Intrapulmonary administration of fuoroquinolone

FIELD: medicine, pharmaceutics.

SUBSTANCE: powder composition for intrapulmonary administration contains particles of ciprofloxacin betaine 3,5-hydrate and an excipient. The particles have a mass median aerodynamic diameter making from approximately 1 to approximately 5 mcm; a pulmonary half-life of betaine 3,5-hydrate makes min. 1.5 h; while a roughness of the composition falls within the range of 3 to 10.

EFFECT: composition may be used to treat an endobronchial infection, such as an infection caused by Pseudomonas aeruginosa, and it is most applicable for treating mucoviscidosis.

6 cl, 8 dwg, 16 tbl, 12 ex

 

This application claims the priority of provisional patent application U.S. No. 61/127780, registered on may 15, 2008, the contents of which are fully incorporated into the present description by reference.

Background of invention

One or more embodiments of the present invention is(are) to pharmaceutical compositions that contain one or more of fluoroquinolones, such as ciprofloxacin. One or more embodiments of the present invention is(are) to powders containing betainovuyu derived one or more of fluoroquinolones, such as ciprofloxacin betaine. One or more embodiments of the present invention is(are) to methods of receipt, use and/or administration of such pharmaceutical compositions, containing dosage forms and devices, systems and methods intended for intra-lungs the introduction of such compositions.

The present invention relates to compositions and methods for treating bacterial infections and primarily relates to the treatment of cystic fibrosis (CF)that is not associated with cystic fibrosis (non-CF) bronchiectasis and acute complications chronic obstructive pulmonary disease.

Cystic fibrosis is the most common shorten the life of genetics the prioritization of disease in the United States and Northern Europe, which affects approximately 30,000 people in the United States and close to that many people in Western Europe. A genetic defect that causes it autosomal recessive disease is a mutation in the gene for cystic fibrosis transmembrane conductance regulator (CFTR), which encodes a protein chloride channel. Individuals with CF, as a rule, suffer from chronic endobronchial infections, sinusitis and malabsorption due to pancreatic insufficiency, excessive loss of salt through sweating, obstructive hepatobiliary disease and reduced fertility. Respiratory disease is a major cause of morbidity and accounts for 90% of deaths among people suffering from CF. An important prognostic factor of survival in CF is lung function (which is examined by a one-second measurement of air volume during forced exhalation (predicted % FEV1)), Biennial term survival for this population of patients with CF is reduced in 2 times for each 10%decrease in predicted % FEV1, and for individuals whose FEV1 is less than 30% of the predicted survival rate for 2 years is less than 50% (Kerem E. and others, "Prediction of Mortality in Patients with Cystic Fibrosis", N Engi J Med 326, 1992, it. 1187-1191). The coefficients of loss of pulmonary function vary between the individual what umami, and for a particular individual over time. A retrospective analysis of changes over time showed that the coefficients of reduction vary from less than 2% of the predicted % FEV1 per year to more than 9% of predicted % FEV1 per year, however, the reduction coefficient is expressed associated with age of death.

Patients with CF suffer from thickening of the mucous membrane, which is believed to be caused by violation of ion transport, impairing the body's defenses-master the lungs, which leads to increased sensitivity to arise at an early age endobronchial infections caused by Staphylococcus aureus, Haemophilus influenzae and Pseudomonas aeruginosa. In the pubertal age, the majority of individuals suffering from CF sputum is present in P. aeruginosa. Chronic antibacterially infections, primarily caused by P. aeruginosa, provoke sustained inflammatory response in the Airways, which accelerates the progression of obstructive disease, characterized by diffuse bronchiectasis; Winnie G.B., and others, "Respiratory Tract Colonization with Pseudomonas aeruginosa in Cystic Fibrosis: Correlations Between AxAi-Pseudomonas aeruginosa Antibody Levels And Pulmonary Function", Pediatr Pulmonol 10, 1991,. 92-100. Significant reduction in survival associated with chronic infection caused by P. aeruginosa (Henry R.L., and others, "Mucoid Pseudomonas aeruginosa is a Marker of Poor Survival in Cystic Fibrosis", Pediatr Pulmonol 123), 1992, her. 158-161), and a strong Association of the acquisition at an early age, chronic infections caused by P. aeruginosa, and child mortality (Demko S. and others, "Gender Differences in Cystic Fibrosis: Pseudomonas aeruginosa infection", J Clin Epidemiol 48, cc. 1041-1049)suggests there is a relationship between acquisition chronic antibacterially infections caused by P. aeruginosa, pulmonary inflammation, loss of lung function and, eventually, death.

Attempts were made treatment caused by P. aeruginosa infections in patients with CF, with the use of various therapeutic approaches. The aim of these therapies were either reduced bacterial loads in the lung, or reduction occurs when the infection inflammation. It was found that such treatment leads to reduction factors reduction of lung function in infected patients, but have certain disadvantages.

Historically, the standard therapy in the treatment of antibacterially of infections caused by P. aeruginosa was parenteral within 14-21 days of the so-called "antipseudomonal" antibiotics (antibiotics that have activity against strains of Pseudomonas aeruginosa), typically comprising an aminoglycoside. However, the lack of ability of these agents to effectively penetrate from the bloodstream into the lung tissue and secrete the respiratory led in the area of the target was achieved only subtherapeutic concentrations. As a result of this repeated parenteral administration of aminoglycosides has led to the development of resistant isolates, with which is associated an increased production of mucus and various virulence factors. To ensure adequate concentrations of the drug in the field of infection by injecting the required levels in serum, which is associated with nephrotoxicity, toxicity vestibule of the labyrinth and ototoxicity ("American Academy of tolaryngology. Guide for the evaluation of hearing handicap", JAMA 241(19), 1979,. 2055-2059); Brummett R.E., "Drug-induced ototoxicity", Drugs 19, 1980, SS-428).

Introduction by inhalation of antibiotics, such as aminoglycosides, was an attractive alternative approach, allowing high concentrations of antibiotics directly into the area of infection in the endobronchial space while minimizing systemic bioavailability.

For example, TOBI®, containing the aminoglycoside tobramycin, allowed for the implementation of inhalation therapy in the treatment of endobronchial infections in patients with CF [NDA 50-753]. After receiving this permission TOBI®(Novartis, Basel, Switzerland) has become the standard treatment for patients suffering from CF, the body of which the chronically colonizer is an R. aeruginosa. Patients enter the nominal dose component 300 mg, with a standard jet nebulizer twice a day. To reduce the possibility of development of resistant bacterial strains patients undergoing a course of treatment consisting of 28 days "on-period" (the period when injected drug), followed consisting of 28 days "off-period" (the period when the drug is not injected). However, this dose component 300 mg, in the lungs only about 10% or 30 mg. Clinical experiments conducted using TOBI®demonstrated that an input by inhalation tobramycin has significantly fewer systemic side effects. The introduction of the aerosol dose volume of 5 ml containing 300 mg of tobramycin in the quarter - normal saline solution, to inhibit P. aeruginosa in the endobronchial space of the patient described in U.S. patent No. 5508269, the content of which is fully incorporated into the present description by reference.

There are some limitations regarding the application of tobramycin for patients suffering from CF. Systemic injection of tobramycin by IV injection can cause serious side effects, including renal toxicity and ototoxicity. The sprayed liquid can cause the action associated with the drug and its introduction is, as well as the development of increased resistance (i.e. higher values of minimum inhibitory concentration, MIC) of P. aeruginosa in the treatment process. Despite the risk of deterioration in lung function, you must follow the treatment regimen, providing therapeutic "he-periods with a duration of 1 month and "off-periods" duration of 1 month in order to avoid development of resistance, allowing sensitive pathogens to carry out the repopulation. Currently understudied prolonged exposure introduced by inhalation of aminoglycosides on renal function. Introduction dose component 5 ml, takes about 15-20 minutes, in addition, additional time is required for charging and cleaning spray. Spraying may also have other disadvantages, such as cost, efficiency, and reproducibility, the risk of bacterial contamination and lack of mobility (the need for bulky compressors or cylinders of compressed gas and energy sources).

In addition to input by inhalation of antibiotics, such as selling products with a trademark TOBI usually prescribe a number of other ongoing for a long time therapies to reduce the number of destructive cycles obstruction, infection and inflammation in the lung of an individual suffering from CF. Yet the kinds of therapy, as intensive clearance of the respiratory tract, inhalation of bronchodilators and introduction mucolytic tools such as recombinant human dornase Alfa, all appointed for a long period of time, thereby creating the preconditions for a substantial increase in treatment-related burden for individuals suffering from CF. Many patients suffering from CF, spend more than four hours daily for exercise therapy. It is not surprising that adherence to therapy is a significant problem for patients with CF, and that the degree of deficiency of the aging treatment may vary depending on the specific treatment. Taking into account the fact that to ensure you a long time, it should be recognized that any of the modes, which can significantly reduce the time and increase convenience associated with the introduction (e.g., device mobility and ease of use), are preferred, they potentially improve patient compliance with treatment and improve treatment results. In addition, the development of alternative intended for inhalation drugs containing antibiotics that can be entered in the "off-period" TOV therapy, can be the basis for an alternative approach to treatment, which does not lead to p is the population of susceptible pathogens and loss of pulmonary function.

Ciprofloxacin is a synthetic fluorinated carboxyquinolone with a wide spectrum of activity. Ciprofloxacin selectively inhibits the synthesis of bacterial deoxyribonucleic acid (DNA) by affecting DNA girazu and topoisomerase IV. These enzymes control DNA topology and participate in replication, repair and transcription of DNA. It was found that Ciprofloxacin has a high bactericidal activity in vitro against many pathogens that cause respiratory infections, including Mycobacterium tuberculosis, Mycobacterium avium-M. intracellulare, Bacillus anthracis, Hemophilus influenzae, Neisseria meningitidis and Pseudomonas aeruginosa. At present Ciprofloxacin is considered as one of fluoroquinolones, which has the highest if not the highest activity against P. aeruginosa and very strong antibacterial properties. Intended for oral and intravenous forms of ciprofloxacin was used in clinical trials for treatment of respiratory tract infections.

Despite the success achieved with the use of ciprofloxacin, there are some factors that limit the clinical applicability of the medicinal product for the treatment of lung infections, these include its low solubility at physiological pH values, bitter taste when its presence in the region is the target and rapid renal clearance. For example, for intravenous enter the dose, component 500 mg, the drug should be diluted to a concentration of <2 mg/ml and implement a slow infusion to avoid deposition in the injection. Ciprofloxacin with intravenous or oral introduction is also characterized by unfavorable pharmacokinetic profiles in the lower respiratory tract, including a relatively short period of elimination (half-life ranges from 1.0 to 1.6 h) and the small area under the curve of the dependence of concentration on time, which ranges from 43 to 113 mg·h/l

It should be expected that the introduction by inhalation ciprofloxacin patients in need, such as patients suffering from CF, suffering from COPD patients and those suffering from anthrax (anthrax) patients, leading to high concentrations of biocide in the respiratory tract. Ciprofloxacin even in subinhibitory concentrations affects the virulence of P. aeruginosa (quorum sensing ("quorum sensing")and the potential to reduce the incidence of chronic respiratory tract infections in patients with CF. Reduction of bacterial load in the respiratory tract and the possible slowdown repeated infections can lead to improved pulmonary function and contribute to improved long-term prognosis. In addition, the use of inhalation C is profloxacin may allow to overcome the possibility of kidney failure, which was noted after treatment with aminoglycosides.

However, it appeared that an effective internal-lung introduction of ciprofloxacin is difficult to implement. Obstacle associated with the introduction of anti-infective tools, such as Ciprofloxacin, light is the possibility of rapid clearance of drugs due to: (a) mucociliary clearance from the respiratory tract; (b) absorption of the drug in the systemic circulation; (C) clearance mediated by pulmonary macrophages. After intratracheal injection of soluble ciprofloxacin hydrochloride is rapidly absorbed from the lungs into the systemic circulation, which is characterized by a half-life of constituting exactly 0.2 h (J.P. Wong, Cherwonogroszky J.W., DiNinno V.L., etc: Liposome-encapsulated ciprifloxacin for the prevention and treatment of infectious diseases caused by intracellular pathogens, in "Liposomes in Biomedical Applications", Ed. by A.T. Florence, Gregoriadis G., published by Harwood Academic Press, Amsterdam, 1995, cc.105-120). This time span is too short to provide effective treatment of endobronchial infections caused by P. aeruginosa, and this represents a significant limitation in the development of the preparative form.

To overcome the rapid clearance of ciprofloxacin hydrochloride from the lungs, the researchers conducted a study of the possibility of encapsulation in the media providing controlremotodesky, such as liposomes. For example, Wong and co-authors demonstrated on models using rodents that liposomes can significantly increase the time required for ciprofloxacin in the lungs that leads to effective treatment of infections caused by Francicella tularensis. Restrictions for administration by nebulization ciprofloxacin using liposomes are: (a) large periods of time required for introduction, due to low levels of drug loading and limitations on the concentration of the dispersion, it is acceptable for spraying (limiting viscosity); (b) lack of control of the kinetics of release. In studies conducted by Wong, applied a standard sprayer. Such dispensers typically provide the flow velocity, comprising from 0.1 to 0.2 ml/min When the concentration of the medicinal product, component 10-40 µg/ml, the flow rate ranged from 1 to 8 mcg/min If we assume that the efficiency is about 10%, the light can only be entered from 0.1 to 0.8 µg/min Therefore, from a practical point of view, using this model, it is impractical to enter into the lungs doses exceeding 10 mg

In clinical practice has not found its development in the use of polymeric carriers as a means of extending the length of BP is like staying hydrochloride ciprofloxacin. Remain concerns with the slow clearance of polymer carriers from the lungs.

At pH values below the pK1(6,0) and above the pK2(8,8) ciprofloxacin has a net charge and has a high solubility. In the pH range from 6.0 to 8.8 connection is zwitterionic and practically insoluble (solubility at pH 7 is 60 µg/ml). The research results showed that in zwitterionic form of ciprofloxacin betaine is characterized by increased residence time in the lungs (R. Endermann, H. Labischinski, Ladel S. and others: Treatment of bacterial diseases of the respiratory organs, application for U.S. patent 2004/0254194 A1). However, Endermann with co-authors did not describe the introduction of ciprofloxacin betaine in a form that enables easy, efficient and reproducible introduction into the patient.

In addition, one of the main obstacles faced in the implementation of intra-lungs the introduction of anti-infective means, is that in this case we require the magnitude of a therapeutic dose of light (>10 mg). Market funds intended for administration in the form of aerosol is dominated by anti-asthma therapeutic agent (e.g., bronchodilators and corticosteroids). As shown in figure 1, Antiasthmatic drugs have vysokoeffektivnoi when introduced into the lungs in doses components less than about 100 micrograms (μg) (see also Weers J., A. dark, P. Challoner, High dose inhaled powder delivery: challenges and techniques. B: "Respiratory Drug Delivery IX, edited by R.N. Dalby, P.R. Byron, J. Peart, J.D. Suman, S.J. Farr, ed-bo Davis Healthcare Inti Publishing, River Grove, IL, 2004, cc.281-288).

Thus, existing therapeutic methods have several disadvantages. Taking into account the known system, intended for insertion containing the antibiotic aerosols, we can assume that there is a need to create a highly efficient and more convenient systems. One or more embodiments of the present invention can satisfy one or more of these needs.

Summary of the invention

The present invention allows to meet the current needs.

One of the objects of the invention is a pharmaceutical composition for intra-lungs introduction, containing fluorochinolon, such as ciprofloxacin, moxifloxacin or levofloxacin, which is in a form suitable for efficient injection into the lungs.

Another object of the invention relates to a powder composition for intra-lungs introduction, consisting of particles that contain fluorochinolon and excipient. The particles have a mass median aerodynamic diameter of from prima is but 1 to about 5 microns. Fluorochinolon characterized by the half-life in the lungs, comprising at least 1,5 hours

The following object of the invention relates to a powder composition for intra-lungs introduction, consisting of particles that contain fluorochinolon and excipient. The particles have a mass median aerodynamic diameter of from about 1 to about 5 microns, and a bulk density comprising less than about 0.6 g/cm3and roughness, comprising from about 3 to about 10. Fluorochinolon characterized by the half-life in the lungs, comprising at least 1,5 hours

Another object of the invention relates to compositions for internal-lung introduction, consisting of particles that contain fluoroquinolone betaine and excipient.

Another object of the invention relates to compositions for internal-lung introduction, consisting of particles that contain fluoroquinolone betaine and excipient where the particles are particles of a powder with a roughness factor of about 3 to about 10.

Another object of the invention relates to compositions for internal-lung introduction, consisting of particles that contain ciprofloxacin betaine, where ciprofloxacin betaine consists mainly of ciprofloxacin betaine 3,5-hydrochloride (ciprofloxacin betaine 3,5H2O).

The another object of the invention refers to a typical dosage form for internal-lung introduction, which is a tank that contains the composition, in powder form, where the composition comprises fluoroquinolone betaine.

Another object of the invention refers to a typical dosage form for internal-lung introduction, which is a tank that contains the composition, in powder form, where the composition comprises fluoroquinolone betaine. The particles have a mass median aerodynamic diameter of from about 1 to about 5 microns, bulk density, comprising less than about 0.6 g/cm3and roughness, comprising from about 3 to about 10.

Another object of the invention relates to a system introduction, which contains the standard dosage form, which is a tank that contains the composition, in powder form, where the composition comprises fluoroquinolone betaine. In addition, the system of the introduction contains inhaler dry powder containing chamber, adapted for insertion of the capsule.

The following object of the invention relates to a method of making particles for internal-lung introduction, namely, that prepare a liquid source product containing fluoroquinolone betaine and excipient. The liquid removed from the original product, receiving particles from the containing a series of fluoroquinolone betaine and excipient. The resulting particles have a mass median aerodynamic diameter of from about 1 to about 5 microns.

Another object of the invention relates to a method of making particles for internal-lung introduction, namely, that prepare a liquid source product containing fluoroquinolone betaine and excipient. The liquid removed from the original product, receiving particles containing fluoroquinolone betaine and exceptiontable particles have a mass median aerodynamic diameter of from about 1 to about 5 microns, bulk density, comprising less than about 0.6 g/cm3and roughness, comprising from about 3 to about 10.

The following object of the invention relates to a method for treatment of endobronchial infections, namely, that the patient who needs it, introduced by inhalation in the effective amount of the composition, where the composition comprises particles containing fluoroquinolone betaine and at least one excipient, and where the particles have a mass median aerodynamic diameter of from about 1 to about 5 microns.

Another object of the invention relates to a method for treatment of endobronchial infections, namely, that the patient who needs it, is administered by inhalation in the effective amount is the song, where the composition comprises particles containing fluoroquinolone betaine and at least one excipient, and where the particles have a mass median aerodynamic diameter of from about 1 to about 5 microns, bulk density, comprising less than about 0.6 g/cm3and roughness, comprising from about 3 to about 10.

Another object of the invention relates to a method for treatment of endobronchial infections, namely, that the patient who needs it, is administered by inhalation in the effective amount of the composition, where the composition comprises particles containing fluoroquinolone betaine and at least one excipient, and where the particles have a mass median aerodynamic diameter of from about 1 to about 5 microns, and where the composition in an effective amount is administered through four or fewer inhalation, preferably through three, more preferably by one inhalation.

Another object of the invention relates to a method for treatment of endobronchial infections, namely, that the patient who needs it, is administered by inhalation in the effective amount of the composition, where the composition contains particles of powder containing fluorochinolon and at least one excipient, and where the particles have a mass median AE is dinamicheski diameter, comprising from about 1 to about 5 microns, and where fluorochinolon has a half-life in the lungs of at least 1,5 hours

Another object of the invention relates to a method for treatment of endobronchial infections, namely, that the patient who needs it, is administered by inhalation in the effective amount of the composition, where the composition contains particles of powder containing fluorochinolon and at least one excipient, and where the particles have a mass median aerodynamic diameter of from about 1 to about 5 microns, bulk density, comprising less than about 0.6 g/cm3and roughness, comprising from about 3 to about 10, and where fluorochinolon has a half-life in the lungs of at least 1,5 hours

One or more embodiments of the present invention is(are) to a powder composition containing fluoroquinolone betaine, such as ciprofloxacin betaine, which can be made in the capsule of size No. 2 (or with less), and which provides for the introduction of intra-lungs via inhalation intake into the lungs dose comprising at least about 10 mg

One or more embodiments of the present invention is(are) to a powder composition containing flu is rohinson betaine, such as ciprofloxacin betaine, which can be made in the capsule of size No. 2 (or with less), and which provides for the introduction of intra-lungs through three or four, or fewer inhalation intake into the lungs of a therapeutic dose.

One or more embodiments of the present invention is(are) to a powder composition containing fluoroquinolone betaine, such as ciprofloxacin betaine, which can be made in the capsule of size No. 2 (or with less), and which provides for the introduction of intra-lungs through two inhalation intake into the lungs of a therapeutic dose.

One or more embodiments of the present invention is(are) to a powder composition containing fluoroquinolone betaine, such as ciprofloxacin betaine, which can be made in the capsule of size No. 2 (or with less), and which provides for the introduction of intra-lungs via inhalation intake into the lungs of a therapeutic dose.

In one or more embodiments of implementation of the present invention the powdered composition is a particle containing from 50 to 70 wt.% crystalline ciprofloxacin betaine, which caused porous coating of the saturated phosphatid is Shalina long chain where the particles have a mass median diameter of from about 1 to about 5 microns mass median aerodynamic diameter of from about 1 to about 5 μm, and the roughness (Sv)constituting from about 3 to about 10.

In one or more embodiments of implementation of the present invention the powdered composition is a particle containing crystalline ciprofloxacin betaine 3.5-hydrate, which has a residual moisture content of 10 to 15 wt.%, and the pH value after recovery, amounting to from 6.0 to 8.8.

In one or more embodiments of implementation of the present invention the powdered composition is a particle containing crystalline ciprofloxacin betaine 3.5-hydrate and excipient, where the specific surface area of the particles is from 8 to 20 m2/g, porosity of the particles is from 5 to 20 cm3/g, and a surface roughness (Sv) is from 3 to 10.

In one or more embodiments of implementation of the present invention the powdered composition is a particle containing crystalline ciprofloxacin betaine 3.5-hydrate, which is applied a porous coating layer of excipient, where the specific surface area of the particles is from 8 to 20 m2/g, porosity of the particles of the composition of AET from 5 to 20 cm 3/g, and a surface roughness (Sv) is from 3 to 10.

In one or more embodiments of implementation of the present invention, the powder containing fluorochinolon contribute to the reservoir, such as a capsule, where the powder has a bulk density measured by the method of uniaxial compression, comprising from 0.1 to 0.6 g/cm3.

In one or more embodiments of implementation of the present invention, the powder containing fluorochinolon contribute to the reservoir, such as a capsule, where the powder has a bulk density measured by the method of uniaxial compression, constituting less than 0.6 g/cm3and more preferably component from 0.2 to 0.5 g/cm3.

In one or more embodiments of implementation of the present invention the pharmaceutical composition is a powder containing a therapeutically effective amount of ciprofloxacin betaine and pharmaceutically acceptable excipients, where the powder is of a particle containing crystalline ciprofloxacin betaine in an amount constituting from 50 to 70 wt.%, the mixture of distearoylphosphatidylcholine and dihydrate calcium chloride in a molar ratio of 2:1 in an amount constituting from 30 to 50 wt.%

In one or more embodiments of implementation of the present invention a standard dosage form is a con is Aner, containing pharmaceutical composition, which is a powder containing a therapeutically effective amount of ciprofloxacin betaine and pharmaceutically acceptable excipients, where the powder is of a particle containing crystalline ciprofloxacin betaine in an amount constituting from 50 to 70 wt.%, the mixture of distearoylphosphatidylcholine and dihydrate calcium chloride in a molar ratio of 2:1 in an amount constituting from 30 to 50 wt.%.

In one or more embodiments of implementation of the present invention system introduction includes an inhaler for dry powder pharmaceutical composition, which is a powder containing a therapeutically effective amount of ciprofloxacin betaine and pharmaceutically acceptable excipients, where the powder is of a particle containing crystalline ciprofloxacin betaine in an amount constituting from 50 to 70 wt.%, the mixture of distearoylphosphatidylcholine and dihydrate calcium chloride in a molar ratio of 2:1 in an amount constituting from 30 to 50 wt.%.

In one or more embodiments of implementation of the present invention a method of manufacture of spray dried particles is that the suspended crystalline ciprofloxacin betaine in the liquid, representing the submicron emulsion is s drops, stable pharmaceutically acceptable excipients, with the formation of the original product, and put the original product was spray-dried to obtain dried by spraying particles, where the particles contain ciprofloxacin betaine, which caused a porous coating of pharmaceutically acceptable excipients, where the particles have a mass median diameter of from 1 to 5 microns mass median aerodynamic diameter of from 1 to 5 μm, and the roughness (Sv)comprising from 3 to 10.

In one or more embodiments of implementation of the present invention a method of manufacture of spray dried particles is that the suspended crystalline ciprofloxacin betaine in fluid representing a submicron emulsion droplets stabilized pharmaceutically acceptable excipients, with the formation of the original product, and put the original product was spray-dried to obtain dried by spraying particles, where the particles contain crystals of ciprofloxacin betaine 3.5-hydrate, which caused a porous coating of pharmaceutically acceptable excipients, where the particles have a mass median diameter of from 1 to 5 microns mass median aerodynamic diameter of from 1 to 5 μm, and roughness (Sv), with the bringing of 3 to 10.

In one or more embodiments of implementation of the present invention is a method of treatment of pulmonary infections is that the patient who needs it, introduced by inhalation in an effective amount of a composition comprising ciprofloxacin betaine, where the composition is in powder form, which are particles that contain ciprofloxacin betaine in an amount constituting from 50 to 70 wt.%, and have a mass median diameter of from 1 to 5 microns mass median aerodynamic diameter of from 1 to 5 μm, and the roughness (Sv)comprising from 3 to 10.

In one or more embodiments of implementation of the present invention powders for internal-lung introduction is made by spray drying of the raw product on the basis of emulsions using a mobile dryer small capacity of the firm Niro when the inlet temperature from 125 to 145°C. and the outlet temperature from 60 to 80°C. the resulting particles are characterized by a lamellar morphology, characteristic of the drug substance, and they are porous coating layer of the excipients, and the roughness (Sv) particles is from 3 to 10.

In one or more embodiments of implementation of the present invention, the powders which are particles that contain fluorochinolon, in osat in capsules No. 2 from hydroxypropylmethylcellulose (HPMC), this made the weight is from 20 to 60 mg.

In one or more embodiments of implementation of the present invention, the powders are proposed in the present invention contain as a medicinal substance ciprofloxacin betaine and have a half-life of greater than 3 h, which contributes to the effectiveness against P. aeruginosa.

In one or more embodiments of implementation of the present invention, the powders containing ciprofloxacin, allow for the treatment of infections caused by Pseudomonas aeruginosa in patients with CF, within a month "off-period"that follows after a month "on-period" of treatment by inhalation of tobramycin TOBI®.

In one or more embodiments of implementation of the present invention, the powders containing ciprofloxacin, allow for the treatment of infections in patients COPD patients.

In one or more embodiments of implementation of the present invention, the powders containing ciprofloxacin, allow treatment caused by anthrax infections.

In one or more embodiments of implementation of the present invention is obtained by spray drying powders containing ciprofloxacin, have a positive impact on the quality of life for patients suffering from CF, by improving p is delitelnou pulmonary function (FEV 1), they require little time, for example, less than five minutes to introduce a handheld inhaler.

In one or more embodiments of implementation of the present invention, the ratio of AUCin sputum/AUCplasmaprovided effective directional introduction of ciprofloxacin betaine in light, greater than 50, preferably greater than 100, and more preferably greater than 250.

In one or more embodiments of implementation of the present invention, the particles proposed in the present invention, which contain ciprofloxacin betaine, you do not want to mix with coarse particles of the medium, which is a lactose to provide a very high fluidization and dispersion of the powder.

In one or more embodiments of implementation of the present invention a composition comprising fluoroquinolone betaine, such as ciprofloxacin betaine, characterized by the efficiency of introducing into the lungs using a portable inhalers passive type for dry powder in excess of 30, 40, 50, 60% or more.

In one or more embodiments of implementation of the present invention combination drug/device contains a composition comprising fluoroquinolone betaine, such as ciprofloxacin betaine, which can provide an introduction to eggie target doses (> 10 mg) with a single inhalation.

In one or more embodiments of implementation of the present invention proposed in this invention therapeutic preparative form containing ciprofloxacin betaine, is intended for the treatment of cystic fibrosis, non-CF bronchiectasis, hospital-acquired pneumonia, acute complications of chronic bronchitis or anthrax.

Other embodiments of the invention include any two or more of the above distinguishing features, aspects, versions or embodiments of the invention.

Part of the additional embodiments and characteristics of the invention are presented in the description below, and the part should be obvious to specialists in this field after studying the description, or they can be implemented when carrying out the present invention in practice. Distinguishing features and advantages of the invention may be realized and attained by using tools, combinations and methods provided in the description.

Description of the drawings

Embodiments of the present invention is additionally explained in the description below, with reference to presents not limit the invention, the drawings on which is shown:

figure 1 is a graph illustrating dimernye doses of various therapeutic agents, you must enter into the lungs through internal-lung route of administration. Presents also the maximum dose that can be introduced into the lungs via inhalation using a portable aerosol devices. Anti-infective agents such as aminoglycosides and fluoroquinolone, require large doses to the lungs (10-100 mg), which leads to the fact that the types of possible preparative forms/devices limited to nebulizers and inhalers dry powder capsule type,

figure 2 is a graph illustrating the solubility of ciprofloxacin in 0,15 KCl, depending on pH values. Ciprofloxacin betaine is present in zwitterionic form at pH values from 6.0 to 8.8. The solubility of ciprofloxacin betaine at neutral pH values is very small (70 µg/ml), so it can be used to obtain preparative forms through a process of preparation of the emulsion, based on the suspension, the implementation of which the crystals are coated with the coating in the form of a porous layer of hydrophobic phospholipid,

figure 3 is a graph which shows isotherms (at T=25°C) equilibrium sorption of water vapor medicinal substance, representing ciprofloxacin betaine (filled circles), inhalation powder ciprofloxacin betaine, etc is dehaemer in the present invention, CIP (filled squares) and powder representing placebo (filled triangles). Presents a separate experimental point (inverted triangle)obtained for the CIP method titrimetry by Karl-Fischer at a relative humidity (RH) of 60%,

on figa-4G - obtained using scanning electron microscope pictures micronized ciprofloxacin betaine (figb, 4G) and inhalation powder ciprofloxacin betaine proposed in the present invention, CIP, unconsolidated powder (figa, 4B) at magnification of 10,000× and 20,000×, respectively,

on figa-5e - obtained using scanning electron microscope pictures of several samples obtained by spray drying inhalation containing ciprofloxacin betaine powder, CIP, where samples have different content of the drug substance 5(a): 50%, lot N; 5(b): 50%, lot N020242; 5(C): 60%, lot N020240; 5(g): 60%, lot N020243; 5(l): 70%, lot N020241 and 5(e); 70%, lot N020244.

figure 6 - comparison of the dispersive ability of the pigment fine ciprofloxacin betaine and obtained by spray drying inhalation powder ciprofloxacin betaine proposed in the present invention, CIP. The dispersibility of the powder was evaluated quantitatively by measuring the median diameter of the particles depending on the pushing pressure is of the spray type RODOS, attached to the laser diffraction device for measuring the size of the firm Sympatec. CIP dispersed to primary particles with much smaller buoyancy pressure than the micronized drug that is a reflection of the decrease in cohesive force between the particles due to the presence of the porous coating of phospholipid,

7 is a graph illustrating the improved ability to directly penetrate into the lungs during inhalation inhalation powder containing ciprofloxacin betaine proposed in the present invention. The left panel shows the difference between the values of Cmaxin plasma after oral administration (PO) 500 mg BID Cipro and administration by inhalation (IH) of 32.5 mg QD inhalation powder ciprofloxacin betaine proposed in the present invention, i.e. the CIP. On the middle panel presents the corresponding levels in the sputum. Finally, on the right panel illustrates the improved directional penetration provided by inhalation, as seen by the ratio of AUC in the sputum and AUC in plasma. Inhalation ciprofloxacin leads to significantly higher concentrations in the sputum and respectively to the low systemic levels of the drug. Directional penetration into the lungs is increased 250-fold with the introduction of drugs by inhalation.

On Fig the-8 - schematic image of the lateral projections illustrating the operation of the inhaler for dry powder, which can be used to retrieve aerosol pharmaceutical formulation proposed in the invention.

Description

Definition

It should be borne in mind that, unless otherwise stated, the present invention is not limited to the specific components of the formulation, systems designed for the introduction of drugs, methods of manufacture, the stages of introduction, or the like, as they can vary. Unless otherwise indicated, reference to a compound or component applies to the specified connection or component individually, and the connection is included in combination with other compounds or components, such as a mixture of compounds.

Before further discussion of the definitions of several concepts, which should contribute to a better understanding of embodiments of the present invention.

In the context of the present description the singular number include the plural, unless the context clearly requires otherwise. For example, the term "phospholipid" refers to one phospholipid, and two or more phospholipids included in a combination or mixture, unless the context clearly requires otherwise.

When specified range led the chin, it is assumed that you have in mind any particular falls into a value that is between the upper and lower bounds on the distance to one-tenth the size of its lower bounds. It includes each smaller range between any specified value or within a specified range value and any other specified value or within a specified range value. Upper and lower limits of these smaller ranges may independently from each other are included in the range or excluded from it, and each range at which any one, either one or both boundaries of enabled(s) in the smaller ranges is also according to the invention to any particular excluded the border in the specified range. When the specified range includes one or both of the border, it also includes ranges that are excluded(s) any one or both of the border.

It should be borne in mind that in the context of the present invention the concept of "one of the embodiments of the invention", "one version or one of the objects include one or more such embodiments of the invention, versions or objects, unless the context clearly requires otherwise.

In the context of the present invention the concept of "cure" and "treatment" refer to reducing the severity and/or frequency of occurrence with which Nemov elimination of symptoms and/or underlying cause, to reduce the likelihood of symptoms and/or underlying causes and reduction or healing damage. Thus, "treating" a patient with active substance proposed in the present invention, includes the prevention of the occurrence of a specific condition, illness or disorders in sensitive individuals, and treatment of individuals with clinical symptoms.

In the context of the present invention the term "therapeutically effective amount" refers to an amount effective to achieve the desired therapeutic result. A therapeutically effective amount of a particular active substance, as a rule, should vary depending on such factors as the type and severity of disorder or disease to be treated, and the age, sex and weight of the patient.

In the context of the present invention, the term "respiratory infections" includes, but is not limited to, infections of the lower respiratory tract, such as bronchiectasis (as with cystic fibrosis and non-cystic fibrosis manifestations), bronchitis (acute bronchitis, and acute complication of chronic bronchitis) and pneumonia (including different types of complications resulting from viral and bacterial infections, including in the hospital and community-acquired and is of infections).

In the context of the present invention the term "bulk density" refers to the density measured using uniaxial compression at a pressure of about 100,000 psi. This pressure corresponds to the pressure applied during automatic powder filling containers, such as capsules.

In the context of the present invention the term "mass median diameter" or "MMD" refers to the median diameter of the set of particles, usually in the form of a polydisperse population of particles, i.e. population, in which the particle sizes are in the range specified. Specified in this description of the MMD values determined using laser diffraction (firm Sympatec Helos, Clausthal-Zellerfeld, Germany), unless the context requires otherwise. Typically, samples of the powder contribute directly to the hopper device for dispersing dry powder type RODOS company Sympatec. This can be done manually or by mechanical shaking, excited by the end of the vibrating infeed element VIBRI. The sample is dispersed to the formation of the primary particles by application of compressed air (at a pressure of from 2 to 4 bar), vacuum pumping, the maximum for a given dispersing pressure. Dispersed particles being probed by a laser beam at a wavelength of 632.8 nm, which Peres is otherwise trajectory of the dispersed particles at right angles. Laser light scattered by the particle falls on a concentric set photometrically detector elements using a set of lenses with the inverse Fourier transform. The scattered light is recorded by time intervals of 5 MS. The particle sizes determined by the method of back-calculation using a proprietary algorithm based on the spatial distribution/intensity distribution of scattered light.

In the context of the present invention relative dispersibility is obtained by spray drying powders is determined according to the method of the firm Sympatec (based on the laser diffraction), varying dispersing pressure dispersing device RODOS, from about 0.2 to 4.0 bar. In the context of the present invention the ratio of the dispersive ability of the pigment, δ (Delta), defined as the ratio of the value of x50measured at a dispersion pressure of 0.2 bar, to the value of x50measured at a dispersion pressure of 4.0 bar. If the ratio δ=1, this indicates that the powder is easily dispersed at low dispersive pressure, while ratios less than 1 indicate that at low dispersive pressure is incomplete dispersion of the powder.

In the context of the present invention, the specific surface area (SSA) represents the SSA is calculated on the basis of the evaluation results of gas adsorption according to theoretical method, developed by Brunauer, Emmett and Teller (J Amer Chem Soc, 60, 1938, s), which is usually called the BET method.

In the context of the present invention, the porosity of the particles represents the total pore volume, expressed in percent, which is calculated on the basis of the results of the evaluation of the absorption of gaseous nitrogen. When nitrogen adsorption is filling (and emptying) then nitrogen in accordance with the equation of capillary condensation Kelvin. With increasing partial pressure of nitrogen gas condensation must begin in small pores and then to cover more and more large pores until then, until the volume (total) condensation. When using this technique, a first nitrogen condense in the pores by setting the partial pressure of nitrogen at the level close to saturating. Then gradually carried out stepwise desorption of nitrogen, lowering the vapor pressure. The distribution of pore sizes calculated by analyzing the desorption isotherms of nitrogen using the Kelvin equation, determining the amount condensed in the pores of nitrogen (assuming that the pores are cylindrical in shape), and the loss adsorbtive at each step represents the volume of the pore channels, devastated at this step. The calculation is made automatically based on the algorithm proposed by Barrett and co-authors (E.P. Barrett, L.G. Joyner, Halenda P.P.: The determination of pore volume and area istributions in porous substances I. computations from nitrogen isotherms. J Amer Chem Soc 73, 1951, SS-380). This approach is applicable for pores with a diameter of up to about 2 nm, i.e. up to the level of micropores.

Roughness (Sv) is a measure of the surface roughness of the produced powder. For the purposes of the present invention, the roughness is calculated on the basis of the specific surface area obtained by the measurement according to BET, the true density measured using helium pycnometry, and the relationship of surface area/volume of the particles obtained by the method of laser diffraction method company Sympatec), namely, by the formula:in which Sv=6/D32.

In the context of the present description, "mass median aerodynamic diameter" or "MMAD" is a median aerodynamic diameter of the set of particles, usually in the form of a polydisperse population of particles. "Aerodynamic diameter" is a diameter of a sphere of unit density that has the same settling velocity as a rule, in the air, and the powder, and therefore is suitable characteristic sprayed in aerosol form of powder or other dispersed particles, or consisting of particles of formulation from the point of view of the process of their deposition. Aerodynamic diameter allows to take into account the shape of the particle and h is stitz, the density and physical size of the particle or particles. For the purposes of the present invention MMAD is determined using a cascade impactor, unless the context clearly requires otherwise.

In the context of the present invention the term "emitted dose" or "ED" refers to the characteristic of the receipt of a dry powder inhalator device after bringing it in action or the formation of a dispersion containing a powder of an element or tank. ED are defined as the ratio of the dose delivered by inhalation device, to the nominal dose (i.e. the mass of delivered powder emitted mass to the mass of a single dose of powder, placed in an appropriate inhalation device before running it). ED is a determined experimentally number and this value can be measured in vitro using a setup that mimics the dose to the patient. According to the present invention for determining the value of ED placed a nominal dose of a dry powder (as defined in the present description) in a suitable device for inhalation, such as a device for inhalation of a dry powder (DPI) Turbospin®(firm PH&T, Italy), is described in U.S. patent No. 4069819 and 4995385, the contents of which are fully incorporated into the present description by reference. The device for inhalation of lead in de is due, by dispersing the powder. Then the resulting cloud aerosol pumped from the device using a vacuum with a speed of 60 l/min) for 2 seconds after setting the device in action, while the aerosol capture in tared glass fiber filter (firm Gelman, 47 mm in diameter)attached to the mouthpiece of the device. The amount of powder that reaches the filter represents the delivered dose. For example, capsules containing 5 mg of dry powder, which is placed in the device for inhalation, if the dispersion of the powder leads to holding 4 mg of powder on a tared filter, the value of ED for the composition of the dry powder is 80% [4 mg (delivered dose)/5 mg (nominal dose)].

In the context of the present description, the term "effective amount" refers to both therapeutically effective amounts, and the prophylactically effective amounts.

In the context of the present description the term "inhaler passive type for dry powder" refers to a device for inhalation, which requires breathing effort of the patient to fluidization and dispersion of the pharmaceutical composition contained in the device in the tank or in the form of a standard dose.

In the context of the present description the term "inhaler active type for dry powder" refers to a device which istwo inhalation, which includes means for supplying energy to fluidization and dispersion of the composition of the medicinal product, such as compressed gas and/or an oscillating or rotating elements.

Full contents and descriptions of each cited in this document, including any and all U.S. patents and patent applications under the PCT (or ex-US) and the publication of patent applications and U.S. patent applications under the PCT (or ex-US)included in the present description by reference for all purposes.

Description of the invention

The present invention relates to intra-lungs the introduction of the active substance in an effective dose to the lungs for the treatment of pulmonary infections.

In one or more embodiments of the invention, represented in the present description, medicinal substance, which represents the active substance is chosen from the family of quinolone or hinolonovykh medicines (including fluoroquinolone), such as, but not limited to, Kalinicheva acid, cinoxacin, norfloxacin, ciprofloxacin, ofloxacin, enoxacin, moxifloxacin, levofloxacin and pefloxacin. In one particular version preparative forms and compositions contain ciprofloxacin, because it has a very high activity against P. aeruginosa.

In one or more embodiments, the OS is the hope of the present invention the residence time in the lungs is not controlled by encapsulation in a system carrier (for example, in liposomes or polymeric carriers), instead, the required residence time in the lungs (as well as intra-lungs introduction in the appropriate areas) provide using preparative forms containing fluoroquinolone betaine, in a form suitable for inhalation, which is presented in the present description. Thus, in one or more embodiments of implementation of the present invention, they contain fluoroquinolone betaine, such as ciprofloxacin betaine, suitable for inhalation, and provide the half-life in the lungs in excess of 3 hours, which is accompanied by increased effectiveness against P. aeruginosa compared to soluble forms fluoroquinolone, such as ciprofloxacin hydrochloride.

Typically, the bacteria causing respiratory tract infections (RTI) types of bronchitis, acute complications of chronic bronchitis (ESV) and CF, are located in the cavities of the respiratory tract, the surface mucous cells and within the tissues of the bronchial mucosa. Established that the pneumonia bacteria are mostly present in the alveoli. In order to achieve its targets, namely causing disease pathogens, administered by oral or intravenous antibacterial agents to penetrate into the alveolar space; agents must pass through the alveolar membrane, which is against the sustained fashion hard permeable, and shall be distributed in the epithelial lining fluid (ELF), covering the surface mucous cells. Thus, the concentration of antimicrobial agents in the ELF/sputum can be considered as suitable for clinical purposes indicator concentrations in the target area. Therefore, the aim of the present invention is to develop a preparative forms for inhalation, which can provide inhaled doses comprising 10-30 mg, for a few breaths (e.g., via one inhalation). One or more embodiments of the invention is(are) to a combination of preparative form/device, ensure the effectiveness of the introduction of light, comprising from 20 to 60 wt.%, this corresponds to the nominal dose comprising from 15 to 150 mg, or from 0.3 to 3.0 mg/kg for a young person weighing 50 kg

One or more options preparative forms proposed in the present invention can achieve high concentrations in the area of infection, exceeding the value of the MIC for P. aeruginosa. Thus, pharmacokinetic characteristics, determining the impact on the growth of P. aeruginosa and reducing the virulence of P. aeruginosa, should have an impact on FEV1 as pharmaco dynamic correlation. In addition, the formulation proposed in the present invention, can reduce the performance by the number of times of occurrence and severity of acute complications and to improve the quality of life of patients with CF due to the significant reduction of time required for the introduction of drugs.

The present invention has additional advantages. For example, as noted above, for most other aerosol therapeutics require significantly higher doses in the lungs, regardless of what they are, for the local treatment of lung disease or as a system. Introduction in light of large doses (>10 mg), which was traditionally carried out using an inkjet nozzles, which is the standard technology using preparative forms and devices for therapeutic treatment of asthma (for example, inhalers with enough scale and parenteral multi-dose inhalers dry powder), is ineffective in the case of doses of this magnitude. As mentioned above, caused by P. aeruginosa infection in patients with cystic fibrosis (CF) (entered at the light dose of ≈ 30 mg), currently treated by jet nebulization of aqueous solutions of the aminoglycoside tobramycin (TOBI®, Novartis, Emeryville, stilborne) by means of a spray type PARI LC Plus. It is established that prolonged the time required for introduction, and the fact that the inkjet nozzles are not portable, as well as the need to carry out a large number of inhalations, have a negative impact on the quality of life of patients is now, suffering from CF. In the doctor encountering problems with adherence, and treatment. Due to the fact that treatment programs are required to strictly comply with, any saving of time required for treatment is seen as a huge incentive for compliance of the patient circuit and mode of treatment and improve their quality of life. The ability to use portable nebulizer that can be worn in a shirt pocket or purse is also a great advantage, since the patient is no longer associated with bulky compressor requiring electric power. Thus, the patient can go for long walks or engage in any activity outside the home and still be able to enter your remedy.

As indicated above, the residence time of the water-soluble fluoroquinolones, such as ciprofloxacin hydrochloride, in the lungs is very short (half-life of approximately 0.2 h) (Wong and others: "Liposomes in biomedical applications", Ed. by A.T. Florence, G. Gregoriadis, ed-in Harwood Academic Press, Amsterdam, 1995, SS. 105-120). Thus, in one version of the present invention are prepared in preparative form of the composition so that fluorochinolon, such as ciprofloxacin, after introduction into the lungs had a half-life average of at least 0,3 am Still Bo is her preferred when the half-life is considerably large, for example, is at least 1.5 h, more preferably at least 3 h, and even more preferably at least 6 hours

It was established that in contrast to its short half-life of soluble ciprofloxacin half-life of zwitterionic forms, such as ciprofloxacin betaine, at pH values close to neutral, significantly more (R. Endermann, H. Labischinski, Ladel S.I. others, Treatment of bacterial diseases of the respiratory organs, application for U.S. patent 2004/0254194 A1).

Thus, one or more embodiments of the present invention is(are) to preparative forms in the form of a dry powder of ciprofloxacin betaine intended for inhalation. Variants of ciprofloxacin betaine (and other fluoroquinolones) and methods of treatment using such compounds are described in published patent application U.S. 2004/0254194, the contents of which are fully incorporated into the present description by reference. Preparative form containing betainovuyu derivatives other fluoroquinolones (e.g., levofloxacin, moxifloxacin), you can apply according to the present invention instead of ciprofloxacin betaine, or in addition to it. Ciprofloxacin betaine has a very low solubility in water (see figure 2). Thus, one or several options to implement the Oia of the present invention is(are) to preparative form of ciprofloxacin betaine in the form of fine crystals, which is applied a coating in the form of a porous layer of hydrophobic excipient, preferably a porous layer of phospholipid. Ciprofloxacin betaine is formed at pH values from 6.0 to 8.8. Preferred are pH values close to neutral.

In one or more embodiments of the invention at least 50% of the crystalline particles of ciprofloxacin betaine have a mass median diameter (x50)of less than about 5 microns, more preferably less than about 3 microns, and even more preferably less than about 2 microns. In one or more embodiments of the invention, at least 90% crystalline particles of ciprofloxacin betaine have a mass median diameter (x90)of less than 10 microns, more preferably less than 7 microns, and even more preferably less than 5 microns. The value of the MMAD of the formed particles of the powder depends on the original size of the particles constituting the crystals of ciprofloxacin betaine. The smaller the value of the MMD of the crystal, the smaller the value of the MMAD of the particulate powder containing ciprofloxacin betaine.

In one or more embodiments of the invention, larger crystals of ciprofloxacin betaine can be cut to the desired size using a standard methodology is grinding, including but not limited to, grinding in a jet mill and grinding mill wet grinding (homogenization at high pressure).

Alternatively or additionally, the grinding can be performed using the processes of deposition, during which the drug is dissolved in the solution and then precipitated. Such methods include spray drying and freeze spray drying. In this area there are other grinding processes, which include but not limited to, processing methods on the basis of a superfluid, such as the methods described in WO 95/01221, WO 96/00610 and WO 98/36825, cryogenic grinding, wet grinding, homogenization ultrasound at high pressure, microfluidizer, crystallization processes, as well as the processes described in US no 5858410, which are all fully incorporated into the present description by reference.

The composition proposed in the present invention, containing fluoroquinolone betaine, such as ciprofloxacin betaine may include the active substance in different quantities. For example, the number fluoroquinolone betaine, such as ciprofloxacin betaine, may be at least about 30, 40, 50, 60, 70, 80 or 90 wt.%. In some embodiments of the invention the desired character of the sticks of fluidization and dispersive ability of the pigment powder get in the case, when fluoroquinolone betaine, such as ciprofloxacin betaine is present in the composition in amounts of about 50 to 70 wt.%.

One or more embodiments of the invention is(are) to pharmaceutical compositions or formulations form containing fluoroquinolone betaine, such as ciprofloxacin betaine, and optionally one or more pharmaceutically acceptable excipients.

In one or more embodiments of the invention pharmaceutically acceptable excipient represents one or more at least partially of hydrophobic excipients. For example, hydrophobic excipients may be one or more substances selected from the group comprising lipids, soap, representing salts of fatty acids with long chain (such as magnesium stearate, potassium stearate), hydrophobic amino acids or peptides (such as leucine, trilastin), and cholesterol.

In one or more embodiments of the invention pharmaceutically acceptable excipients are lipid such as a phospholipid. In one of the versions form a phospholipid matrix. Examples of phospholipid matrices described in WO 99/16419, WO 99/16420, WO 99/16422, WO 01/85136 and WO 01/85137, and in U.S. patent No. 5874064; 5855913; 5985309 and 6503480, and in the process simultaneously the military review and co-owned application U.S. patent No. 10/750934, registered December 31, 2003, the contents of all these documents are fully incorporated into this description by reference.

In one or more embodiments of the invention the excipients present in the form of rough porous coating of the active substance. When they are thus selected and included in the formulation, excipients provide improved ability of powder to fluidization and its dispersibility compared to smooth surfaces, characterized by low porosity or roughness.

Phospholipids derived from natural or synthetic sources, can be used in different quantities. When phospholipids are present, their number, as a rule, should be sufficient for the active(s) substance(s) can be applied phospholipid layer, sufficient for the formation of porous coating. The content of phospholipids, in the case when they are present, usually ranges from about 10 to about 70 wt.%, for example, from about 30 to about 50 wt.%.

Generally, suitable phospholipids are phospholipids, which have a temperature of phase transition from gel to liquid crystals greater than about 40°C., for example greater than about 60°C., or greater than about 80°C. Suitable is to enable the phospholipids can be a saturated lipids with relatively long chain (e.g., With16-C22). Examples of phospholipids that can be used in the stabilized formulation, proposed in the invention, include, but are not limited to, phosphatidylcholine, such as dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine, and hydrogenated phosphatidylcholine from egg yolk or soy (for example, E-100-3, S-100-3, marketed by the company Lipoid KG, Ludwigshafen, Germany). Naturally occurring phospholipids are preferably hydrogenated with low iodine number (<10).

Phospholipids optional can be combined with a divalent metal ion. The presence of such a divalent metal ion reduces the hydration of the head groups of the phospholipid, thereby increasing the phase transition of phospholipid from gel to liquid crystals, and the wettability of powders in the fluid lining of the lungs.

Examples of metal ions can serve as, but not limited to, divalent cations, including calcium ions, magnesium, zinc, etc. for Example, when using the phospholipids, the pharmaceutical composition may also contain polyvalent cation, as described in WO 01/85136 and WO 01/85137, the contents of which are fully incorporated into the present description by reference. Polyvalent cation may be present in a quantity effective the La increase the melting temperature (t PL) phospholipid so that the pharmaceutical composition had tPLgreater than about 60°C., preferably greater than about 80°C. or greater than about 100°C. the Molar ratio of polyvalent cation and phospholipid may be at least approximately 0.05:1, for example, from approximately 0.05:1 to about 0.5:1. In one or more embodiments of the invention the molar ratio of polyvalent cation and the phospholipid is about 0.5:1. It is assumed that the divalent metal ion is bound to the phosphate group on zwitterionic the head group of phosphatidylcholine, displacing in the process, the water molecules. If the molar ratio of metal ions and phospholipid than 0.5, it can lead to the fact that free metal ions will not contact with the phosphate groups. This can significantly increase the hygroscopicity of the resulting dry powder. When the polyvalent cation is a calcium ion, it may be in the form of calcium chloride. Although the phospholipid often include metal ions, such as calcium, does not require the presence of other ions (e.g., phosphate, which can lead to precipitation of calcium ions in the form of calcium phosphate) in the preparative form, and their presence can lead to certain problems.

In one or not is how many versions of the song, proposed in the present invention, excipient may additionally or alternatively include additives to further improve the stability and biocompatibility of the preparative form. For example, for this purpose it is possible to consider various salts, buffers, chelators and masking the unpleasant taste of the substance. The use of such additives are known to the ordinary skilled in the field, and their specific amounts, ratios and types of substances can be determined empirically without conducting unnecessary experiments.

In one or more embodiments, the composition proposed in the present invention, excipient may additionally or alternatively include excipients that perform similar and/or alternative features. For example, the composition may include excipients that provide directional migration, to enhance directional transfer of particles to specific cells (for example, pulmonary macrophages). In one version of the invention the pharmaceutical formulation can contain one or more providing directional transfer agents. For example, the pharmaceutical formulation can include providing directional transfer agent, which sends particles and/or the active substance to the target cells, such as lung macrophages. This is especially important in case the AE, when pharmaceutical preparative form is administered for the treatment of infectious diseases when the pathogen is absorbed by pulmonary macrophages. Such infectious diseases are difficult to treat common methods of systemic therapy using anti-infective agents. However, if you enable them in providing directional transfer agent particles can more easily resist the absorption of pulmonary macrophages and more efficiently transported to the area of infection. This treatment is especially effective in the treatment of tuberculosis, diseases caused by major bacterial agents, such as anthrax, and some types of cancer. Providing directional transfer agents may represent, for example, one or more of these substances, as phosphatidylserine, hIgG and muramyldipeptide described in PCT publications WO 99/06855, WO 01/64254, WO 02/09674 and WO 02/87542 and in U.S. patent 6630169, the contents of all documents are fully incorporated into this description by reference. The process of directional migration may be more effective in the case where the active substance remains in the lungs for an extended period of time. In accordance with this, in one version, the pharmaceutical formulation form includes providing a directional lane is the nose, the agent and the lipid component in the quantity sufficient to ensure that the active ingredient will be present in the lung within a predetermined period of time sufficient for the treatment of infectious diseases, in the case where the pathogen is absorbed by pulmonary macrophages. When pharmaceutical preparative form contains this provides directional transfer agent, it is particularly important that the particle size was preferably less than 6 μm, since larger particles can not easily be absorbed by pulmonary macrophages.

In one or more embodiments, the composition proposed in the present invention, excipient may additionally or alternatively include paglierani phosphatidylethanolamine, such as PEG2000-Feh and/or PEG5000-Feh (where the number indicates the molecular weight of the PEG-link), to further increase the time spent in the lungs due to the fact that avoids the clearance with macrophages, and/or to facilitate the penetration of the particles of the composition in the layer of mucus or sputum lining of the lung epithelium. Particles having dimensions less than 1 μm, can also penetrate into the biological membrane of Pseudomonas aeruginosa.

Ciprofloxacin betaine can be obtained in the form of various polymorphs and/or hydrates. In one or more embodiments of the invention ciprofloxacin betaine n which appears in the form of a 3.5-hydrate, which, as it was established, has a very high chemical and physical stability under conditions of use in accordance with the present invention. In one or more embodiments of the invention ciprofloxacin betaine included in the composition, is almost entirely in the form of a 3.5-hydrate. As shown in figure 3, the 3.5-hydrate is present in the case, when the water content in the resulting spray dried powders is about 10 to 15 wt.%. You can apply alternative or additional other polymorphs or hydrates, or mixtures of ciprofloxacin betaine, however, in the conditions of application of the present invention, it is preferable to 3.5-hydrate. In the claimed invention, it was found that polymorphic ciprofloxacin betaine becoming one polymorphic form, namely 3.5-hydrate, when performing spray drying with the application presented in this description of the process of spray drying with the use of emulsion. This transformation takes place, despite the fact that the crystals remain undissolved in the manufacturing process. Other processing methods typically produce a mixture of hydrates.

In one or more versions of a composition for intra-lungs the introduction is in the form of discrete particles, each of which soda is incorporated fluorochinolon and excipient. Fluorochinolon is present in the form in which its half-life in the lungs is at least 1,5 hours for Example, fluorochinolon can be fluoroquinolone betaine, such as ciprofloxacin betaine. According to this version the particles have a mass median aerodynamic diameter of from about 1 to about 5 microns, and a bulk density comprising less than about 1.0 g/cm3more preferably less than about 0.6 g/cm3and even more preferably from about 0.2 to about 0.5 g/cm3.

In one or more versions of fluoroquinolone betaine, such as ciprofloxacin betaine, include in the matrix excipient, which forms a discrete particle, and the pharmaceutical composition is a set of discrete particles. The discrete particles can be calibrated so that they could easily enter, and/or so that they can be applied as needed. For example, in case suitable for aerosol pharmaceutical composition of the particles should have a size that allows the particles to form an aerosol and allows you to enter them in the respiratory tract of the patient by inhalation.

In some versions, the pharmaceutical composition is in the form of particles which have a mass median diameter of m is it than about 10 microns, for example, less than about 5 microns, less than about 3 microns, or less than about 1 μm, and it can be from 1 to 10 μm, for example, about 1 to 5 μm. In one or more embodiments of the invention, the mass median particle diameter of the powder is about 1 to 3 microns.

In one or more embodiments of the invention the bulk density obtained by spray drying of the powder is approximately 1.0 g/cm3more preferably less than about 0.6 g/cm3and even more preferably from 0.2 to 0.6 g/cm3.

In one or more embodiments of the invention the pH value of the powder after the restore is from 6.0 to 8.8. In one or more embodiments of the invention the pH is a value that allows you to get crystal ciprofloxacin betaine after recovery.

In one or more embodiments of the invention, the moisture content in the powder is about 10 to 15 wt.%. In one or more embodiments of the invention, the moisture content in the resulting spray dried powder is such that allows you to get polymorph representing crystalline ciprofloxacin betaine 3.5-hydrate.

In one or more embodiments of the invention Ude the other surface area of the powder particles is from 8 to 20 m 2/year In one or more embodiments of the invention, the porosity is from about 5 to 20%. In one or more embodiments of the invention, the surface roughness (Sv) is from 3 to 10. In one or more embodiments of the invention the powder is proposed in the present invention is characterized by at least two of the above in the present description of the values of specific surface area, porosity and roughness. In one or more embodiments of the invention the powder is proposed in the present invention is characterized by at least three of the above in the present description of the values of specific surface area, porosity and roughness.

In one or more embodiments of the invention the powder is proposed in the present invention, has a mass median aerodynamic diameter of from about 1 to about 5 μm, for example, from about 1.5 to about 4 microns, or from about 2 to about 4 microns. As a rule, if the particles are too large, then only a small number of particles can reach the lower part of the lung. If the particles are too small, then a greater percentage of the particles may be removed as a result of exhalation. To ensure receipt in light doses exceeding 10 mg, for the required number of inhalations, etc is doctitle, order dose of respirable particles, i.e. particles with a size less than 4.7 µm, was more than 10 mg, more preferably exceeding 16 mg, and even more preferably exceeding 20 mg

In one or more embodiments of implementation of the present invention to apply the process of spray drying the emulsion to obtain crystals fluoroquinolone betaine, which are coated in a porous layer consisting of a hydrophobic excipient. The resulting particles can be entered in the high dose needy in patients who suffer from CF, by means of a minimum number of inhalations, for example, by less than four, preferably at least three, more preferably two or less, and most preferably one inhalation.

In one or more embodiments of the invention the composition proposed in the present invention are in the form of powders consisting of discrete particles. In one or more embodiments of the invention, the powders obtained by the process of solvent removal. Although according to the present invention can be applied several treatments, the most preferred embodiments of the invention generally relate to the perforated microstructures or porous particles, which are formed when the dispersion is positive drying or freeze-drying. It is well known that spray drying is a process in which the transformation of the liquid of the original product in the dried powder particles. Regarding applications in the pharmaceutical industry, it should be borne in mind that spray drying is used to obtain a powdery product intended for administration by various routes, including inhalation.

In one or more embodiments the invention, the powder composition proposed in the present invention, receive spray drying. In serves as example of the embodiment of the invention, the original product is fluoroquinolone betaine. For example, in one version, the original product is a finely ground crystals fluoroquinolone betaine, such as ciprofloxacin betaine, dispersed in a continuous phase constituting the emulsion of the type oil-in-water. The original product may also contain hydrophobic excipient, such as a phospholipid. The dispersed phase in the submicron emulsion droplets may contain fluorocarbon, but may not contain it. In one or more embodiments of the invention, the fluorocarbon selected from the group including performancebased, perpendicular, perforation and mixtures thereof. In one or more embodiments, the OS is supervising the invention, the fluorocarbon stabilized with a monolayer of excipient, representing a phospholipid. In the process of spray drying the emulsion droplets contributes to the formation of porous phospholipid coating on the surface of the crystals of betaine. The concentration of the active ingredient and optional active substances depends on the amount of active ingredient in the final powder and the type of inhaler intended to apply. In one or more embodiments of the invention, these concentrations may be assigned in advance. The amount of fluorocarbon faction in the original product, if the fluorocarbon is present, may range from 3 to 50% (wt./vol.), preferably about 5 to 30% (wt./vol.). Examples obtained by spray drying of the particles constituting the crystals with a lipid coating, can be found in WO 2004/060351, in U.S. patent 7326691 and in the application for U.S. patent 2006/0165606, the contents of all documents are fully incorporated into this description by reference.

In one or more embodiments of the invention the original product may contain a blowing agent. The blowing agent is preferably a fluorinated compound (e.g., perference, perforative, perpendicular, performativity), which evaporates in the spray drying process, usually leaving behind porous particles, such as crystals of betaine with a porous coating of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), which are aerodynamically light". As described in more detail below, can be applied to other suitable pore-formers, such as non-fluorinated oils, chloroform, freon, ethyl acetate, alcohols and hydrocarbons. As suitable pore-formers may also be treated gaseous nitrogen and carbon dioxide.

Although the perforated microstructure preferably should be formed using the above-mentioned blowing agent, it should be borne in mind that in some cases you do not need to apply additional pore and the water dispersion of drug and/or excipients and surfactants or surface-active substances can be directly subjected to spray drying. In such cases, a new form should be suitable for the process conditions (e.g., elevated temperatures), which can lead to the formation of a relatively porous microparticles.

In the claimed invention, it was found that regardless of how the pore-forming eventually selected, if it is present at all suitable microstructure is most effective can be obtained with the use of spray miniscule type Buchi model B-191, Switzerland). Professionals in this field must be known that the temperature at the inlet of RA is opylitelei dryer and the outlet temperature of the spray dryer should be selected at this level, in order to achieve the desired particle size to obtain a product having the desired activity of the drug. Therefore, the temperature at the entrance and at the exit adjust depending on the melting characteristics of the components of the formulation and composition of the original product. Specialists in this area is known for selling spray dryers, and for any given variance, you can easily find suitable adjustment parameters by standard empirical testing, taking into account the information provided in the following examples.

The most preferred embodiments of the present invention relate to the resulting spray-dried preparations containing surface active agent, such as a phospholipid, and the active ingredient, representing ciprofloxacin betaine. In other embodiments of the invention are obtained by spray drying the drug may further include excipient containing hydrophilic fragment, such as a carbohydrate (namely, glucose, lactose or starch), apart from any selected surfactants. For this purpose, according to the present invention can be applied to various starches and derivateservlet starches. Other optional component of the AMI can be a conventional viscosity modifier, buffers, such as phosphate buffer or other conventional biocompatible buffers or substances that are essential for regulation of the pH value, such as acids or bases, and substances that are essential for regulation of osmotic pressure (to ensure isotonicity, hyperosmolarity or hypoosmolality). Examples of suitable salts are sodium phosphate (as monobasic and dibasic), sodium chloride, calcium phosphate, calcium chloride and other physiologically acceptable salt.

When the material matrix used phospholipids, preferably in the original product additionally include polyvalent cation, as described in PCT WO 01/85136 and WO 01/85137, the contents of which are fully incorporated into the present description by reference. Suitable polyvalent cations are preferably divalent cations, including cations of calcium, magnesium, zinc, iron, etc. Polyvalent cation is present in a quantity effective to increase the tPLphospholipid so that consisting of particles of composition had tPLexceeding the storage temperature tsat least 20°, preferably at least 40°C.

Whatever components were not selected, the initial stage of obtaining particles, as a rule, consists in the preparation of the original product. Preferably, the selected drug is dissolved in water to obtain a concentrated solution. In the case of insoluble crystalline active ingredients that usually takes place in the implementation of the present invention, the drug can directly dispersing the emulsion. The used concentration of the active substance or has biological activity of a substance depends on the amount of agent in the final powder and operating characteristics of the device for injection (for example, the dose of respirable particles to the device type (MDI inhaler dosing with scale) or DPI (inhaler for dry powder)). If necessary, to the original product, you can add additional excipients, for example, from the number above.

In certain embodiments of the invention are then prepared in a separate vessel emulsion of the type oil-in-water. As the oil is preferably applied fluorocarbon (e.g., performancebased, perpendicular), which emuleret using surfactants, such as saturated phospholipid long chain. For example, it is possible to homogenize one gram of phospholipid in 150 g of hot distilled water (for example, at 60°C) using a suitable mechanical mixer with a high shear forces (e.g., mixer-type Ultra-Turrax model T-25) at 8000 rpm for lane is an ode to time, comprising from 2 to 5 minutes As a rule, is added dropwise with stirring at 5 to 25 g of the fluorocarbon to dispergirovannom the solution of surface active substances. Then the resulting emulsions of perfluorocarbons in the water treated by using a high-pressure homogenizer to reduce the particle size. Typically, the emulsion is treated at a pressure of from 12,000 to 18,000 pounds per square inch, through 5 separate switching device, and maintained at a temperature of from 50 to 80°C.

In each case, the machining conditions such as the temperature at the inlet and outlet, the rate of recharge, the spray pressure, the flow rate of air used for drying, and the configuration of the nozzle, should be selected in accordance with the manufacturer's instructions to obtain particles of the desired size and yield of the final product in the form of dry microstructures. Examples of the adjustment parameters are: inlet temperature from 60 to 170°C; water inlet temperature from 40 to 120°C; the rate of recharge from 3 to about 15 ml/min; and the flow rate of inhaled air 300 l/min and the flow rate of air used for drying, comprising from 25 to 50 l/min Select the appropriate device and treatment conditions within the competence of the person skilled in the art after reading this description it can be done without excessive is xperimento. In any case, the application of these and other equivalent methods provides for the formation of porous "aerodynamically light" microspheres with diameters of particles that may lead to the deposition of aerosol in the lung, i.e. porous microstructures, which look almost like a honeycomb or their appearance resembles foam. In the most preferred embodiments of the invention the perforated microstructure are obtained porous spray dried particles. The solids content in the resulting spray drying the original product, as a rule, should be from 0.5 to 10 wt.%, for example, from 1.0 to 5.0 wt.%. The adjustment parameters, of course, must vary depending on the type of equipment used. In any case, the application of these and other equivalent methods ensures the formation of crystals coated, which have diameters that may be a deposition of aerosol in the lung. One of the crucial points is that the outlet temperature and the temperature of the collector of the dryer should be maintained at levels that do not exceed values of tPLthe resulting formulation.

The original product-based emulsion can be obtained by carrying out first dispersion is of a polyvalent cation and phospholipid in hot distilled water (for example, at 70°C) using a suitable mechanical mixer with a high shear forces (e.g., mixer-type Ultra-Turrax model T-25). The usual process conditions may be stirring at 8000 rpm for a time period of 2 to 5 minutes Then added dropwise with stirring a fluorocarbon to a solution of dispersed surfactant. Then the formed fluorocarbon emulsion in water can be treated by using a high-pressure homogenizer to reduce the particle size. Typically, the emulsion is treated at a pressure of from 8000 to 20,000 pounds per square inch, through five separate runs of the device, resulting in a gain droplets with a median diameter of less than 600 nm. Then in the continuous phase of the emulsion type fine ciprofloxacin betaine and mixed and/or homogenized.

In one version, the pharmaceutical formulation consists of porous microstructures and is characterized by a bulk density less than 1.0 g/cm3more preferably less than 0.5 g/cm3more preferably less than 0.3 g/cm3and in some cases less than 0.1 g/cm3. In one specific versions of the apparent density of the powder is from 0.2 to 0.6 g/cm3. Through the creation of particles with very low bulk density decreases mini the actual weight of the powder, which you can make into a container designed for the standard dose that reduces and often eliminates the need for particles-carriers. Thus, the relatively low density powders, proposed in the present invention allows to provide reproducible introduction of relatively low doses of pharmaceutical compounds. In addition, the absence of particles-carriers of potentially should minimize deposition in the throat and any "gag" effect, since large particles are used as the carrier lactose, which are usually used in this field, have an impact on the throat and upper respiratory tract due to its size. The application of the present invention may allow to eliminate the need for such large particles.

In one or more embodiments of the invention powdered preparative form proposed in the invention contains the active ingredient, such as fluorochinolon, in an amount constituting from about 50 to about 70 wt.%, more preferably about 65 wt.%, hydrophobic excipient, such as a phospholipid in an amount constituting from about 15 to about 35 wt.%, more preferably about 20 wt.%, the material containing the metal cation in an amount constituting from about 1 to about 3 wt.%, more preferred the equipment about 2 wt.%, water in an amount constituting from about 10 to about 15 wt.%, more preferably about 12 wt.%. In one specific versions powder preparative form proposed in the invention contains ciprofloxacin betaine, preferably in the form of a 3.5-hydrate in an amount constituting from about 50 to about 70 wt.%, more preferably about 65 wt.%, distearoylphosphatidylcholine in the amount constituting from about 15 to about 35 wt.%, more preferably about 20 wt.%, and the dihydrate of calcium chloride in the amount of about 1 to about 3 wt.%, more preferably about 2 wt.%, water in an amount constituting from about 10 to about 15 wt.%, more preferably about 12 wt.%, and the residual quantity of performancebased average of <1 wt.%.

Powdered pharmaceutical preparative form can be entered using the device to create the aerosol. In a preferred version of the new form is a powder and administered using inhalers dry powder according to the procedure described in application for U.S. patent, ser. room 09/888311, registered on June 22, 2001, in WO 02/83220, in U.S. patent 6546929 and in the application for U.S. patent ser. room 10/616448 registered 8 July 2003, In an alternative embodiment, the device for generating an aerosol can pre is to provide a dispenser, described in WO 99/16420. The contents of all patents and patent applications are fully incorporated in the present description by reference.

In one version, the powdered composition is in the form of a dry powder and is contained in the tank, calculated at the standard dose, which can be inserted into aerosolise device or placed next to it to turn into a standard aerosol dose of the composition. This version has the advantage that the dry powder form can be stored in the tank, calculated on the standard dose for an extended period of time. In addition, this version is convenient because in this case, to obtain aerosol requires no cooling, no external energy source.

In some cases it is desirable to introduce into the lungs via inhalation the standard dose of the active substance, component 5 mg or more, more preferably 10 mg or more, and even more preferably 16 mg or more. Described above containing phospholipid porous particles of a dry powder allow you to enter through a single inhalation and convenient way dose comprising 5 mg or more, 10 mg or more, 16 mg or more, 25 mg or more, and 32 mg or more. Alternatively, the dose can be administered by two, three or four inhalations. To ensure this bulk is latest powder should preferably be less than 1.0 g/cm 3more preferably less than 0.6 g/cm3. In General, in cases where you want to enter into the lungs doses exceeding 5 mg, it is also desirable that the load of the medicinal product amounted to more than 5%, more preferably more than 10%, even more preferably more than 20%, even more preferably more than 30%, and most preferably more than 40%. Such standard dose pharmaceutical preparative forms may be contained in capsules that can be inserted in aerosolise device. To them it was possible to place the pharmaceutical preparative form and to pharmaceutical preparative form was in usable condition, the capsules must have an appropriate shape, size, and must be made of appropriate material. For example, the capsule may have a wall made from a material that does not enter into an unwanted reaction with the pharmaceutical preparative form. In addition, the wall may be made of material that allows you to open the capsule in order to be able to transform pharmaceutical preparative form in the aerosol. In one version, the wall consists of one or more materials, such as gelatin, hypromellose (HPMC)containing polyethylene glycol GPMC, hydroxypropyl lulose, agar or the like, In one version of the capsule may be composed of telescopically connected sections, as described, for example, in U.S. patent 4247066, the content of which is fully incorporated into the present description by reference. Capsule size should be chosen in such a way that it matches the contained dose of the pharmaceutical formulation.

Capsule sizes typically range from size 5 to size 000, with outer diameters ranging from about 4,91 to becomes 9.97 mm, a height ranging from about 11,10 to about 26,14 mm, and the amounts range from about 0.13 to about to 1.37 ml, respectively, as illustrated in table 1. Suitable capsules are sold, for example, companies such as Shionogi Qualicaps Co., NAPA, Japan and Capsugel, Greenwood, Stugna Carolina. After filling the upper part can be placed on top of the bottom, resulting in a form of capsules containing a powder, as described in U.S. patent 4846876 and 6357490, and the patent application PCT WO 00/07572, published February 17, 2000, the contents of which are fully incorporated into the present description by reference. In one version, the powder make into capsules of size 2 or smaller.

Preferably used capsules of size 2 and 3 in order to maximize the dose, which you can enter, but will not exceed what the volume or mass of powder, which is/which can be administered by one inhalation child suffering from CF.

Table 1
Dimensions capsules
Capsule size00000012345
Volume (ml)1,370,950,680,500,370,300,210,13

After filling the upper part can be placed on top of the bottom, resulting in a form of capsules containing a powder, as described in U.S. patent 4846876 and 6357490, and the patent application PCT WO 00/07572, published February 17, 2000, the contents of which are fully incorporated into the present description by reference. After the upper part is placed over the bottom part, the capsule can tie optional.

Example aerosolizing device for dry powder that n is the most suitable for aerosolization pharmaceutical formulation 100, proposed in the present invention, is schematically illustrated figa. Aerosolizing device 200 includes a housing 205 defining a chamber 210, which has one or more inlet holes 215 for air and one or more outlet openings 220 for air. The camera 210 has a size that allows you to put in her capsule 225, which contains suitable for aerosolization pharmaceutical preparative form. For example, the capsule may contain a composition in the form of particles containing fluoroquinolone betaine, such as ciprofloxacin betaine. These mechanism 230 includes connectors element 235, which can move inside the chamber 210. Near the outlet 220 or directly adjacent to it is the end section 240, which may be of such size and shape that allows you to enter it into the mouth or nose of the user so that the user may inhale through the opening 245 in the tail section 240 that connects to the outlet 220.

In aerosolizing device 200 for dry powder aerosolization pharmaceutical formulation, located in the capsule 225, apply the air flowing through the chamber 210. For example, on figa-8E illustrates the working version aerosolizing device 200, in which for the aerosolization of the pharmaceutical formulation in enaut air, flowing through the inlet opening 215, and aerosolizable pharmaceutical preparative form flows through the exhaust hole 220 so that it can enter the body of the user through the opening 245 in the tail section 240. Aerosolizing device 200 for dry powder shown in the initial state on figa. The capsule 225 is placed in the chamber 210, and pharmaceutical preparative form is a capsule 225.

When applying aerosolizing device 200 open access to pharmaceutical formulations form contained in the capsule 225, to convert it into the form of an aerosol. In the version illustrated in figa-8E, connectors mechanism 230 progressive move in the chamber 210 by application of force 250 to connectors mechanism 230. For example, the user can press on the surface 255 connectors mechanism 230 in order to make these mechanism 230 to slide inside the housing 205 so that the connectors are element 235 has come in contact with the capsule 225 in chamber 210, which is illustrated in figb.

If you continue to apply a force of 250, it makes these element 235 to penetrate into and through the wall of the capsule 225, illustrated in figv. These element can have one or more pointed ends 252 to facilitate penetration through with the evaluation of the capsule 225. Then these mechanism 230 return back to the position shown in Figg, leaving a hole 260 in the wall of the capsule 225, opening access to pharmaceutical formulations form contained in the capsule 225. After that leak air or other gas through the inlet 215, as shown by the arrows 265 on Figg. The airflow causes the transformation of the pharmaceutical formulation in the aerosol.

When the user carries out a breath 270 through the end section 240, aerosolizable pharmaceutical preparative form enters the respiratory tract of the user. In one version of the air flow 265 may be created when performed by the user inhaling 270. In another version to create aerosolizing air flow 265 can admit compressed air or other gas through the inlet 215.

Specific version aerosolizing device 200 for dry powder described in U.S. patent 4069819, U.S. patent 4995385, applications for U.S. patent No. 10/298177; 10/295783; 10/821652; 10/821624; 10/822850; 10/704160; 10/714511 and 10/313419, the contents of which are fully incorporated into the present description by reference. With this arrangement, the camera 210 has a longitudinal axis that generally coincides with the direction of inhalation, and the capsule 225 is placed in a longitudinal position in the chamber 210 so that the longitudinal axis of the capsule was inserted is entrusted to the longitudinal axis of the chamber 210. The camera 210 has a size sufficient to fit the capsule 225 containing pharmaceutical preparative form, so that the capsule had the ability to move inside the chamber 210. Inlet 215 have several tangentially oriented slits. When the user performs inhale through the end section, it causes external air to flow through the tangential slots. This air flow creates a swirling air flow inside the chamber 210.

Swirling the air flow causes the capsule 225 come in contact with the partition and then move inside the chamber 210 so that it forced the pharmaceutical preparative form out of the capsule 225 and be captured by vortex air flow. This version is most effective for the aerosolization of high doses of the pharmaceutical formulation. In one version, the capsule 225 rotates inside the chamber 210 so that the longitudinal axis of the capsule remains at an angle less several degrees, and preferably less than 45° with respect to the longitudinal axis of the chamber. The movement of the capsule 225 in the chamber 210 can be invoked in the case, when the width of the camera 210 is less than the length of the capsule 225. In one specific versions of the camera 210 has a beveled section, which ends at the edge. Under the action of varennogo flow of air in the chamber 210, the front end of the capsule 225 comes into contact with the wall and remains on it, and the side wall of the capsule 225 comes into contact with the edge and slide and/or rotate along the edge. Such movement of the capsule is most effective for the release of large quantities of pharmaceutical formulation through one or more holes 260 in the rear part of the capsule 225.

In another version aerosolizing device 200 for dry powder may have a configuration other than the configuration shown in figa-8. For example, the camera 210 may be of such size and shape to place in her capsule 225 capsule 225 was placed orthogonal to the direction of inhalation, as described in U.S. patent 3991761, the content of which is incorporated into this description by reference. In U.S. patent 3991761 also described that these mechanism 230 can pierce both ends of the capsule 225. In another version of the camera, you can put the capsule 225 so that the air flow through the capsule 225, as described, for example, in U.S. patent 4338931 and U.S. patent 56199S5. In another version of aerosolizable pharmaceutical formulation can be done with the help of compressed gas flowing through the inlet openings, as described, for example, in U.S. patent 5458135, U.S. patent 5785049 and U.S. patent 6257233, or by using a propellant, as this description is about in published PCT application WO 00/72904 and U.S. patent 4114615. The contents of all the above references are fully incorporated into the present description by reference.

In one version, the powder particles contribute to the reservoir of the capsule type and is used in the inhaler, for example, one of the types presented on figa-8. In one or more embodiments of the invention emitted from the capsule weight is more than about 50 wt.%, more preferably more than about 60 wt.%, more preferably more than about 70 wt.%, and even more preferably more than about 80 wt.% or more than about 90 wt.%. The relative standard deviation for emitted dose may preferably be less than 7%, and preferably 4% or less. This provides a very high content uniformity of the dose that can meet increasingly strict regulatory standards. The composition, which is obtained in accordance with the present invention, may not satisfy this criterion.

Alternatively, you can use other inhalers dry powder passive or active type. In one version preferably used an inhaler for dry powder passive type due to the simplicity of its application and the currently playing aerosolization. Suitable inhalers dry powder passive type can serve to the capsule to inhalers, and blister inhalers. Most preferred are capsule inhalers passive type due to the fact that they can apply a standard dose of a larger volume (compared to modern blister devices), which facilitates the introduction of large doses in a single breath.

You can also use devices that are on the market or are sold under the following trademarks and/or following trademarks: Handihaler (firm Boehringer Ingelheim), Eclipse (firm Aventis), AIR inhaler (firm Alkermes), Cyclohaler (firm Plastiape), Concept 1 (Novartis), Flowcaps (firm Hovione), Turbospin (firm PH&T), Monohaler (firm Pfizer), Spinhaler (firm Aventis), Rotahaler (GSK). Suitable blister inhalers are: Diskus and Gemini (GSK), the device Nektar Therapeutics described in the patent application PCT US 2007/022830, the contents of which are incorporated into this description by reference, Gyrohaler (company Vectura), E-Flex, Microdrug, Diskhaler (GSK). Under the scope of the present invention are also inhalers dry powder active type, which are described in U.S. patent 6257233, the content of which is incorporated into this description by reference, Aspirair (company Vectura) and Microdose inhaler (firm Microdose).

The device of the passive type in combination with powders, proposed in the present invention, allow independent from the flow rate of the deposition in the lungs, due to the comp is ncacii differences in inertial deposition with increasing peak velocity of the inhaled flow (PIFR) in the establishment of several more dispersed powder. In contrast, the device of the active type can result in an inverse relationship to flow rate, i.e. when the variance of the powder is constant, but increasing the inertial seal with increasing PIFR may result in lower deposition at higher values PIFR.

The pharmaceutical composition is presented in one or more embodiments of implementation of the present invention typically has a higher efficiency from the perspective of the emitted dose. Therefore, the pharmaceutical composition can be introduced in high doses using aerosolizing devices and methods presented in the present description.

In one or more versions of the present invention the pharmaceutical composition comprising ciprofloxacin betaine, you can aerosolizable so that it can enter into the lungs of the patient by inhalation by the patient. The result of this is contained in the pharmaceutical composition ciprofloxacin delivered directly to the area of infection. This represents an advantage compared with systemic administration. Since the current(s) substance(s) often cause renal or other toxicity, it is often the dose is determined on the basis of minimizing systemic exposure. Therefore the amount of active substance or active substances the TV, which one(s) you can enter into the lungs is not intra-lungs ways, for example, by systemic injections, limited to the minimum pharmacologically effective dose. With the introduction of the active substance or active substances directly into the lungs they can enter more in the area that requires treatment, significantly reduce systemic effect.

Thus, one or more pharmaceutical compositions proposed in the present invention are effective in the treatment of cystic fibrosis, including through the implementation of additional remedial measures.

In one or more embodiments of the invention the pharmaceutical composition comprising fluoroquinolone betaine, such as ciprofloxacin betaine, is introduced into the lungs of a patient in need thereof. For example, the patient may be a patient who has been diagnosed with cystic fibrosis, non-CF bronchiectasis, COPD or hospital-acquired pneumonia.

Thus, pharmaceutical compositions offered in one or more embodiments of implementation of the present invention can be used for the treatment and/or prophylaxis of patients with a wide range of diseases. The patient, suitable for use with methods of treatment and/or prophylaxis in the present invention may be any mlekovita is it need first of all a sick person or a sick animal. Examples of patients include, but are not limited to, sick children, adults and elderly patients.

In one or more versions of aerosolising pharmaceutical composition comprising ciprofloxacin betaine, is introduced into the lungs of a patient in such a way as to ensure the effective concentration of ciprofloxacin in the lung, particularly in the lower part of the lung and/or in the upper respiratory tract. In one or more embodiments of the invention, the amount or concentration of ciprofloxacin and/or ciprofloxacin betaine, which reaches the lung, is a therapeutically effective amount such as an amount, effective for the treatment of CF. In one or more embodiments of the invention, the amount of ciprofloxacin betaine, which reaches the lungs with the introduction of a single dose may be from about 10 to about 50 mg, for example from about 30 to about 40 mg.

In one or more embodiments of the invention therapeutic dose of ciprofloxacin betaine is injected into the patient, in need thereof, through three or four inhalations, or fewer, for example, two inhalation, or via inhalation. In a preferred is the option of carrying out the invention therapeutic dose of ciprofloxacin betaine is injected into the patient, in need thereof, by three or fewer inhalation, for example, two inhalation, or via inhalation. In one or more embodiments of the invention therapeutic dose of ciprofloxacin betaine is administered for a period of time amounting to less than three minutes, preferably less than about two minutes, or less than about one minute.

In one or more embodiments of the invention introduction suitable for inhalation formulations of ciprofloxacin betaine suffering from cystic fibrosis patient using the compositions and devices presented in this description leads to a significant improvement in quality of life or improving patient compliance regime and regimen, or to both these results.

Treatment using ciprofloxacin betaine proposed in the present invention can be applied individually or in combination with means intended for the treatment of endobronchial infections, particularly infections caused by P. aeruginosa. According to this object of the invention one or more of the funds used for the treatment of endobronchial infections, may(may) be an antibiotic, and it(they) can be entered during the first period of treatment using ciprofl Katsina betaine (or other fluoroquinolone betaine), during the second period, during which ciprofloxacin betaine is not injected into the endobronchial system of the patient, or during both the first and second periods of treatment. In one embodiment, the implementation of this object of the invention one or more of the funds used for the treatment of endobronchial infections, administered during the second period, during which ciprofloxacin betaine is not injected into the endobronchial system of the patient. Suitable facilities for the treatment of endobronchial infections are, for example, aminoglycosides, such as tobramycin, non-aminoglycoside anti-infective agents such as monobactam, β-lactam, macrolide and/or compounds from the group of glycopeptides antibiotics. For example, a non-aminoglycoside anti-infective agent may be aztreonam.

According to one specific treatment regimens proposed in the present invention, fluoroquinolone betaine, such as ciprofloxacin betaine, imposed during the "off-periods" treatment with tobramycin. For example, tobramycin, you can enter during the "on-period" (for example, for about one month and then not to enter during the "off-period" (e.g., within approximately one month). In this version, powder, proposed in the present invention, imposed during the "off-period". In alternate the nom variant or optional powder, proposed in the present invention, it is possible to enter during the "on-period". The duration of the "on-period" and "off-periods" may be one day, several days, one week, several weeks, 28 days, one month or several months, or you can apply any combination of these options.

In other versions of the composition may contain one or more active ingredients other than those described above fluoroquinolones. For example, according to the present invention can be prepared preparative form, including any insoluble and/or crystalline active substance.

The above description should be more clear after reading the following examples. However, these examples are only representative of the ways to implement in practice one or more embodiments of the present invention and they should not be construed as limiting the scope of invention.

Examples

Example 1. The solubility of ciprofloxacin depending on pH values

The solubility of ciprofloxacin in water depends on pH of the solution (figure 2). At pH below the pK values for carboxylic acids (pK1=6,0) the drug is in the form of hydrochloride and has a very high solubility in water. Drug is redtwo soluble when pH values, above the pK value for the amino group (pK2=8,8). Solubility zwitterionic ciprofloxacin betaine at pH values close to neutral, sharply decreases to approximately 70 mg/ml

Example 2. Dynamic vapor sorption containing ciprofloxacin powder

In one version powdered preparative form contains ciprofloxacin betaine 3.5-hydrate in the amount of about 65 wt.%, distearoylphosphatidylcholine in the amount of about 20 wt.%, and the dihydrate of calcium chloride in the amount of about 2 wt.%, water in an amount comprising about 12 wt.%, and residual perforative in number which is less than 1 wt.%. Below this description, this new form is designated as CIP (powder ciprofloxacin for inhalation).

Equilibrium sorption isotherms of water vapor (at 25°C) CIP, drug substance and powder placebo are presented in figure 3. All isotherms were measured by gravimetric adsorption of water vapor. To assess the accuracy of obtaining the isotherm CIP, the sample powder was balanced at 25°C/60% RH and measured water content titrimetric method Karl Fischer. A good level of coincidence of the measured quantity of water with the value obtained by gravimetric adsorption suggests that the latter method allows the OS is to conduct accurate measurement of isotherms. The curves on the isotherm of the drug substance, representing ciprofloxacin characteristic of crystalline material forming stoichiometric hydrates. Tilt isotherms at RH values, equal to about 5%, 17% and 65%, due to the transformations of type hydrate-hydrate. In the studied range of values of RH are the most stable solid phase composition exists in the wide flat area when the values of RH from 20 to 60%. In this area, the composition is in the form corresponding to the formula ciprofloxacin · 3,5H2O (or ciprofloxacin2· 7H2O), in which theoretical water content is of 16.0 wt.%. The presence of crystalline 3,5-hydrate was confirmed using Raman spectroscopy (data not shown). Isotherm sorption of water vapor CIP qualitatively and quantitatively corresponds isothermal of its components, drug product that represents ciprofloxacin, and obtained by spray drying placebo (pseudocomponents containing DSPC and CaCl2). Qualitatively isotherm CIP reminds isotherms of its components; isotherm CIP has kinks, characteristic of the drug substance, representing ciprofloxacin, and has a slightly greater slope at each point (compared to the isotherm of the drug substance), which is Bukovina presence DSPC/CaCl 2. From a quantitative point of view isotherm CIP represents approximately a linear superposition of the isotherm of the drug substance, which represents the ciprofloxacin and placebo. So, isotherm CIP is approximately 69% of the distance between isotherms its main components, as would be expected, based on the content of the drug substance in CIP (nominal content of 70%). This is not unexpected. Because of the medicinal substance and the phospholipid is present in CIP mostly in the form of separate phases, the isotherm of the product, representing preparative form must be approximately the weighted sum of the isotherm of its components.

In the field of RH values from about 20 to 65% of ciprofloxacin betaine is present in the form of a 3.5-hydrate. This corresponds to a moisture content in the resulting spray dried powder comprising from 10 to 15 wt.%. The presence of 3,5-hydrate obtained by spray drying the powders was confirmed by the method of Raman spectroscopy. It was found that the 3.5-hydrate is stable during storage.

Example 3. The receipt contains ciprofloxacin powder intended for inhalation

Containing ciprofloxacin powder intended for inhalation (CIP)was developed with a specific purpose, namely, for the street is Ksenia directional transfer of ciprofloxacin in the bronchial Airways compared with oral and parenteral introduction, and raising this also ease of use by the patient (i.e., improve portability and reduce the time required for introduction) compared to the currently used spray antibiotics.

CIP was obtained by using spray drying homogeneous submicron emulsion of the type oil-in water of perflubron (perforative, PFOB) and water for irrigation (WFIr)containing 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), calcium chloride and suspended ciprofloxacin betaine in the amount indicated in the following table 2. Finely ground particles of ciprofloxacin betaine was obtained using standard processes of grinding in a jet mill or homogenization at high pressure. The composition of the original product, obtained on the basis of the suspension, for a given batch size of 1 kg of detail specified in table 2. The volume fraction of dispersed PFOB is approximately 0.1, and the mass ratio of PFOB/DSPC is about 20/1.

Table 2
The composition of the raw product used to prepare 1 kg CIP
ComponentThe specified number for the batch total amount of 1000 g
Ciprofloxacin betaine700,0
1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC)280,0
The dihydrate of calcium chloride20,0
Perflubron [perforative (PFOB)]15760,0
Water for irrigation (WFIr)230333,0
1used as a tool to facilitate processing, to remove residues during processing
2used as a tool to facilitate processing, a large part removed during processing

The original product get through the first dispersion DSPC and CaCl2warm WFIr using a high-speed mixer (e.g., type UltraTurrax) with the formation of multilayer liposomes. Then slowly add with stirring PFOB with the formation of a coarse emulsion. Then the size of the droplets formed emulsion is reduced by homogenization at high pressure using a homogenizer plunger-valve type or microfluidizer. Then micronized drug substance is added to the emulsion, receiving demand is th original product on the basis of the suspension. PFOB and the aqueous phase containing the drug substance of the original product-based emulsion/suspension is evaporated by spray drying in a spray dryer type Niro Mobile Minor, receiving ciprofloxacin betaine, DSPC and calcium chloride in the form of dry particles. Obtained by spray drying the particles contain a residual amount of water and PFOB, which are shown in table 4.

Table 3
The composition obtained by spray drying CIP
Components and quality standardFunctionConcentration (according to the label)
50 mg/capsule
Nominal amount per capsule (mg)wt.%
CiprofloxacinUSPPharmaceutical active ingredient32,565
1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)Nearmonopoly product (laboratory sample)1020
The dihydrate of calcium chlorideUSP/EP/JPStabilizing particles of matter12
Water for irrigation (WFIr)1USPThe tool facilitates the processing612
Perflubron [perforative(PFOB)]2USPThe tool facilitates the processing0,51
Only50100
1used as a tool to facilitate processing; the greater part is removed during processing
2used as a tool to facilitate processing, to remove residues during processing

All Neformal Anya excipients comply with the requirements specified in the relevant monographs of the USP/NF.

Preparative form in the form of loose powder make in individual suitable for use in inhalation transparent capsules from hydroxypropylmethylcellulose (HPMC) of size 2 containing the CIP in nominal amount of 50 mg (CIP contains ciprofloxacin betaine in an amount of about 65%, therefore each capsule contains ciprofloxacin betaine in number, amounting to 32.5 mg or at least about 32 mg).

Example 4. Physico-chemical properties of unconsolidated powder CIP

Physico-chemical properties of the four parties of unconsolidated powder CIP, obtained according to the method described in example 3 are presented in table 4. Identity, content and purity of ciprofloxacin were determined using liquid chromatography high-resolution reversed-phase (RP-GHUR) with UV detection (according to the monograph of the European Pharmacopoeia, is devoted to the description of ciprofloxacin). Testing identity CIP was performed on the basis of the criterion of identity retention time (retention time of the peak for sample ciprofloxacin should not differ by more than 0.5 min from the retention time for the reference standard), and the criterion of identity of the UV-spectrum (in the UV spectrum of the sample ciprofloxacin peak absorption is observed at a wavelength of 278±2 is m). The content of ciprofloxacin were identified in relation to its content in the reference standard, and the purity was calculated by standardizing the square. The eligibility criteria for the content of ciprofloxacin was the presence of ciprofloxacin in the amount of 90 to 110% of the target average amount (target number = 32,5 mg) ciprofloxacin on the capsule. Quantitatively assessed present in the ciprofloxacin impurities b, C and D indicated in the EP, and as eligibility criteria for each type impurity took value ≤0,50%.

The water content of the CIP was measured by the coulometric method of titrimetry according to Karl Fischer. Measuring system according to Karl Fischer includes comonomer Karl Fischer type Metrohm, model 831 model 800 Dosino and oven-sampler for sample, model 774 Oven Sample Processor. To analyze the sample, the sampler makes a vial with the sample in an oven at 140°C. Over the heated sample is passed a stream of dry nitrogen (60±5 ml/min) to transfer the evaporating water in titration the cell, where it reacts with anhydrous Karl Fischer reagent. The titration is complete when the relative stop the drift reaches a value equaled to 5 µg/min the performance of the system was checked by measuring the water content in the standard samples of potassium citrate monohydrate (oven type Hydranal®-Water Standard KF, firm Riedel de Haen, 3448) before and after measurements for samples with unknown water content. Each sample was weighed on 10-70 mg powder CIP in a glass vial, which was closed tube and introduced into the sampler. Samples were prepared in triplicate. To estimate the amount of water introduced KF-system and environment, in the same conditions (RH and temperature)were used for sample preparation powder, to prepare three blank "control" of the bubble.

The average water content in the read control of the water content obtained by titration for each sample.

The residual quantity of perflubron in unconsolidated powder was measured by gas chromatography using a flame ionization detector. The percent residual content of perflubron in unconsolidated powder CIP was determined on the basis of comparison with the reference standard USP of perflubron. The limit of the quantitative evaluation was 0.05 wt.%.

Were tested for microbial purity (Microbial Limit Test, MLT) to confirm that the contents of germs in the powder contained in the capsules, meets the requirements specified in the draft guidance and the European Pharmacopoeia. The acceptance limits the total number of aerobic microorganisms and the total number of yeasts and moulds were selected on the basis of the relevant limits for input by inhalation products, supply the data in Pharmacopeial Forum, vol. 29(5), s. The acceptance limits for gram-negative bacteria and enterobacteria were selected so that they meet the requirements specified in Ph. Eur.5.1.4 regarding products intended for introduction into the respiratory tract. Limit eligibility to specific pathogens was selected on the basis of the USP<61>.

Table 4
Physico-chemical properties of unconsolidated powder CIP
DescriptionEligibility criteria and published informationlot of 10,744lot 10857lot 10858
The content of ciprofloxacinFrom 0,553 to 0,748 mg/mg0,6590,6520,657
The purity of ciprofloxacinAccording to the reportat 99.95%at 99.95%from 99,93 up of 99.98%
Individual impurities ≥0,10%According to the reportno nono
Water contentAccording to the report12,2%11,9%12.1%
pHAccording to the report7,46,76,8
Residual perflubronNMT 1.00 wt.%from <0,05% 0,05%<0,05%<0,05%
The size of the primary particlesX50: NMT 5.0 µm2.5 μm2.5 μm2.5 μm
Limit the number of microorganismsThe total number of aerobic microorganisms NMT 100 CFU/g<50 CFU/g<50 CFU/g<50 CFU/g
The total number and yeast and moulds NMT 10 CFU/g<10 CFU/g<10 CFU/g<10 CFU/g
The total number of other gram-negative bacteria NMT 10 CFU/g<1 CFU/g<1 CFU/g<1 CFU/g
No; Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Salmonella spp., Enterobacteriaceaemeetsmeetsmeets
CFU = colony forming units; NLT = not less than; NMT = not more than; RSD = relative standard deviation

The content of ciprofloxacin sufficiently met the eligibility criteria. The process of spray drying had a negligible effect on the purity of the drug substance, as the purity was maintained at >99,93% for all four lots, the level of any individual impurity not more than 0.1%. The impurity profile for ciprofloxacin is well characterized and consistent with the specifications of the drug substance specified in the monographs USP and EP. Impurities b, C and D were the only impurities present in the drug substance, and admixture With represented only a related substance, which was also a product of the cleavage of ciprofloxacin. Other famous for cipro is loxacin impurities (E and F), even though they are listed in the EP <1089>, was not present either in the raw product, representing ciprofloxacin, nor in the product formulation. None of the individual impurities were not present in the CIP in the amount exceeding 0.1 wt.%.

Due to the fact that the generated particles were obtained using a water suspension of the medicinal product, the size of the primary particles is largely determined by the size distribution of the particles of the drug substance. For the four lots, described in detail in table 4, the value of x50ranged from 2.4 to 2.5 μm (when dispersing pressure 2 bar).

Residual levels of perflubron was below the quantitative limit of detection (LOQ) for the three tested lots (LOQ=0.05 per cent), and only slightly exceeded the LOQ (0,07%) for the fourth lot. Low residual levels indicate that used in the implementation process AIDS effectively removed in the manufacturing process (see table 4).

The test results on microbiological purity conducted to determine the total number of yeasts and moulds, as well as specific pathogens, all met the eligibility criteria established for the products in the form of a dry powder, intended for inhalation.

Example 5. Aerosols the properties CIP-001

Aerosol properties CIP of the three lots, prepared according to the method described in example 3 was evaluated for aerosols generated by use of the portable inhaler for dry powder (namely the inhaler illustrated in figa-8E)are presented in table 5.

The average emitted by weight of the powder, as a rule, was more than 90 wt.%, with RSD values, typically less than 5%. The mass median aerodynamic diameter was approximately 3.6 μm, and the proportion of respirable particles (FPF<4.7 µm) was about 60 wt.% from the nominal dose. It can be expected that the resulting FPD<4.7 µm after inhalation dose of ciprofloxacin betaine, part of 32.5 mg, ensures the achievement of therapeutic doses of less than 3 breaths or less than two breaths, for example, in one breath.

Table 5
Aerosol properties CIP with the introduction of using the inhaler presented on Fig
DescriptionEligibility criterialot of 10,744lot 10857lot 10858
The emitted mass of powder The average emitted by weight powderof 45.7 mg47,9 mg47,5 mg
RSD, %9,1%1,8%1,5%
The number of launches outside 75-125% from the average value000
The number of starts out 65-135% from the average value000
The distribution of the windMMADthe 3.6 µm3,6 mcmthe 3.7 µm
FPD<4.7 µm20.2 mg19.5 mg18,9 mg
FPF % <4.7 µm62%60%58%
particle sizesAverage weight (mg) ciprofloxacin on stage and sudivshegosya on the filterstage 0: 0,3 mgarticle the stump 0: 0,3 mg stage 0: 0,3 mg
levellevellevel
1: 1,0 mg1: 1.1 mg1: 1.2 mg
levellevellevel
2: 3,3 mg2: 3,4 mg2: 3.6 mg
levellevellevel
3: 10,4 mg3: 10,3 mg3: 10,1 mg
step 4: 7,1 mgstep 4: 6,8 mgstep 4: 6,5 mg
levellevellevel
5: 2,0 mg5: 1,9 mg5: 1.8 mg
levellevellevel
6: 0,1 mg6: 0,2 mg6: 0,2 mg
STU is Yan levellevel
7: 0,0 mg7: 0,0 mg7: 0,0 mg
filter:filter:filter:
0.5 mg0.4 mg0.4 mg

Example 6. The storage stability formulation CIP

The storage stability formulations of CIP, obtained according to the method described in example 3, at 25°C/60% RH (table 6) and at 40°C/75% RH (table 7), described in detail below. Preparative form CIP had a very high physical, chemical and aerosol stability within thirty months in storage conditions at 25°C/60% RH and 6 months in storage conditions at 40°C/75% RH.

Water content
Table 6
Compilation of data on the stability of the CIP, lot 10655 (T=25±2°C/60% RH±5% RH
Descriptionsource1 month3 months6 months 12 months18 months24 months30 months
The content of ciprofloxacinof 33.5 mg33.6 mgto 32.2 mg33.3 mgof 33.5 mg33,1 mg33,1 mg34,0 mg
The purity of ciprofloxacinat 99.95%at 99.95%of 99.96%99,94%at 99.95%of 99.96%at 99.95%at 99.95%
Individual impurities>0,10%nononononononono
12,3%12,5%12,4%12,5%12,8%13,8%12,9%13,0%
The average mass of the emitted powder (RSD)93,0%92,6%90,8%of 91.6%93,4%.93,4%.93,0%93,0%
RSD (5) for the mass of the emitted powder2,83,17,61,72,43,12,11,9
The mass median aerodynamic diameterthe 3.6 µmthe 3.6 µmthe 3.6 µm 3.5 µmthe 3.6 µmthe 3.6 µmthe 3.6 µmthe 3.6 µm
Description3 months6 months12 months18 months24 months30 months
Dose18,5 mg18,2 mg17,8 mgof 16.9 mg18,1 mg17.9 mg

Table 7
Compilation of data on the stability of the CIP, lot 10655 (T=40±2°C/75% RH±5% RH
FeaturesSource1 month3 months6 months
The content of ciproflo Satina of 33.5 mg33.6 mg33.3 mg33,7 mg
Purity ciprofloxacinat 99.95%of 99.96%of 99.96%99,94%
Individual impurities ≥0,10%nononono
Water content12,3%12,6%12,4%12,8%
The average mass of the emitted powder (RSD)93,0%94,4%93,8%95,2%
RSD (%) mass emitted powder2,84,01,92,4
The mass median aerodynamic diameterthe 3.6 µmthe 3.6 µmthe 3.6 µmthe 3.6 µm
Dose respirable the s particles < 4.7 µm19,0 mg18,3 mgof 19.1 mg18.6 mg

No significant changes in the content of ciprofloxacin, the purity of ciprofloxacin, water content, average weight and RSD (%) of the emitted powder mass median aerodynamic diameter and a dose of respirable particles <4.7 µm in the specified storage conditions.

Example 7. The influence of the composition of formulation on the properties of powder

The impact of variations formulation on the properties of the powder CIP illustrated in table 8. The powder samples were prepared according to the method described in example 3. These lots was obtained with the use of spray dryer Buchi type. For the qualitative analysis of the morphology of the obtained spray-dried particles was used scanning electron microscopy (SEM) (figa-5e). For this purpose, the samples were fixed on a silicon wafer, which is then secured on the upper side of double-sided carbon tape on an aluminum rack for SEM. On the fixed sample powder was applied by spraying the coating of gold-palladium using a spray installation for coating type Denton within 60-90 s at a pressure of 75 mtorr and current of 42 mA. It was possible to create a coating thickness of approximately 150 Å. And what the considerations applying received by system type Philips XL30 ESEM using source LaB 6working in the mode of deep vacuum, and with the use of detector type Everhart-Thornley to capture secondary electrons to visualize the composition. Accelerating voltage was set at 20 kV and the current in the beam was set at 33 mA. Working distance ranged from 5 to 6 mm fine Structure of ciprofloxacin betaine had the form of a flat plate crystals with a wide distribution of sizes from tens of nanometers to several microns (figb, 4G). The drug nanocrystals are present in the form of agglomerates with larger crystals. The large contact area characteristic of flat crystals, caused between the particles of large cohesive forces. In contrast, obtained by spray drying unconsolidated powder CIP had a more spherical shape and a lower content of nanoparticles. Morphological feature in the form of a porous surface clearly expressed in particles obtained by the method of PulmoSphere (figa, 4B, 5A-5e). It was not revealed changes of the characteristics of unconsolidated powder (MMS, purity, moisture content) when variations of the drug load in the range from 50 to 70 wt.%.

Table 8
The impact of lekarstvennayaforma on the properties of the powder, consisting of the resulting spray dried particles containing ciprofloxacin betaine
Lot # The content of drug substance (wt.%)DSPC (wt.%)CaCl2(wt.%)MMD (μm)purity (%)Moisture content (%)
N0202395046,73,32,199,910,5
N0202406037,42,62,299,911,5
N0202417028,02,02,299,912,3
N0202425046,73,32,399,910,8
N020243 6037,42,62,299,911,7
N0202447028,02,02,299,912,4

Aerosol properties above preparative forms are described in detail in table 9. Variations of drug loading (up to content medicines, constituting 70%) did not lead to changes in the required aerosol characteristics, namely the emitted dose (ED), MMAD and FPF. Thus, the drug load, comprising 50 or 60, or 70 wt.%, fall under the scope of the preferred embodiments of the present invention.

Table 9
Aerosol properties of the resulting spray dried particles containing ciprofloxacin betaine, depending on the content of the drug substance
Lot # The emitted dose (%)MMAD (µm)%FPF<4.7 microns
N02023993±0,63,755
N02024093±1,13,655
N02024194±1,93,654
N02024295±0,93,660
N02024395±1,13,751
N02024494±4,23,749

Example 8. Physico-chemical properties of micronized ciprofloxacin betaine and CIP

Surface characteristics of powders CIP obtained by spray drying complex source product containing fine ciprofloxacin betaine, dispersed in a continuous phase of the emulsion of the type oil - in water are presented in table 10. It is seen that the specific surface area, porosity and roughness (Sv) particles with phospholipid coating is substantially higher than the micronized drug substance. It should be expected that the increase-is vitasti surface and/or porosity should lead to a reduction in cohesive forces between particles in the case of created particles, thereby increasing fluidization and dispersibility of the powder. This ultimately leads to the achievement of the observed very high ability to form aerosol (big emitted mass, low value RSD) and to improve directional introduction of the aerosol into the lungs.

Table 10
Surface characteristics micronized ciprofloxacin and obtained by spray drying CIP
Lot # DesignationSpecific surface area (m2/g)Porosity (cm3/g)Sympatec Sv (m2/cm3)Roughness Sv*
BXA1GE7API4,42,74,911,1
HCIP11,010,03,165,0
HCIP10,992 3,504,5
* for API associated with a form factor = 1,27

Example 9. The influence of surface roughness on dispergirovanija powder Relative dispersible powder preparative forms can be studied using the method of laser diffraction in varying dispersive pressure in the dosing device type RODOS. Comparison of the characteristics of micronized ciprofloxacin betaine and unconsolidated powder CIP presented on Fig.6. Although both curves converge to values of x50"composing from 2.3 to 2.4 μm, dispersing a pressure of approximately 4 bars, but at lower dispersing pressure curves differ significantly. Value xso For micronized ciprofloxacin betaine when dispersing pressure of 0.2 bar was 3.5 μm, while the value of x50for the obtained spray-dried powder CIP was 2.9 μm. The ratio of the median particle sizes measured at low and high dispersing pressures, represents the characteristic of the dispersive ability of the pigment powder. In the present study for micronized drug substance was obtained dispersive ability of the pigment δ, equal to 0.67, and obtained by spray drying powder - 0,78. Sledovat is Ino, to the dispersion obtained by spray drying powder CIP requires much less energy than for dispersion of micronized drug substance.

Example 10. The influence of volume fraction of PFOB on the properties of the powder CIP

The influence of volume fraction of PFOB on the properties of the powder CIP illustrated in table 12 and table 13. Powders were obtained according to the method described in example 3, for a batch size of 100 g using the compositions of the raw product for spray drying, listed in table 11. These lots were prepared using spray dryer type Niro Mobile Minor according to the method described in example 3 and tested using the same method described in examples 4 and 5.

Table 11
The composition of the original product for spray drying, used to get lots CIP weight 100 g
ComponentThe target number for the nominal lot size 100 g
9,0% (wt./about.) PFOB6,75% (wt./about.) PFOB4,5%(wt./about.) PFOB0% (wt./about.) PFOB
Ciprofloxacin betaine70,070,070,070,0
1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC)28,028,028,028,0
The dihydrate of calcium chloride2,02,02,02,0
Perflubron [perforative (PFOB)]576,0432,0288,00,0
Water for irrigation (WFIr)3033,03108,03183,03333,0

Variations of the volume fraction of PFOB in the range from 4.5 to 9% (wt./about.) in containing ciprofloxacin betaine source product for spray drying did not change the size of the primary particles (x10x50and x90) (table 12) and the content of ciprofloxacin or required aerosol characteristics, namely EATING, MMAD and FPF (table 13). However, if PFOB no, the size of the primary characteristics of h is STIC shift towards smaller particles, as obtained by spray drying containing ciprofloxacin betaine particles does not form a porous coating of DSPC (table 12). Furthermore, the lack of PFOB in the original product for spray drying leads to the formation of particles, which are less effective fluidizers and disperse from the filled capsules (table 13). Decrease ability to fluidizable powder is reflected in the decrease in the average emitted mass (EM) (82% compared with 93-94%), and higher variability of emitted mass (RSD=9,4% compared with 1.0%) compared to preparative forms containing a pore-forming agent. The decrease in the dispersive ability of the pigment powder in the case of preparative forms, not containing a pore-forming agent, is reflected in the increasing MMAD and the reduction in FPF. Although these differences were relatively small in the applicable test conditions (Q=60 l/min, V=2 l), we should expect that the magnitude of the differences between preparative forms will further increase at low flow rates and respirable volumes, which, as you might expect, characteristic of some patients suffering from CF. Thus, the initial products to obtain a spray drying CIP, which contain a volume fraction of PFOB in excess of 4.5% (wt./about.) fall under the scope of the preferred embodiments of this image is etenia.

Table 12
The influence of volume fraction of PFOB on the characteristics of unconsolidated powder CIP
Lot # PFOB (% wt./about)The size of the core particles, determined by the method of the firm Sympatec (µm)The content of ciprofloxacin (%)
N020486-19x10:1,020,654
x50:2,56
x90:5,03
H6.75x10:0,980,668
x50:2,59
x90:5,41
N020486-24.5x10:1,020,649
x50:2,52
x90:5,13
N020486-30x10:0,68 0,639
x50:2,36
x90:5,35

Table 13
The influence of volume fraction of PFOB on aerosol characteristics of unconsolidated powder CIP
Lot # PFOB (% wt./about.)The emitted mass ±RSD (%)MMAD (µm)FPF<4.7 µm (%)1
N020486-1994±0,73,776
H6,7594±0,93,775
N020486-24,593±1,03,775
N020486-3082±9,4a 3.968
1expressed in the form FPF on the stages of the impactor, not in the de percentage of the nominal dose.

Example 11. The influence of the size of the crystals of ciprofloxacin betaine on aerosol characteristics obtained by spray drying CIP

The influence of the distribution of particle sizes of micronized ciprofloxacin betaine on spray characteristics of the spray dried powders CIP illustrated in table 14.

Table 14
The influence of the size of the crystals of ciprofloxacin betaine on aerosol characteristics CIP
APICIP
Lot # x50(µm)x90(µm)EM±SD (%)MMAD (µm)FPF<4.7 µm (%)FPD<4.7 µm (mg)
BV01VLH2,244,4393±1,82,87124,7
BX01V3U2,986,8994±1,53,4 6019,5
BX01VLJ4,3410,3492±1,84,14616,0

It was found that with increase in the size of crystals containing ciprofloxacin drug substance there has been a significant increase in MMAD and the reduction in FPF and FPD. It should be noted the fact that the ability to fluidizable powder, which is determined by the porous nature of the phospholipid coating on the crystals of the drug substance, was preserved regardless of the size of the crystals.

Example 12. Pharmacokinetic characteristics entered by inhalation CIP

Pharmacokinetic characteristics of ciprofloxacin was studied in healthy volunteers and patients with CF after administration by inhalation of a single dose of CIP. Pharmacokinetic characteristics in plasma and sputum are presented in table 15 and table 16 respectively. Compared with input by inhalation hydrochloride ciprofloxacin (ciprofloxacin·HCl), for which the half-life in the lungs of rats is less than 1 h, CIP had a longer residence time in the lungs (the half-life in the sputum was from 5.5 to 9.0 h in C is (depending on dose). It was found that systemic levels of ciprofloxacin was very low.

Improved directional introduction in light entered through inhalation CIP compared to oral input by the ciprofloxacin is illustrated in Fig.7. Directed the introduction of the lungs characterized by the ratio of AUC in the sputum/AUC in plasma, the value of which if entered by inhalation CIP, more than 250 times higher than the corresponding value achieved through oral introduction of ciprofloxacin.

Table 15
Pharmacokinetic characteristics entered by inhalation CIP plasma
Experience 1: Healthy individualsExperience 2: Patients with CF
Dose50 mg CIP (or 32.5 mg ciprofloxacin) N=650 mg CIP (or 32.5 mg ciprofloxacin) N=6100 mg CIP (65 mg ciprofloxacin) N=6
The geometric meanGeometric value CV (%) The geometric meanGeometric value CV (%)The geometric meanGeometric value CV (%)
AUC (mg×h/l)0,35430,30,42512,11,0015,1
Cmax(mg/l)0,05632,20,07919,21,8217,4
tmax(h)0,630,25-1,501,50,5-2,01,260,75-1,50
t1/2(h)9,5419,666,3066,8of 8.0637,0
MRT (h)for 10.6814,816,4837,77,27 25,5

Table 16
Pharmacokinetic characteristics entered by inhalation CIP sputum suffering from CF patients
Dose50 mg CIP (or 32.5 mg ciprofloxacin) N=6100 mg CIP (65 mg ciprofloxacin) N=4
The geometric meanGeometric value CV (%)The geometric meanGeometric value CV (%)
AUC (mg×h/l)72,5179,4472323,8
Cmax(mg/l)33,0443,52001013,5
tmax(h)0,980,8-2,500,920,85-1,43
t1/2(h) 9,0445,0of 5.5340,7
MRT (h)3,0248,54,0079,1

Although the present invention has been described in greater detail by the example of certain preferred versions, other versions, and specialists in this field after reading the description and studying the drawings should be obvious modifications, permutations and equivalents of the illustrated version. You can also combine a variety of ways various distinctive features provided in this release, receiving additional versions of the present invention. In addition, it should be borne in mind that the specific terminology has been used for clarity of description, but not to limit the present invention. Consequently, any of the items of the attached claims is not limited in this description of the preferred versions, and it should include all such modifications, permutations, and equivalents, which correspond to the true nature and scope of the present invention.

1. Powder composition for intra-lungs introduction g the e powder composition contains:
particles containing ciprofloxacin betaine 3.5-hydrate and excipient, in which the particles have a mass median aerodynamic diameter of from about 1 to about 5 microns and in which ciprofloxacin betaine 3.5-hydrate has a half-life in the lungs of at least 1.5 h, and
when this composition is characterized by a roughness of from 3 to 10.

2. The composition according to claim 1, where the composition provides when using the inhaler passive type for dry powder receiving the emitted dose comprising at least about 50%.

3. The composition according to claim 1, which is in the tank for the standard dose, with a lot of songs that are in the tank for standard doses, sufficient for insertion into a light dose comprising at least about 10 mg

4. The composition according to claim 3, where the composition is kept in the tank for the standard dose contains ciprofloxacin betaine 3.5-hydrate in the amount of at least about 16 mg.

5. The composition according to claim 1, in which excipient contains a phospholipid, a substance containing a metal ion or both of these substances.

6. The composition according to claim 1, in which the particles have a bulk density less than 0.6 g/cm3.



 

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1 tbl, 2 dwg

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10 cl, 8 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: invention refers to a vaccine containing a combination of non-living antigens of Lawsonia intracellularis, Mycoplasma hyopneumoniae and porcine circovirus, and a pharmaceutically acceptable carrier. The invention also refers to a kit comprising a first container with the non-living antigens of Lawsonia intracellularis, one or more other containers with the antigens of Mycoplasma hyopneumoniae and porcine circovirus, and an instruction for mixing the antigens of Lawsonia intracellularis, Mycoplasma hyopneumoniae and porcine circovirus for preparing one combined vaccine for systemic vaccination.

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8 tbl, 3 ex

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11 cl, 1 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: intratympanic composition used for treating an ear disease contains: (a) an antimicrobial agent consisting of a number of particles; and (b) a polyoxyethylene and polyoxypropylene copolymer; the composition (i) is a liquid at room temperature; (ii) has a gelling point within the range of 19°C to 42°C; (iii) has a gel viscosity of 15000 sP to 1000000 sP; (iv) has an osmolarity less than 1000 mOsm/l; and the intratympanic composition release the antimicrobial agent in an ear for at least 5 days, and it is introduced at room temperature.

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13 cl, 9 tbl, 5 dwg, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to indolyl-substituted derivatives of thiadiazinones prepared from oxamic acid thiohydrazide of general formula: , wherein R represents H; R1 represents pyridinyl; phenyl substituted by alkyl C1-C5, Hal, CF3; R2 represents H; alkyl C1-C5; -CH2COOR4; benzyl substituted by Hal, OR4; benzoyl substituted by Hal, OR4, while R4 represents unsubstituted alkyl C1-C4.

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2 cl, 2 dwg, 2 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents an antibacterial composition of chitosan and a gel former, containing polyvinyl alcohol, and/or glycerol, and/or polyethylene glycol and/or polyvinyl pyrrolidone, differing by the fact that the antibacterial agent is presented by low-molecular water-soluble chitosan of molecular weight 3.5 to 4.9 kDa in the amount of 0.01 to 10 wt %; the gel former is polyvinyl alcohol 2 to 15 wt %, and/or glycerol 10 to 90 wt %, and/or polyethylene glycol 1 to 20 wt %, and/or polyvinyl pyrrolidone 10 to 50 wt %; water is the rest.

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5 ex, 4 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

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9 cl, 9 dwg, 5 ex

FIELD: chemistry.

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23 cl, 8 tbl, 8 ex

FIELD: medicine.

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4 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to therapy and pulmonology, and may be used for the purpose of the pharmacological correction of lung tissue disorders developed after the cytostatics have been prescribed. For this purpose, 3 hours after having prescribed a cytostatic, and then 1, 3, 7, 10 days thereafter, the neuroleptic agent haloperidol is administered into laboratory animals; besides every time 1 hour before administering haloperidol, hyaluronidase immobilised on polyethylene is introduced intranasally.

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1 dwg, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents using a human tissue factor pathway inhibitor (TFPI) or its biologically active homolog having a sequence more than 90 per cent identical to TFPI as a single active ingredient for preparing a drug effective for treating or reducing a risk of extravascular fibrin accumulation in the human alveolar or bronchoalveolar spaces by the intra-tracheal, intra-alveolar or intra-bronchial introduction through the respiratory passage.

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14 cl, 2 ex

FIELD: medicine, pharmaceutics.

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14 cl, 2 ex

Organic compounds // 2496479

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for preparing an inhaled fine or crystalline glycopyrronium powder salt. The declared method involves suspending the crystalline glycopyrronium salt in acetone to prepare a suspension, homogenising the suspension at pressure 500-2000 bar to prepare glycopyrronium salt particles at average particle size less than 10 mcm, and drying the glycopyrronium salt particles to remove residual acetone if any.

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7 cl, 2 tbl, 4 ex

FIELD: medicine, pharmaceutics.

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5 cl, 4 ex

Synbiotic mixture // 2495927

FIELD: chemistry.

SUBSTANCE: invention relates to a synbiotic preparation containing N-acetyl-lactosamine and/or an oligosaccharide containing N-acetyl-lactosamine and a probiotic strain Lactobacillus sp. The oligosaccharide containing N-acetyl-lactosamine is lacto-N-tetraose or lacto-N-neotetraose. The probiotic strain Lactobacillus sp. is Lactobacillus rhamnosus ATCC 53103, Lactobacillus rhamnosus CGMCC 1.3724, Lactobacillus reuteri ATCC 55730 or Lactobacillus reuteri DSM 17938.

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6 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

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EFFECT: what is prepared is the new salt of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one effective in treating the pathological pulmonary conditions, particularly asthma or chronic obstructive pulmonary disease.

11 cl, 3 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: invention refers to veterinary science. The method for preventing respiratory diseases in calves involves the immunisation by subcutaneous injections of donor animals' hyperimmune blood serum containing antihemagglutinin in titres to herpes virus -3 1:1280, to rednose virus - min. 1:256, to viral diarrhoea -1:1024 and to adenovirus -1:128; besides, 20-30 minutes before feeding, a pytopreparation of an alcohol tincture prepared of purple echinacea (Echinacea purpurea L) herb and blossom, common pine (Pinus sylvestris) buttons, horseheal (Inula helenium) roots and rhizomes, common liquorice (Glycyrrhiza glabra L.) roots and harmala shrub (Peganum harmala) herb taken in relation 1:1:1:1:0.5 in the amount of 7-8% of aqueous solution is administered in a dose of 2.0-2.5 ml/kg of body weight for 15 days every 24 hours.

EFFECT: invention provides the optimum preventive effect which is expressed in reducing the number of infected calves and milder course.

1 cl, 3 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology, and concerns an iRNA agent for reducing the levels of viral protein, iRNA, or respiratory syncytial virus titre in an individual's respiratory cell. The present iRNA agent contains a sense chain and an antisense chain, wherein the above sense chain comprises at least 15 consecutive nucleotides complementary to the gene P of the RSV virus, and the antisense chain comprises at least 15 consecutive nucleotides complementary to said sense chain, wherein said antisense chain comprises 15 or more consecutive nucleotides of a sequence consisting of nucleotides 1-19 of the sequence SEQ ID NO:6.

EFFECT: invention may be used in treating the respiratory diseases and preparing the RSV vaccines.

8 cl, 5 dwg, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry and concerns a dry powder preparation containing micronised: salmeterol xinafoate and fluticasone propionate. The preparation contains a carrier consisting of lactose of average particle size 100-120 mcm and sodium benzoate. What is also described is a method for producing the preparation.

EFFECT: formulation possesses higher percentage of a respirable fraction of the active substances.

4 cl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, and concerns an inhalation pharmaceutical composition containing a therapeutic agent, a soluble excipient, a surfactant, and a hydrophobic substance for reducing moisture sensitivity, and representing leucine; a method for preparing the above composition; a kit for administering the therapeutic agent in the form of a water dispersion containing the premeasured amount of the above composition.

EFFECT: group of inventions provides a sudden increase of both of the active fraction and fine fraction.

39 cl, 1 ex, 10 dwg, 4 tbl

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