359,029,7
ka (h-1)3,3432,599,8 a 50.5
CLr (l/h)3,4015,463,936,7
CLt/F 14 day (l/h)45,28,0137,130,7
Vc/F day 14 (l)2508,5127,030,8
SDintSerum0,056,02
SDslpUrine0,709,16
SDintUrine0,03
Minimum value of objective function=-258,6

The quality of fit to the observed versus Bayesian secondary tests for individual fit data on the concentration of serum was wonderful with General r20,98.

The AUC values for the data in the serum and acrate shown in tables 2 and 3, respectively. The median AUC values for sputum were 286 and 978 times higher than the median values of AUC for serum on day 1 and day 14, respectively. Judging by the large values of CV% in the sputum was obvious large variability (117% at 1 day and 91.2% on day 14) compared with the AUC values of serum (51,9% on day 1 and 42.4% on day 14).

Table 2
A summary of the values of AUC serum1- all patients
Study dayNAverageSDMinMedianMax
1 Day248,274,29to 3.67to 6.8820,1
Day 1424to 12.05,08the 5.6510,830,1
1Values of AUC in mg/ml•h

Table 3
When the APC AUC values sputum 1- all patients
Study dayNAverageSDMinMedianMax
1 Day203830450078,70197017200
Day 1419125001140017401057850000
1Values of AUC in mg/ml•h

Concentration in serum (r2=0,98) and urine (r2=0,38) were, respectively, well and moderately fitted model. At 7, 14 and 21 days observable change for FEF25-75%was 0.49 (p<0,001), of 0.42 (p=0.02) and 0.34 (p=0.04), respectively. At 7 and 14 days observable change for FEV1it was of 0.24 (p=0.002) and 0.13 l (p=0,10), respectively, and was $ 7,49 (p<0.001) and to 4.38 (p=0.03) for FEV1% predicted. Identified significant relationships (p≤0,05) between log10And SOME attitude AUC/MIC in serum and between the change log10And SOME FEV1, FEV1% predskazan the defense and high-flow.

Had PFT data for baseline and on day 14 for all 24 patients and PFTs, held on 7 and 21 days of 23 patients. These microbiological analysis were available for all 24 patients. Since the MIC values collected prior to dose on day 1 to study 2, not reported, as the initial values used screening MIC values and SOME values.

Using t-test for one sample, were assessed statistical significance of average deviations from baseline for each of the above dependent variables. Using rank correlation coefficient (rs), have assessed the direction and strength of relationship between each dependent variable and the ratio of AUC:MIC for serum and sputum.

Average changes in PFT values on day 7 from baseline were statistically significant for all endpoints PFT. Also were statistically significant average changes FEV1% predicted and FEF25-75%on day 14 compared with baseline levels (p=0,029 and p=0.016, respectively). By 21 day average change FEF25-75%baseline was the only PFT, which remained statistically significant (p=being 0.036). Regardless of the day in question of the study, the average deviation of log10CFU from baseline was not statistically significant.

As shown in table 4, the correlation IU the remote control changes the values PFT relative to the original level and the ratio of AUC/MIC or in the sputum, or in serum were not statistically significant, regardless of assessed whether changes in the 7 and 14 days. As shown in table 5, the correlation between the deviation log10SOME of the initial level and the ratio of AUC/MIC in serum was statistically significant and at 7 and 14 days. The increasing ratio of AUC/MIC in serum was due to the large decrease in log10SOME of the 7 (rs= -0,46, p=0,048) and day 14 (rs= -0,45, p=0,048) relative to the initial level.

Correlation between changes in both quantities PFT and log10SOME 7 and 14 days from baseline were statistically significant for FEV1, FEV1% predicted and high-flow (p<0,05).

Table 4
The relationship between the deviation values of the test lung function from baseline and attitude AUC:MIC for serum and sputum - all patients
The day of the study
AUC:MIC
Rank
correlation
Spearman
Deviation of PFT values from baseline
FEV1FEV1% predictedFEF25-75%High-flow
day 7 serumr s20,0720,0066<0,00010,021
p-value0,210,710,970,51
day 14 serumrs20,0460,00730,000180,0012
p-value0,310,690,950,87
7 day sputumrs20,0330,0400,00850,19
p-value0,460,410,710,06
14 day sputumrs20,0250,0520,00530,06
p-value0,510,350,770,31

Table 5
The relationship between the change log10And SOME attitude AUC:MIC for serum and sputum - all patients
The day of the study
AUC:MIC
Rank correlation
Spearman
log10SOME
day 7 serumrs20,21
p-value0,048
day 14 serumrs20,20
p-value0,048
7 day sputumrs20,017
p-value0,64
14 day sputumrs2 0,0031
p-value0,84

Although the average deviation log10CFU from baseline on the 7th and 14th day was not statistically significant, the correlation between the deviation log10CFU from baseline at both time points and the ratio of AUC:MIC serum was statistically significant; Increase in AUC:MIC serum was associated with lower log10SOME. On the contrary, this relationship with the AUC:MIC sputum was not supported, which confirms the significant variability in the kinetics of liposomal amikacin in sputum, which was also shown with TOBI (Geller, Pitlick et al. 2002).

The presence of significant relationships between the change log10And SOME attitude AUC:MIC serum and between changes in PFT values and log10SOME and the lack of significant reduction in log10SOME P. aeruginosa during two weeks of treatment the liposomal amikacin for inhalation suggest that may require a higher dose for a more reliable effect on a large population of patients.

A summary of the testing phase 1a/2b

Was made on two tests of phase 1a/2b using liposomal amikacin 50 mg/ml of the Two trials were similar in design. In total, 24 patients with CF (FEV1≥ 40% of predicted) received 500 mg liposome is inogo amikacin daily for 14 days. The drug was administered via nebulizer PARI LC Star over a period of two 20-minute sessions with a 5 minute interval for rest between sessions. There were 13 patients included in trial 1, and 11 patients in test 2. Demographic data of patients were similar, except for the initial levels of Pseudomonas MICs. In test 1, the average value of MIC (μg/ml) was 8 (range 1.5-16), and in test 2 average MIC value was 41 ág/ml (range 8-192). Patients included in trial 2 had previous experience inhalation of antibiotics, and the Protocol they were allowed to resume treatment TOBI®/Colistin after 28 days of testing. Patients trial 1 had no experience inhalation of antibiotics and did not receive additional inhalation of antibiotics during the period of observation. The dose of 500 mg of liposomal amikacin (50 mg/ml) was well tolerated and in some patients who had improved lung function and reduced the density of P. aeruginosa in the sputum. Details of the demographic data of patients for trials 1 and 2 (combined) are shown in table 6.

Table 6
Demographic data of patients in trials 1 and 2
VariableAverageSDMedianMax
Age23,7of 6.9622,514,038,0
Weight (kg)59,113,058,643,499,6
Height (cm)1688,10168155194
BMI (kg)61,48,9960,047,987,7
CrCL (ml/min)12520,9126of 76.8173

All efficacy studies in these clinical trials phase 1b/2a were exploratory in nature. The endpoint of effectiveness included:

Deviation from baseline density of P. aeruginosa (log10CFU/g) in sputum;

Deviation from baseline pulmonary function tests (FEV1, FEV1% before is shown, High-flow and FEF25-75%).

Changes in the density of P. aeruginosa in the sputum, FEV1and FEV1% predicted at day 14 were identified as the main endpoint of efficacy.

Produced quantitative culturing of sputum samples and subsequent testing for sensitivity to amikacin for each morphologically excellent P. aeruginosa. Was recorded MIC of amikacin for isolates with the highest MIC, cultivated from each individual, at screening and on day 14. Density (CFU per gram of sputum) P. aeruginosa in the sputum was calculated as the number of log10for the sum of all morphotypes.

A summary of the baseline characteristics for the combined population (n=24) are presented in table 7.

Table 7
The source of measurement for patients in trials 1 and 2
VariableAverageSDMedianMinMax
FEV1 (l)2,381,072,181,156,10
Predicted FEV1 % (l/s)65,5 18,962,540,0119
FEF25-75 (l/s)1,711,261,490,555,50
High-flow (l)3,320,92with 3.271,675,28
Figure log10 CFU7,051,37,33,518,98
MIC (mcg/ml)3556102192

Test 1:In this test included CF patients infected with isolates of P. aeruginosa sensitive to amikacin (MIC of amikacin < 64 µg/ml), and individuals without experience of inhalation of antibiotics. The introduction of liposomal amikacin 500 mg once daily for 2 weeks caused the average deviation of the log of the total number of P. aeruginosa from baseline on day 14, equal 1,09 (n=13, 95% confidence interval from 2.09 to 0,09). The reduction was observed in the 9 of 13 individuals. The treatment of the liposomal amikacin did not lead to the selection of resistant strains of P. aeruginosa. The average MIC of amikacin against P. aeruginosa was 8,04 µg/ml on day 0 and 30,79 µg/ml on day 14. On day 14, only one isolate from one individual had not sensitive MIC (> 256 µg/ml); all other isolates on day 14 were sensitive to amikacin. Not one person was hospitalized or received intravenous antibiotics against Pseudomonas. In addition, there was an improvement in lung function to improve measured relative to the initial level on day 14 to +260 ml (n=13; 95% confidence interval of +30 ml to 500 ml). The corresponding change in FEV1 % predicted compared to the initial level on day 14 was +7.2 per cent. The increase in FEV1 was observed in 9 out of 13 individuals. It was also seen to increase the FEF(25-75%)(average: 570 ml) and high-flow (average: 180 ml).

Test 2: Test 2 was conducted on a population of patients with CF who were infected with P. aeruginosa and had experience of treatment with inhaled antibiotic. In these patients the introduction of liposomal amikacin 500 mg once daily for 2 weeks did not cause any significant changes in the density of P. aeruginosa during the test (p value≥0,297 for changes relative to 1 day). The proportion of patients with mucoidal P. aeruginosa remained constant throughout testing. There was not a statistically significant change is tions FEV 1, FEV1% predicted, high-flow and FEF(25-75%)after administration of liposomal amikacin 500 mg However, there was a trend toward improvement in FEV1% predicted, high-flow and FEF(25-75%)on day 7, day 14 (end of treatment) and day 15.

Summary total efficiency: tests 1 and 2

Data for the combined population of 24 patients in trials 1 and 2 are summarized below in tables 8, 9, 10 and 11. Microbiological endpoint changes CFU P. aeruginosa showed a decrease in the density of bacteria in the combined population, but it did not reach statistical significance. However, the analysis of data for patients who had no previous experience inhalation antibiotic (test 1), at the end of the test there was a decline in CFU. Factors that could explain this effect are inherent in the sputum specimen variability, inter-laboratory variability of the methodology and reporting in quantitative Microbiology and the inclusion of patients with large MICs (including resistant isolates) in test 2. All of the above optionally is combined with the small sample size of each test.

To evaluate the clinical benefits by measurements in the pulmonary function tests showed a significant improvement in pulmonary function, as measured by the increase in FEV1relative to the initial level on day 7 to +240 ml (n=23; p-value 0,0024). Effect on 1 day represented an increase of 126 ml compared to baseline FEV 1which was not statistically significant. Corresponding statistically significant increase in FEV1 % predicted from baseline to day 7 was +7,49% (n=24; p-value is 0.0002) and +4,37% on day 14 (n=24; p-value 0,0285). Improvement in pulmonary function was also noted in the evaluation of small airway dimension FEF(25-75%), which increased by 7 day +494 ml (n=23, p-value 0.001) and on day 14 +423 ml (n=24, p-value 0,0162). These data confirm a clinically significant improvement in lung function in CF patients with chronic Pseudomonas infection who received a 14-day course of treatment the liposomal amikacin.

Table 8
The change in FEV relative to the original level over different time intervals in all patients
The time pointNAverageCVP-value
day 7 (before dose)230,241,40,0024
day 14 (prior to dose)240,1262,86 0,1006
21 days230,0734,910,3397

Table 9
Change in% - predicted FEV relative to the original level over different time intervals in all patients
The time pointNAverageCVP-value
day 7 (before dose)237,4911,09is 0.0002
day 14 (prior to dose)244,3792,100,0285
21 days232,7133,250,1544

Table 10
Change FEF25-75relative to the original level over different time intervals in all patients
The temporal is I point NAverageCVP-value
day 7 (before dose)230,4941,260,001
day 14 (prior to dose)240,4231,890,0162
21 days230,3382,150,0361

Table 11
The change in CFU from baseline through different time intervals in all patients
The time pointNAverageCVP-value
day 719-0,154-7,370,5616
day 1420-0,315-4,42 0,3242
21 days200,24of 5.40,4182

Example 2

Clinical trial phase 1

There were two clinical trials phase 1 single dose for compounds 20 and 20 mg/ml of liposomal amikacin in healthy volunteers and patients with CF, respectively. Six healthy volunteers received a single dose of 120 mg of liposomal amikacin, moved well and showed prolonged latency of radioactively labeled liposomes in the lung with the measured pologist 46 hours.

Liposomal amikacin was administered to individuals with CF with chronic P. aeruginosa infection in a clinical trial phase 1 human (test 3). A single dose of 90 mg (n=6), 270 mg (n=6) or 500 mg (n=4) were introduced individuals with CF to assess the safety, tolerability and pharmacokinetics of liposomal amikacin for inhalation. In total were evaluated 24 session dose for patients with single dose of liposomal amikacin or placebo by inhalation via nebulizer Pari LC Star. It was reported two serious adverse events (both occurred in the placebo group). Both events were resolved without complications. During the test in 17 of the 24 sessions dose patients (71%) which was awarded a total of 41 adverse events (AE). Of the reported AEs 10 of 16 patients (62.5%) and that reported adverse events that were in the active group and 7 out of 8 patients (87,5%) were in the placebo group. The most common AE was headache in the active group, and no patient was excluded from the study due to AEs. Liposomal amikacin was well tolerated and was safe up to a single dose of 500 mg, administered via inhalation.

In addition, the PK data confirm minimal systemic drug level and a high level of drugs in the sputum, and pharmacodynamic modeling has established long pologize elimination, presumably due to the slow release from the liposomes.

Example 3

Clinical trial phase 2

Design tests are summarized in figure 4. Patients enrolled in the trial were CF patients aged six years and older with chronic P. aeruginosa infections. Patients were cancelled inhalation of antibiotics for 28 before the test. Patients were divided by baseline FEV1 (% pred.) and randomized 2:1 for ArikaceTMor placebo (1.5% of NaCl). Group 1 received 280 mg, and group 2-560 mg of active drug or placebo for 28 days by inhalation via nebulizer PARIeFlow® and were monitored for 28 days, during which inhalation antibiotics were not administered. Weekly during the AI 56-day test period were evaluated safety, pharmacokinetics, the density of Pa in sputum, quality of life (CFQ-R) and the rate of deterioration.

Briefly, the daily introduction of 280 mg and 560 mg of liposomal amikacin for 28 days looked safe and well-tolerated. The introduction of liposomal amikacin 280 mg and 560 mg for 28 days caused a dose-dependent improvement in lung function, which persists for at least 28 days after dose. Patients treated with liposomal amikacin, were less likely to have an exacerbation (7,14%) compared with placebo (18,18%). In addition, the period of time to exacerbation was longer in the group of amikacin (41 days) compared with placebo (19 days). The group treated with amikacin, not experienced pulmonary exacerbations during the 28-day treatment period. Patients treated with liposomal amikacin showed greater clinical benefit compared with placebo as measured by improvement in the quality of life for respiratory scale CFQR.

In figures 5 and 6 presents graphs showing the change in oxygen saturation from baseline in children (ages 6 to 12) compared with placebo. The results show the improvement in oxygen saturation during the 28-day treatment period and continued beyond the period of treatment. A similar improvement in oxygen saturation observed the axis also in patients over the age of 12.

In figures 7a and 7b shows the change in lung function, measured by forced expiratory volume (FEV1) in the placebo group and the group of amikacin, respectively, divided into age groups. Patients in the placebo group show a General decrease in FEV1to 56 days, while patients receiving liposomal amikacin, consistently showed higher FEV1and during treatment, and up to 28 days after treatment. In the placebo group had the following changes in the values of pulmonary function (measured in ml):

td align="center"> 18+
Table 12
Changes in FEV1in the placebo group
ageday 7day 1421 days28 day35 day56 day
6-12-79-88 (117)260 (61)-6-4
13-18872 (80)2526 (149)25-65
102-22 (150)4636 (135)-24-56

In the group of amikacin were the following changes in the values of pulmonary function (ml):

Table 13
Changes in FEV1in the group with treatment with amikacin
ageday 7day 1421 days28 day35 day56 day
6-12173232 (117)138154 (165)110178
13-18136133 (157)143158 (153)7944
18+10394 (107)6846 (95)295

Comparison of changes in FEV1(measured in ml) from baseline for all patients in groups 560 mg, 280 mg, and placebo are presented in figure 8. And again the data show a lasting effect, and continuing on day 56 patients receiving liposomal amikacin, and the effect in the group 560 mg, even more pronounced than in the group of 280 mg. of the figure 9 shows the change from baseline in percent. FEV1 was significantly increased in the group of 560 mg of the continued therapeutic effect in the form of increase in 224 ml (17.6 per cent) compared with placebo on day 56.

These tests also showed a significant reduction in SOME patients receiving liposomal amikacin compared with placebo, and this reduction was maintained at least up to 35 days. The reduction in CFU was whiter pronounced in the group treated with 560 mg of amikacin, compared with the group 280 mg, as seen in figure 10. The figure 11 shows the change in log CFU for Mokoena strains. These results demonstrate that the density of P. aeruginosa according to the measurement log CFU was reduced in groups treated with liposomal amikacin, compared with placebo, and this effect persisted at least up to 35 days of testing. Patients with mukoidnyi strains of P. aeruginosa were sensitive to the treatment of the liposomal amikacin. In the group 280 mg, there was a decline of 1.2 log TO the, and in the group of 560 mg decrease was 2.0 log. The reduction was maintained at 35 day group 560 mg with decrease of 1.8 log CFU, whereas the reduction in the group 280 mg was preserved when reducing 0,4 log CFU.

Pharmacokinetic data revealed a high level of amikacin in the sputum of patients receiving liposomal amikacin, with an average Cmax (CV) 3496 (0,973) ág/g mean value of the area under the curve (AUC) was $ 13120 (1,63) µg/g*h for group 280 mg, while the average AUC was 22445 (0,831) µg/g*h. On the other hand, the pharmacokinetic data for serum showed low systemic exposure with amikacin with an average Cmax (SD) of 2.27 (1,58) µg/ml.

In patients receiving liposomal amikacin was observed also reduced the incidence and time to onset of pulmonary exacerbation. Table 14:

Table 14
Pulmonary exacerbation
ArikacePlacebo
Sick3/42 (7.1 per cent)3/22 (13.6 per cent)
Time to exacerbation (days)40,6*19,3
*No exacerbations during the treatment period

As can be seen from that the support 14, the percentage of exacerbations in patients treated with the liposomal amikacin (including groups and 280 mg and 560 mg) was lower compared with the placebo group. Moreover, the time before the onset of exacerbation in patients receiving liposomal amikacin was significantly longer (40.6 days) compared to 19.3 days in the placebo group.

Relieving treatment against Pseudomonas was also reduced in patients receiving liposomal amikacin, compared with the placebo group, as can be seen from table 15.

Table 15
Relieving treatment against Pseudomonas
ArikacePlacebo
Sick4/42 (9.5%), the3/22 (13.6 per cent)
Time to exacerbation (days)43,0*21,3
*No disposal during treatment

As can be seen from table 15, a lower percentage of patients receiving inhalation of liposomal amikacin needed relieving treatment against Pseudomonas compared with the placebo group. In addition, the time needs to deliver the treatment was reduced in patients with liposomal Amica is a Qing (43.0 days) compared with the placebo group (1.3 days).

Example 4

Spray liposomal amikacin

Aerosol properties of liposomal amikacin obtained from eFlow 40L, shown in table 15. When compared with the dispersion of the LC Star value weighted median aerodynamic diameter (MMAD) for eFlow ~ 0.5 μm more. Valid dependent on the size distribution of the masses and of the ACI (eFlow), and from NGI (LC Star) cascade impactors for sprayed liposomal amikacin shown in figure 1. Measurements of aerosol from eFlow/ACI were slightly narrowed size distribution in comparison with the aerosol of the LC Star/NGI. This difference is reflected in the lower mean geometric standard deviation (GSD) (1,66 against 1,99), which is a measure of the width of the distribution around the MMAD, see values in table 16. This is a more narrow distribution compensates for any potential effect of a larger MMAD and, therefore, the amount of powdered medication in the respirable range (the size of the droplets <5 μm) comparable to eFlow and LC Star.

Table 16
Properties of liposomal amikacin, sprayed with spray eFlow and LC Star
Raspy-amplifierProperties of aerosol dropletsThe percentage associated the th amikacin
Used cascade impactorMMAD (µm)GSD (betras-dimensional)Respirable fraction*Before raspy-populationAfter raspy-ing
EFlowAndersen3,68±0,261,66±0,0772,9±5,5the 96.3±2,1%66,3±5,8%
LC StarNGI3,18±0,181,99±0,0574,5±2,6the 96.3±2,1%62,1±7,4%

Cascading the Andersen impactor was used at a flow rate of 28.3 l/min, C and 50% humidity. The impactor NGI used at a flow rate of 15 l/min and 5ºc to achieve >60% humidity. *Percentage of the mass of the nominal dose with diameter less than 5 microns.

Example 3

Effect of liposomal amikacin on pulmonary P. Aeruginosa infection in rats

The effectiveness of liposomal amikacin for inhalation was investigated using a model of chronic pulmonary infection (Cash, Woods et al. 1979), in which P. aeruginosa enclosed in a matrix of agarose beads, were grafted in tra is it rats. This animal model mulenga Pseudomonas was designed for playback of chronic Pseudomonas infections observed in patients with CF (Cantin and Woods 1999). The lungs of rats were inoculable 104SOME mulenga strain of P. Aeruginosa (momigny strain 3064), a source selected from a CF patient. After three days was administered 60 mg/kg of liposomal amikacin (75 mg/ml) by inhalation once a day in the amount of 14 doses (Q1Dx14) or a day of 7 doses (Q2Dx7) (6 mg/kg per dose). For comparison introduced tobramycin by inhalation BID for 14 days (30 mg/kg per dose to obtain a total of 60 mg/kg daily). In all three treatment groups showed a significant decrease in the density of bacteria compared with the control saline solution (see figure 2). Between the three treatment groups of rats was not significant difference in reducing log10/easy. It should be noted that in this model liposomal amikacin (75 mg/ml), injected every other day for 14 days (Q2Dx7), which effectively gave half the cumulative dose of aminoglycoside was as effective as daily doses.

As shown in figure 3, when in this model, the dose exceeded 28 days was observed equivalent reduction in CFU in animals treated with liposomal amikacin, administered daily in a dose of ~60 mg/kg or every other day at a dose of ~120 mg/kg, However, it was a hundred is isticheskie significant only for the latter group when compared with animals which earned 1.5% saline under the same schemes (p=0,24 and 0.03, respectively). In both cases in the control group with saline there was a significant number of animals, which was also observed 2 log reduction in CFU. Longer (after 14 days) treatment with inhaled saline solution, apparently, increases spontaneous ability of rats to clear their lungs from infection and, presumably, from balls that can support the conditions for chronic infection. Rats that received liposomal amikacin ~120 mg/kg daily for 14 days and observed for 14 days and the idea was put on 35 day. The lungs of these animals contained bacteria below the threshold, as in the case of a group, which received tobramycin 60 mg/kg (injected twice a day) daily for 8 days and then userswindows. Data show that in this experiment liposomal amikacin, administered at a dose of 120 mg/kg once daily for 14 days, was as effective as tobramycin 60 mg/kg/day (enter twice a day) for 28 days. This result suggests the existence of a greater AUC and perhaps more lasting effect after the introduction of antibiotic liposomal amikacin at 10 mg/kg

Links

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American Thoracic Society 97th International Conference, San Francisco, California, Aerogen, Inc.

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5. Cow, G. D. and A. Morgan (2007c). 30 Day Inhalation Toxicity Study of SLIT™ Amikacin in Rats with a 30 day Recovery Period, Charles River Laboratories: 870.

6. Cow, G. D. and A. Morgan (2007d). 30 Day Inhalation Toxicity Study of SLIT™ Amikacin in Dogs with a 30 Day Recovery Period, Charles River Laboratories: 777.

7. Doring, G., S. P. Conway, et al. (2000). "Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus."Eur RespirJ16(4): 749-67.

8. Geller, D. E., W. H. Pitlick, et al. (2002). "Pharmacokinetics and bioavailability of aerosolized tobramycin in cystic fibrosis."Chest122(1): 219-26.

9. Gibson, R. L., J. L. Burns, et al. (2003). "Pathophysiology and management of pulmonary infections in cystic fibrosis."Am J Respir Crit Care Med168(8): 918-51.

10. Gibson, R. L., J. Emerson, et al. (2003). "Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis."Am J Respir Crit Care Med167(6): 841-9.

11. Gilbert, C. E., C. Knight, et al. (1997). "Tolerance of volunteers to cyclosporine A-dilauroylphosphatidylcholine liposome aerosol."Am J Respir Crit Care Med156(6): 1789-93.

12. Goss, S. N. and M. Rosenfeld (2004). "Update on cystic fibrosis epidemiology."Curr Opin Pulm Med10(6): 510-4.

13. Gunther, A., C. Ruppert, et al. (2001). "Surfactant alteration and replacement in acute respiratory distress syndrome."Respir Res2(6): 353-64.

14. Hug, M. (2007a). Characterization of the PARI eFlow® (40L to 50L) and Liposomal Amikacin™ (48 to 79 mg/ml(1)) PARI GmbH, erosol Research Institute: 10.

15. Hug, M. (2007b). Aerosol Characterization of the PARI eFlow® 40L an Transave Liposomal Amikacin™ for Inhalation (70 mg/ml(1)), PARI GmbH, Aerosol Research Institute: 12.

16. Hung, A. R., S. C. Whynot, et al. (1995). "Pharmacokinetics of inhaled liposome-encapsulated fentanyl."Anesthesiology83(2): 277-84.

17. Landyshev Iu, S., A. A. Grigorenko, et al. (2002). "[Clinico-experimental aspects of liposomal therapy of bronchial asthma patients with hydrocortisone therapy]."Ter Arkh74(8): 45-8.

18. Lass, J. S., A. Sant, et al. (2006). "New advances in aerosolised drug delivery: vibrating membrane nebuliser technology."Expert Opin Drug Deliv3(5): 693-702.

19. Li, Z. (2007). Droplet Size of Liposomal Amikacin™: Comparison of Nebulizate for the eflow Electronic Nebulizer and the PARI LC STAR Jet Nebulizer. Monmouth Junction, Transave Inc.: 20.

20. Martini, W. Z., D. L. Chinkes, et al. (1999). Lung surfactant kinetics in conscious pigs."Am J Phvsiol277(1 Pt 1): E187-95.

21. Myers, M. A., D. A. Thomas, et al. (1993). "Pulmonary effects of chronic exposure to liposome aerosols in mice."Exp Lung Res19(1): 1-19.

22. There were fewer than, R. W., T. M. Carvajal, et al. (1992). "Nebulization of liposomes. III. The effects of operating conditions and local environment."Pharm Res9(4): 515-20.

23. There were fewer than, R. W. and H. Schreier (1990). "Nebulization of liposomes. I. Effects of lipid composition."Pharm Res7(11): 1127-33.

24. There were fewer than, R. W., M. Speer, et al. (1991). "Nebulization of liposomes. II. The effects of size and modeling of solute release profiles."Pharm Res8(2): 217-21.

25. Ramsey, B. W., M. S. Pepe, et al. (1999). "Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group."N Engl J Med340(1): 23-30.

26. Skubitz, K. M. and P. M. Anderson (2000). "Inhalational interleukin-2 liposomes for pulmonary metastases: a phase I clinical trial."Anticancer Drugs11(7): 555-63.

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28. Ten, R. M., P. M. Anderson, et al. (2002). "Interleukin-2 liposomes for primary immune deficiency = MKD using the aerosol route."Int Immunopharmacol2(2-3): 333-44.

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The incorporation by reference

All cited in the present description the U.S. patents and published patent applications U.S. included so as a reference.

Equivalents

Experts in the art should understand or be able to verify with minimal experimentation that there are many equivalents to the specific implementation of the invention described in the present description. Implying that such equivalents are covered by the following claims.

1. A method of treating pulmonary disorders in a patient, comprising an introduction to the patient an effective dose of the powdered composition of liposomal amikacin during the treatment cycle, including the period of introduction from 15 to 75 days, followed by the cancellation period for the t 15 to 75 days;
where a treatment cycle is repeated at least twice and effective dose ranges from 100 to 2500 mg of amikacin daily during the period of introduction,
this improvement in lung function is maintained for at least 15 days after the end of the period of introduction and improvement of lung function includes the increase in the forced expiratory volume in one second (FEV1).

2. The method according to p. 1, where the period is from 15 to 35 days.

3. The method according to p. 1, where the period is from 20 to 35 days.

4. The method according to p. 1, where the cancellation period is from 15 to 35 days.

5. The method according to p. 1, where the cancellation period is from 25 to 75 days.

6. The method according to p. 1, where the period is about 28 days and the cancellation period is about 28 days.

7. The method according to p. 1, where the period is about 28 days and the cancellation period is approximately 56 days.

8. The method according to p. 1, where the effective dose ranges from 250 to 1500 mg of amikacin.

9. The method according to p. 1, where the effective dose is from about 280 to about 560 mg of amikacin.

10. The method according to p. 1, where the effective dose is about 280, or about 560 mg of amikacin.

11. The method according to p. 1, where pulmonary violation is a P. aeruginosa infection.

12. The method according to p. 1, where the lung is a violation b is angioectasia.

13. The method according to p. 1, where Cmaxamikacin in serum of the patient is less than approximately 10 μg/ml during the period of introduction.

14. The method according to p. 1, where Cmaxamikacin in the sputum of the patient is at least 1000 μg per 1 g of sputum for injection.

15. The method according to p. 1, where Cmaxamikacin in sputum is at least 1000 μg per 1 g of sputum for at least 15 days after injection.

16. The method according to p. 1, where the patient is characterized by a decrease in log10SOME bacterial infection in the lungs of at least 0.5 for at least 15 days after the end of the period of introduction.

17. The method according to p. 16, where the decrease in log10SOME is at least 1,0.

18. The method according to p. 1, where the improvement includes the growth of blood oxygen saturation.

19. The method according to p. 1, where the patient has FEV1that is increased at least 5% above FEV1before the treatment cycle.

20. The method according to p. 19, where FEV1increases from approximately 5 to approximately 50%.

21. The method according to p. 18, where the oxygen saturation is increased at least 1% above the oxygen saturation before treatment cycle.

22. The method according to p. 1, where the time until the onset of lung disease in a patient is approximately 20 days or more.

23. The method according to p. 1, where the composition of the liposomal amikacin includes a lipid and amikacin,and the ratio of lipid to amikacin is from about 0.3 to about 1.0 by weight.

24. The method according to p. 1, where the composition of the liposomal amikacin comprises a lipid selected from the group consisting of egg phosphatidylcholine (EPC), phosphatidylglycerol eggs (EPG), phosphatidylinositol eggs (EPI), phosphatidylserine eggs (EPS), phosphatidylethanolamine (ORE), phosphatidic acid (EPA), soy phosphatidylcholine (SPC), phosphatidylglycerol soybean (SPG), phosphatidylserine soy (SPS), phosphatidylinositol soy (SPI), soy phosphatidylethanolamine (SPE), phosphatidic acid soybean (SPA), hydrogenated egg phosphatidylcholine (NURSE), hydrogenated phosphatidylserine eggs (HEPG), hydrogenated phosphatidylinositol eggs (HEPI), hydrogenated phosphatidylserine eggs (HEPS), hydrogenated phosphatidylethanolamine (NERA), hydrogenated phosphatidic acid (NERA), hydrogenated soy phosphatidylcholine (HSPC), hydrogenated phosphatidylserine soybean (HSPG), hydrogenated phosphatidylserine soy (HSPS), hydrogenated phosphatidylinositol soybean (run inline with the blow), hydrogenated soybean phosphatidylethanolamine (HSPE), hydrogenated phosphatidic acid soybean (HSPA), dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylcholine (DMPG), dipalmitoylphosphatidylcholine (DPPG), distearoylphosphatidylcholine (DSPC), distearoylphosphatidylglycerol (DSPG), dioleoylphosphatidylcholine (DOPE), is palmitoyloleoylphosphatidylcholine (PSPC), palmitoyloleoylphosphatidylglycerol (PSPG), manualearphonesinstallation (SEA), cholesterol, ergosterol, larosterna, tocopherol, ammonium salts of fatty acids, ammonium salts, phospholipids, ammonium salts, glycerides, myristamine, polymethylene, laurylamine, stearylamine, dilauroylglycerophosphocholine (DLEP), dimyristoylphosphatidylcholine (DMEP), dipalmitoylphosphatidylcholine (DPEP) and distearoylphosphatidylcholine (DSEP), N-(2,3-di-(9-(Z)-octadecanoyloxy))-prop-l-yl-N,N,N-trimethylammonium chloride (DOTMA), 1,2-bis(oleolux)-3-(trimethylammonio)propane (DOTAP), phosphatidylglycerols (PGs), phosphatidic acids (PAs), synthesised (PIs), phosphatidylserines (PSs), distearoylphosphatidylglycerol (DSPG), dimyristoylphosphatidylcholine acid (DMPA), dipalmitoylphosphatidyl acid (DPPA), distearoylphosphatidylcholine acid (DSPA), dimyristoylphosphatidylcholine (DMPI), dipalmitoylphosphatidylcholine (DPPI), distearoylphosphatidylglycerol (DSPI), dimyristoylphosphatidylcholine (DMPS), dipalmitoylphosphatidylcholine (DPPS), distearoylphosphatidylcholine (DSPS) and their mixtures.

25. The method according to p. 1, where the composition of the liposomal amikacin comprises a phospholipid and a Sterol.

26. The method according to p. 1, where the composition of the liposomal amikacin comprises DPPC and cholesterol.

27. The method according to p. 26, where the composition of the liposomal amikacin comprises DPPC and cholesterol in a ratio of about 2 to by weight.

28. The method according to p. 27, where the composition of the liposomal amikacin has the ratio of lipid to the drug from about 0.3 to about 1.0 by weight.



 

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