MX2007005139A - Particles for treatment of pulmonary infection - Google Patents

Abstract

Formulations have been developed to treat or reduce the spread of respiratory infections, especially chronic or drug resistant infections, particularly tuberculosis (TB), severe acute respiratory syndrome (SARS), meningococcal meningitis, Respiratory syncytial virus (RSV), influenza, and small pox. Formulations include a drug or vaccine in the form of a microparticle, nanoparticle, or aggregate of nanoparticles, and, optionally, a carrier, which can be delivered by inhalation. Giving the drugs via an inhaler sidesteps the problems associated with oral or injectable drugs by bypassing the stomach and liver, and delivering the medication directly into the lungs. In one embodiment, the particle containing the agent is a large porous aerosol particle (LPPs). In another embodiment, the particles are nanoparticles, which can be administered as porous nanoparticle aggregates with micron diameters that disperse into nanoparticles following administration. Optionally, the nanoparticles are coated, such as with a surfactant or protein coating. The formulation may be administered as a powder or administered as a solution or via an enteral or non-pulmonary parenteral route of administration. The formulation is preferably administered as a pulmonary formulation. In the preferred embodiment for treatment of TB, the vaccine is a BCG vaccine that is stable at room temperature, or is an antibiotic effective againstTB, such as capreomycin or PA-824, loaded at a very high percentage into the microparticles or nanoparticles. In one embodiment, a patient is treated with formulations delivering both antibiotic and vaccine.

Description

PARTICLES FOR THE TREATMENT OF PULMONARY INFECTION BACKGROUND OF THE INVENTION The government of the United States has rights to this invention by virtue of grant number NIH 5 U01 AI61336-02 of the National Institute of Allergy and Infectious Diseases. This application claims the priority of U.S.S.N. 60 / 623,738 filed on October 29, 2004. TB, or tuberculosis, is a disease caused by bacteria called Mycobacterium tuberculosis. Bacteria can attack any part of the body, but usually attack the lungs. TB disease was once the leading cause of death in the United States. In the 1940s, scientists discovered the first of several drugs now used to treat TB. As a result, TB slowly began to disappear in the United States. However, drug-resistant strains and infection of compromised patients have resulted in an increase in TB. Between 1985 and 1992, the number of TB cases increased; More than 16,000 cases were reported in 2000 in the United States. TB claims approximately 2 million lives each year. India, China, and Africa are places of danger, and the disease is increasing in a worrisome proportion in Eastern Europe and the nations that were formerly members of the Soviet Union. TB spreads through the air from one person to another. Bacteria are placed in the air when a person with TB disease of the lungs or throat coughs or sneezes. Nearby people can breathe in these bacteria and become infected. When a person breathes TB bacteria, the bacteria can settle in the lungs and begin to grow. From there, they can move through the blood to other parts of the body, such as the kidney, spine and brain. TB in the lungs or throat can be infectious. This means that the bacteria can spread to another person. TB in other parts of the body, such as the lung or spine, is usually noninfectious. People with TB disease are much more likely to spread it to people who spend time with them every day. This includes family members, friends and co-workers. People who are infected with latent TB do not feel sick, have none of the symptoms, and can not spread TB, but they may develop TB disease at some time in the future. People with TB disease can be treated and cured if they seek medical help. Even better, people who have latent TB infection but still do not get sick can take medicine so they will never develop TB disease. TB vaccination currently involves needle injection of Bacille Camette-Guerin (BCG). This vaccine needs to be refrigerated before it is given. However, refrigeration is not always available, especially in developing countries. Lyophilization can be used to prepare a vaccine that is stable at room temperature, if the molecules are not denatured during this procedure. However, when BCG is lyophilized, most of its activity is lost. Therefore there is a need for a method to make a vaccine more stable for TB. Currently, drugs and vaccines for the treatment or prevention of TB are supplied to patients orally or by needle injections. A less painful and simpler method is needed to deliver drugs and vaccines. Giving patients a full • route of drugs is one of the biggest problems in eradicating TB. After two to three months of treatment, patients feel better, then stop taking their medications. But they need six months of therapy to cure the disease. The drugs given by injection are painful and have toxic side effects. The pills are easier to take, but too many can cause liver and stomach problems that include nausea, diarrhea and vomiting. There are several other major respiratory infectious diseases that suffer from the same deficiencies in treatment, including severe acute respiratory syndrome (SARS), meningococcal meningitis, influenza, respiratory syncytial virus and smallpox. It is therefore an object of the invention to provide improved methods and formulations for use in reducing or limiting the spread of tuberculosis and other infectious respiratory diseases. It is another object of the invention to provide improved formulations for the treatment of tuberculosis and other infectious respiratory diseases that do not have to be injected. It is another object of the present invention to provide a more stable vaccine for TB and other infectious respiratory diseases and methods for making the vaccine. BRIEF DESCRIPTION OF THE INVENTION Formulations have been developed to treat or reduce the spread of respiratory infections, especially chronic or drug-resistant infections, particularly tuberculosis (TB), severe acute respiratory syndrome (SARS), meningococcal meningitis, respiratory syncytial virus (RSV-). ), influenza and smallpox.

The formulations include a drug or vaccine in the form of a microparticle, nanoparticle or aggregate of nanoparticles, and, optionally, a carrier, which can be delivered by inhalation. By giving the drugs through an inhaler, the problems associated with oral or injectable drugs are avoided by not going through the stomach and the liver, and by delivering the medication directly into the lungs. In one embodiment, the particle containing the agent is a large porous aerosol particle (LPPs). In another embodiment, the particles are nanoparticles, which can be administered as aggregates of porous nanoparticles with micron diameters that are dispersed in nanoparticles after administration. Optionally, the nanoparticles are coated, such as with a surfactant or protein coating. The formulation can be administered as a powder or administered as a solution or via an enteral or parenteral non-pulmonary administration route of administration. The formulation is preferably administered as a pulmonary formulation. In the preferred embodiment for the treatment of TB, the vaccine is a BCG vaccine which is stable at room temperature, or is an antibiotic effective against TB, such as capreomycin or PA-824, loaded at a very high percentage in the microparticles or nanoparticles, preferably at least 50% by weight, more preferably at least 80% by weight. In one embodiment, a patient is treated with formulations that supply both the antibiotic and the vaccine. The example demonstrates the preparation and analysis of a porous particle of inhalable capreomycin, which has a diameter of approximately 4.2 microns, and thick nanometer walls, which have excellent aerodynamic properties, drug loading and stability. BRIEF DESCRIPTION OF THE DRAWING Figures 1A, IB and 1C are time-dependent stability graphs of (A) geometric diameter, (B) fine particle fraction (FPFTD) < 5.8 um of particles, and (c) capreomycin content of an initiator aerosol powder containing 80% capreomycin, stored under various conditions of. aggression. Key of the legend:? 4 ° C, | dark RT; | RT light; At 40 ° C / 75% closed RH; * 40 ° C / 75% open RH. DETAILED DESCRIPTION OF THE INVENTION I. Particle Formulations The formulations include drug particles and, optionally, excipient, optional excipient or pharmaceutical carrier. The formulations may be nanoparticles, microparticles, or microaggregates of nanoparticles. The aggregates can be coated. The formulations may be in the form of a powder for inhalation, or dispersed in a solution or encapsulated for delivery via a route other than the pulmonary route, such as nasal, buccal, oral or injection, although pulmonary is preferred. Particles, Nanoparticles and Aggregates of Nanoparticles The particles are preferably formed of drug to be delivered in combination with excipient by spray drying a drug and excipient solution. The conditions of spray dehydration determine the size of the particles, as well as the density. The size and density determine if the particle is inhaled in the lung. The diameter of particles in a sample depends on factors such as particle composition and synthesis methods. The size distribution of the particles or aggregates in a sample can be selected to allow optimal deposition within the target sites within the respiratory tract. A FPFTD < 3.3 μp? represents the percentage of aerosols that must be deposited in the lower respiratory tract, while a FPFTD < 5.8 μp? represents the percentage of aerosols that must be deposited in the middle to the lower respiratory tract. ? Unless stated otherwise, the particles or aggregates described herein will have a FPFTD <; 5.8 μ ?? In a preferred embodiment, the particle or aggregates of particles are aerodynamically light, having a preferred size, for example, a geometric mean volume diameter (CMGD or geometric diameter) of at least about 5 microns. In another embodiment, the VMGD is from about 5 microns to about 15 microns. The particles in the example immediately have a diameter of approximately 4.2 microns. In another embodiment, the particles have a VMGD ranging from about 10 μm to about 15 μ ?a, and as such, more successfully prevent phagocytic swallowing by alveolar macrophages and evacuation of the lungs, due to the exclusion of the size of the lungs. particles of the cytosolic space of the phagocytes. Phagocytosis of the particles by the alveolar macrophages decreases precipitously as the particle diameter increases beyond about 3 μta and less than about 1 μp? (Kawaguchi et al., Biomaterials 7: 61-66, 1986; Krenis and Strauss, Proc. Soc. Exp. Med., 107: 748-750, 1961; and Rudt and Muller, J. Contr. Re., 22: 263. -272, 1992). In other embodiments, the aggregates have a medium diameter (MD), MMD, a medium mass envelope diameter (MMED) or a median geometric mass diameter (MMGD). of at least 5 um, for example from about 5 um to about 30 The nanoparticles contained within the aggregates have a geometric diameter of approximately less than about 1 μ? T ?, for example, from about 25 nanometers to about 1 μm. Such geometric diameters are small enough that escape by evacuation of the body by macrophages, and can reside in the body for long periods of time. Suitable particles or aggregates can be manufactured or separated, for example, by filtration or centrifugation, to provide a particle sample with a preselected size distribution. For example, greater than about 30%, 50%, 70% or 80% of the particles or aggregates in a sample can have a diameter within a selected range of at least about 5 μp ?. The selected range within which a certain percentage of the particles or aggregates can fall can be, for example, between about 5 and about 30 μp ?, or optimally between about 5 and about 25 μ ??. In a preferred embodiment, at least a portion of the particles or aggregates have a diameter between about 5 and about 15 μp ?. optionally, the particle sample can also be manufactured in which at least about 90% or optionally about 95% or about 99%, have a diameter within the selected range. The diameter of the particles or aggregates, for example, their VMGD, can be measured using an electrical zone sensor instrument such as a Multisizer lie, (Coulter Electronic, Luton, Beds, England), or a laser diffraction instrument (for example, Helos, manufactured by Sympatec, Princeton, NJ) or by SEM visualization. O Other instruments for measuring particle diameter are well known in the art. Experimentally, the aerodynamic diameter can be determined by employing a gravitational settling method, whereby the time for an assembly of particles to settle a certain distance is used to directly infer the aerodynamic diameter of the particles. An indirect method for measuring the mass median aerodynamic diameter (MMAD) is the multistage liquid striker (MSLI). The aerodynamic diameter, daez, can be calculated from the equation: daer = dgAptap where dg is the geometric diameter, for example the MMGD and p is the approximate particle mass density by the density of the dust hit. The particles are preferably formed using spray dehydration techniques. In such techniques, a spray dehydration mixture, also referred to herein as "feed solution" or "feed mix", is formed to include nanoparticles comprising a bioactive agent and, optionally, one or more additives that are fed to a spray drier. Spray dehydration is a process used in the food, pharmaceutical and agricultural industries. In sprinkler dehydration, moisture is evaporated from an atomized feed (spray) by mixing droplets sprayed with a dehydrating medium (eg, air or nitrogen). This process dries the droplets of its volatile substance and leaves non-volatile components of "dry" particles that are of a size, morphology, density, and volatile content controlled by the dehydration process. The mixture that is sprayed can be a solvent, emulsion, suspension, or dispersion. Many factors of the dehydration process can affect the properties of the dry particles, including the type of nozzle, size of the drum, flow rate of the volatile solution and the circulating gas, and environmental conditions (Sacchetti and Van Oort, Spray Diying and Supercritical Fluid Partiole Generation Techniques, Glaxo Wellcome Inc., 1996). Typically the process of spray dehydration involves four processes, dispersing a mixture into small droplets, spray misc and dehydration medium (eg, air), evaporation of dew moisture, and separation of the dried product from the dehydration medium (Sacchetti and Van Oort, Spray Diying and Supercritical Fluid Partiole Generation Techniques, Glaxo Wellcome Inc ., nineteen ninety six). The dispersion of the mixture in small droplets greatly increases the surface area of the volume that dries, resulting in a faster dehydration process. Typically, a higher energy of dispersion leads to smaller droplets obtained. The dispersion can be achieved by any means known in the art, including pressure nozzles, two fluid nozzles, rotary atomizers, and ultrasonic nozzles (Hinds, Aerosol Technology, Edition 2, New York, John Wiley and Sons, 1999). After the dispersion (spray) of the mixture, the resulting spray is mixed with a dehydration medium (for example, air). Typically, mixing occurs in a continuous flow of heated air. The hot air improves the transfer of heat to the spray droplets and increases the evaporation rate. The air stream can already be emptied into the atmosphere after dehydration or recycled and rejected. Air flow is typically maintained by providing positive and / or negative pressure at either end of the stream (Sacchetti and Van Oort, Spray Drying and Supercritical Fluid Partition Generation Techniques, Glaxo Wellcome Inc., 1996).

When the droplets come into contact with the dehydration medium, the evaporation takes place rapidly due to the high specific surface area and small size of the particles. Based on the properties of the dehydration system, a residual level of moisture can be retained within the dry product (Hinds, Aerosol Technology, 2nd Edition, New York, John Wiley and Sons, 1999). The product is then separated from the dehydration medium. Typically, the primary separation of the product takes place at the base of the dehydration chamber, and the product is then recovered using, for example, a cyclone, electrostatic precipitator, filter, or scrubber (Masters et al., Spray Diying Handbook. UK, Longman Scientific and Technical, 1991). The properties of the final product that include particle size, fine moisture, and yield depend on many factors of the dehydration process. Typically, parameters such as the inlet temperature, air flow rate, liquid feed rate, droplet size, and concentration of the mixture are adjusted to create the desired product (Masters et al., Spray Drying Handbook , Harlow, ÜK, Longman Scientific and Technical, 1991). The inlet temperature refers to the temperature of the heated dehydration medium, typically air, as measured before it flows into the dehydration chamber. Typically, the inlet temperature can be adjusted as desired. The temperature of the dehydration medium at the recovery site of the product is referred to as the exit temperature, and is dependent on the inlet temperature, average dehydration flow expense, and properties of the sprayed mixture. Typically, higher inlet temperatures provide a reduction in the amount of moisture in the final product (Sacchetti and Van Oort, Spray Drying and Supercritical Fluid Partiole Generation Techniques, Glaxo Wellcome Inc., 1996). The expense of air flow refers to the flow of the dehydration medium through the system. The air flow can be provided by maintaining the positive and / or negative pressure at either end or within the spray dewatering system. Typically, higher air flow costs lead to a shorter residence time of the particles in the dehydration device (i.e., the dehydration time) and leads to a higher amount of residual moisture in the final product. (Masters and collaborators, Spray Drying Handbook, Harlow, UK, Longman Scientific and Technical, 1991).

The flow rate of the liquid feed refers to the amount of liquid supplied to the dehydration chamber per unit time. The higher the yield of the liquid, the more energy is needed to evaporate the droplets to particles. Thus, higher flow costs lead to lower exit temperatures. Typically, reducing the flow expense while maintaining the inlet temperature and the constant air flow expense reduces the moisture content of the final product (Masters et al., Spray Diying Handbook, Harlow, UK, Longman Scientific and Technical, 1991). . Droplet size refers to the size of the droplets dispersed by the spray nozzle. Typically, smaller droplets provide lower moisture content in the final product with smaller particle sizes (Hinds, Aerosol Technology, 2nd Edition, New York, John Wiley and Sons, 1999). The concentration of the mixture that is dehydrated by spraying also influences the final product. Typically, higher concentrations lead to larger particle sizes of the final product, since there is more material per sprayed droplet (Sacchetti and Van Oort, Spray Drying and Supercritical Fluid Partiole Generation Techniques, Glaxo Wellcome Inc., 1996). Systems for spray dehydration are commercially available, for example, from Armfield, Inc. (Jackson, NJ), Brinkmann Instruments (estbury, NY), BUCHI Analytical (New Castle, DE), Niro Inc. (Columbra, MD), Sono-Tek Corporation (Milton, NY), Spray Drying Systems, Inc. (Randallstown, MD), and Labplant, Inc. (North Yorkshire, England). The final moisture content of spray dried powder can be determined by any means known in the art, for example, by thermogravimetric analysis. This moisture content is determined by the thermogravimetric analysis when heating the powder, and by measuring the loss of mass during the evaporation of moisture (Maa et al., Pharm. Res., 15: 5, 1998). Typically, for a sample containing cellular material (eg, bacteria), the water will be evaporated in two phases. The first phase, referred to as free water, is mainly the water content of the dry excipient. The second phase, referred to as binding water, is mainly the water content of the cellular material. Both the free water and the binding water can be measured to determine whether the powder contains a desired moisture content in either the excipient or cellular material (Snyder et al., Analytica Chimica Acta, 536: 283-293, 2005). The spray dehydrator used to form the particle can employ a centrifugal atomization assembly, which includes a disk or spin wheel to break the fluid into droplets, for example, a 24-vane atomizer or a 4-vane atomizer. The rotation disk typically operates within the range of from about 1,000 to about 55,000 rotations per minute (rpm). Alternatively, the atomization of the hydraulic pressure nozzle, the pneumatic atomization of two fluids, the sonic atomization or other atomization techniques, as known in the art, can also be employed. Spray dehydrators commercially available from suppliers such as Niro, APV Systems, Dermiark, (for example, the APV Anhydro Model) and Swenson, Harvey, III., As well as ascending sprayers suitable for industrial capacity production lines. they can be used to generate the particles as described herein. Commercially available spray dehydrators generally have water evaporation capacities ranging from about 1 to about 120 kg / hr. For example, a Niro Mobile Minor® spray drier has a water evaporation capacity of approximately 7 kg / hr. Spray dehydrators have a two-fluid external mixing nozzle, or a 2 fluid internal mixing nozzle (eg, a NIRO Atomizer Portable spray drier). Suitable spray dewatering techniques are described, for example, by K. Masters in "Spray Drying Handbook," John iley & amp;; Sons, New York, 1984. Generally, during spray dehydration, the heat of a hot gas such as heated air or nitrogen is used to evaporate the solvent from the droplets formed by atomizing a continuous liquid feed. Other spray dehydration techniques are well known to those skilled in the art. In a preferred embodiment, a rotary atomizer is employed. An example of a suitable spray drier using rotary atomization includes the Mobile Minor® spray dryer manufactured by Niro, Denmark. The hot gas can be, for example, air, nitrogen or argon. Preferably, the particles are obtained by spray drying using an inlet temperature of about 90 ° C and about 400 ° C and an outlet temperature between about 40 ° C and about 130 ° C. Suitable organic solvents that may be present in the mixture to be spray dried include, but are not limited to, alcohols, for example, ethanol, methanol, propanol, isopropanol, butanols and others. Other organic solvents include, but are not limited to, perfluorocarbons, dichloromethane, chloroform, ether, ethyl acetate, methyl tert-butyl ether and others. Another example of an organic solvent is acetone. Aqueous solvents that may be present in the feed mixture include water and regulated solutions. Both organic and aqueous solvents may be present in the feed of the spray-drying mixture to the spray drier. In one embodiment, an ethanol: water solvent is preferred with the ratio of ethanol: water ranging from about 20:80 to about 90:10. The mixture can have an acidic or an alkaline pH. Optionally, a pH buffer solution can be included. Preferably the pH may vary from about 3 to about 10. In another embodiment, the pH varies from about 1 to about 13. The total amount of solvent or solvents used in the spray-dried mixture is generally greater than about 97% in weight. Preferably, the total amount of the solvent or solvents used in the spray-dried mixture is generally greater than about 99% by weight. The amount of solids (nanoparticles having bioactive agent, additives and other ingredients) present in the spray-dried mixture is generally less than about 3.0% by weight. Preferably, the amount of solids in the mixture that is dehydrated by spray varies from about 0.05% · to about 1.0% by weight.

Pharmaceutically Active Agents Agents to be delivered include therapeutic, prophylactic and / or diagnostic agents (collectively, "bioactive agents") for the treatment of infectious respiratory diseases such as TB, severe acute respiratory syndrome (SARS), influenza, and smallpox. Suitable bioactive agents include agents that can act locally, systemically or a combination thereof. The term "bioactive agent", as used herein, is an agent, or its pharmaceutically acceptable salt, which is then released in vivo, possesses the desired biological activity, for example therapeutic, diagnostic and / or prophylactic properties in vivo. Examples of bioactive agents include, but are not limited to, inorganic and synthetic organic compounds, proteins, peptides, polypeptides, DNA and RNA nucleic acid sequences or any combination or mimic thereof, which have therapeutic, prophylactic or diagnostic activities . Compounds with a wide range of molecular weight can be used, for example, compounds with weights between 100 and 500,000 grams or more per mole. In a preferred embodiment, the bioactive agent is an antibiotic for the treatment of a respiratory infection such as tuberculosis, such as capreomycin, PA-824, rifapycin, rifapentine and quinolones (for example Moxifloxacin (BAY 12-8039), aparfloxacin, gatifloxacin, CS-940, Du-6859a, sitafloxacin, HSR-903, levofloxacin, WQ-3034), ciprofloxacin and levofloxacin. Capreomycin is a relatively hydrophilic antibiotic molecule. It is currently used as a second line defense molecule in the prevention of TB. Capreomycin shows a decrease of one to two records in the units that form the colony ("CFU") after one month against non-replicating TB in vitro, thus there is potential for the treatment of latent TB, as reported by Heifets , and collaborators Ann. Clin. Microbiol. Antimicrobiol. 4 (6) (2005). PA-824 is a bactericidal antibiotic that targets a F420 flavenoid and also prevents mycolic acid synthesis and lipid biosynthesis. Rifapentine inhibits RNA polymerase by binding to the β subunit of the protein and acts as a bactericidal antibiotic. In another preferred embodiment, the bioactive agent is a vaccine, such as a BCG vaccine, which is effective against TB, or antigens of the flu. For the treatment of viral respiratory infections, the bioactive agent is preferably an antiviral alone or in combination with the vaccine. Four antiviral medications are commonly prescribed for category a of influenza viruses, amantadine, rimantidine, zanamavir and oseltamivir widely accumulated. These are neuraminidase inhibitors, which block the virus from replicating. If taken within a couple of days of the beginning of the disease, they can lighten the severity of some symptoms and reduce the duration of the disease. Multidrug-resistant tuberculosis (MDR-TB) is emerging as a significant public health trend, creating an unmet medical need that requires the development of new treatment procedures. In a preferred embodiment many doses of high-dose drugs are delivered to the site of primary infection for rapid sterilization of the lung mucosa and reduction in the duration of MDR-TB therapy. The formulation for the treatment of drug-resistant forms of infection may include very high loading of one or more antibiotics or a combination of antibiotic and vaccine. The nanoparticles can contain up to about 100% (w / w) of bioactive agent. In the preferred embodiment, the particles contain at least 50.00%, 60.00%, 75.00%, 80.00%, 85.00%, 90.00%, 95.00%, 99.00%, or more, of the bioactive agent (dry weight of the composition). In the case of capreomycin and other similar drugs, the preferred dosage load is at least 50% by weight, more preferably 80% by weight. The amount of bioactive agent used will vary depending on the desired effect, the planned release levels, and the duration over which the bioactive agent will be released. Excipients and Pharmaceutical Carriers Acceptable As used herein, an additive is any substance that is added to other substances to produce a desired effect in, or in combination with, the primary substance. As generally used herein, an "excipient" means a compound that is added to a pharmaceutical formulation in order to confer an adequate consistency. For example, the particles may include a surfactant. As generally used herein, the term "surfactant" refers to any agent that preferentially absorbs an interface between two immiscible phases, such as the interface between the water and an organic polymer solution, a water / air interface, a water / oil interface, an interface of water / organic solvent or an interface of organic solvent / air. Surfactants generally have a hydrophilic portion and a lipophilic portion, such that, on absorption to the microparticles, they tend to have portions in the external environment that do not attract similarly coated particles, thereby reducing particle agglomeration. Surfactants can also promote the absorption of a therapeutic or diagnostic agent to increase the bioavailability of the agent.

The particles and components thereof may be drug, drug and excipient, or drug in a polymer, which may be biodegradable or non-biodegradable, or a material such as silica, sterols such as cholesterol, stigmasterol,. beta. -sitosterol, estradiol; cholesteryl esters such as cholestyril stearate; C12-C24 fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, and lignoceric acid; mono-, di- and triacylglycerides of C18-C36 such as glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate, glyceryl monocosoate, glyceryl monomiristate, glyceryl monodicentoate, glyceryl dipalmitate, glyceryl didocosoate, glyceryl dimyristate, dideocene of glyceryl, glyceryl tridocosanoate, glyceryl trimyristate, glyceryl tridecenoate, glyceryl tristereate and mixtures thereof; esters of sucrose fatty acids such as sucrose distearate and sucrose palmitate; sorbitan fatty acid esters such as sorbitan monostearate, sorbitan monopalmitate and sorbitan tristearate; C16-C18 fatty alcohols such as cetyl alool, myristyl alcohol, stearyl alcohol, and cetostearyl alcohol; esters of fatty alcohols and fatty acids such as cetyl palmitate and cetearyl palmitate; fatty acid anhydrides such as stearic anhydride; phospholipids including phosphatidylcholine (lecithin), phosphatidylcerin, phosphatidylethanolamine, phosphatidylinositol, and lyso derivatives thereof; sphingosine and derivatives thereof; espingomyelins such as stearyl, palmitoyl and tric esanyl espingomyelins: ceramides such as stearyl and palmitoyl ceramides; glycosphingolipids; lanolin and lanolin alcohols; and combinations and mixtures thereof; in a preferred embodiment, the liquid that is spray dried optionally includes one or more phospholipids, such as, for example, a phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcerin, phosphatidylinocitol or a combination thereof. In one embodiment, the phospholipids are endogenous to the lung. Specific examples of phospholipids are shown in Table 1. Combinations of phospholipids can also be employed. Table 1: Phospholipids Dilauriliphosphatidylcholine (Ci 2; 0) DLPC Dimyristoylphosphatidylcholine (C 14; 0) DMPC Dipalrnitoylphosphatidylcholine (Ci 6: 0) DPPC Distearoylphosphatidylcholine (Ci 8: 0) DSPC Dioleoylphosphatidylcholine (Ci 8: 1) DOPC Dilaurilolylphosphatidyl-glycerol DLPG Dimiristoylphosphatidylglycerol DMPG Dipalrnitoylphosphatidylglycerol DPPG Distearoylphosphatidylglycerol DSPG Dioleoylphosphatidylglycerol DOPG Acid Dimyristoyl phosphatidic DMPA acid dimyristoyl phosphatidic DMPA Dipalmitoyl phosphatidic acid DPPA Dipalmitoyl phosphatidic acid DPPA Dimyristoyl phosphatidylethanolamine DMPE Dipalmitoyl phosphatidylethanolamine DPPE Dimyristoyl phosphatidylserine DMPS Dipalmitoyl phosphatidylserine DPPS Dipalmitoyl esfingornielina DPSP Distearoyl esfingornielina DSSP charged phospholipids can also be used to generate particles containing nanoparticles comprising bioactive agents . Examples of charged phospholipids are described in the North American patent application 20020052310. In addition to the lung surfactants, such as, for example, the phospholipids discussed in the foregoing, suitable surfactants include but are not limited to cholesterol, fatty acids, fatty acid ethers, sugars, exadecanol; fatty alcohols such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; an active surface fatty acid such as palmitic acid or oleic acid; glycocholate; surfactin; and polaxamer; an ester of sorbitan grade acid such as sorbitan trioleate (Span 85), Rween 80 (Polyoxyethylene Sorbitan Monooleate); Tyloxapol, polyvinyl alcohol (PVA), and combinations thereof. Methods for preparing and administering particles including surfactants, and, in particular, phospholipids, are disclosed in U.S. Patent No. 5,855,913 to Hanes et al. And in U.S. Patent No. 5,985,309 to Edwards et al. The particles may additionally comprise an amino acid, including but not limited to leucine, isoleucine, alanine, valine, phenylalamine, glycine and tryptophan. Combinations of amino acids can also be used. Amino acids occurring that are not naturally suitable include, for example, beta-amino acids. The configurations of both D, L and racemic mixtures of hydrophobic amino acids can be used. Suitable amino acids may also include amino acid derivatives or analogues. As used herein, an amino acid analog includes the D or L configuration of an amino acid having the following formula: - H-CHR-CO-, wherein R is an aliphatic group, a substituted aliphatic group, a benzyl group, a substituted benzyl group, an aromatic group or a substituted aromatic group and wherein R does not correspond to the side chain of a naturally occurring amino acid. As used herein, the aliphatic groups include branched or cyclic, straight-chain, C 1 -C 8 hydrocarbons that are fully saturated, containing one or two heteroatoms such as nitrogen, oxygen or sulfur and / or containing one or more units of insatu'ration. Aromatic or aryl groups include carboxylic aromatic groups such as phenyl and naphthyl groups and heterocyclic aromatics such as imidazolyl, indolyl, thienyl, furanyl, pyridyl, pyranyl, oxazolyl, benzothienyl, benzofuranyl, qunilinyl, isoquinolinyl and acridintyl. A number of suitable amino acids, amino acid analogs and salts thereof can be obtained commercially. Others can be synthesized by methods known in the art. Synthetic techniques are described, for example, in Green and Wuts, "Protecting Groups in Organic Synthesis" John Wiley and Sons, Chapters 5 and 7, 1991. The amino acid or salt thereof may be present in the particles in an amount of about 0% to about 60% by weight, preferably, about 5% by weight to about 30% by weight. Methods for forming and supplying particles that include an amino acid are described in U.S. Patent No. 6,586,008. Spray dewatered particles can include nanoparticles that contain one or more bioactive agents or other materials. The nanoparticles can be produced according to methods known in the art, for example, emulsion polymerization in a continuous aqueous phase, emulsion polymerization in a continuous organic phase, grinding, precipitation, sublimation, interfacial polycondensation, spray dehydration, melted microencapsulation. in hot, phase separation techniques (solvent removal and solvent evaporation), nanoprecipitation as described by?. L. Le Roy Boehm, R. Zerrouk and H. Fessi (J. Microencapsulation, 2000, 17: 195-205) and phase inversion techniques. Methods to produce include evaporated precipitation, as described by Chen et al. (International Journal of Pharmaceutics, 2002, 24, pp 3-14) and the use of supercritical carbon dioxide as an antisolvent (as described, for example, by J. "- A. Lee et al, Journal of Nanoparticle Research, 2002, 2, pp 53-59.) Nanocapsules can be produced by the method of F. Dalencon, Y. Amjaud, C. Lafforgue, F. Derouin and H. Fessi (International Journal of Pharmaceutics., 1997, 153: 127-130). US Pat. Nos. 6,143,211, 6,117,454 and 5,962,566; Amnoury (J. Pharm. Sci., 1990, pp 763-767); Julienne et al., (Proceed, Intern Symp. Control, Reí. Bioact. Mater., 1989, pp. 77-78); Bazile et al. (Biomaterials 1992, pp 1093-1102); Grefet al. (Science 1994, 263, pp 1600-1603); Colloidal Drug Delivery Systems (edited by Jorg Kreuter, Marcel Dekker, Inc., New York, Basel, Hong Kong, pp 219-341); and WO 00/27363, describes the manufacture of nanoparticles and incorporation of bioactive agents, for example, drugs in nanoparticles. The preformed (intact) nanoparticles can be added to the solution (s) to be dehydrated by spraying. Alternatively, reagents capable of forming nanoparticles during the mixing and / or spray drying process can be added to solutions that are spray dried. The excipient / carrier can be present in the particles in an amount ranging from about 5 weight percent (%) to about 95% by weight. Preferably, they may be present in the particles in an amount ranging from about 20% to about 80% by weight. Optionally the particles or aggregates are coated. Suitable coatings include proteins and surfactant. Coatings can be used to direct specific tissues or cells, or to increase bioadhesion. The particles or aggregates may also include other additives, for example, regulatory salts. II. Particle Delivery Methods and Devices for Administration Preferably, the bioactive agent is delivered to a target site, eg, a tissue, organ or whole body, preferably the lungs, in an effective amount. As used herein, the term "effective amount" means the amount necessary to achieve the desired therapeutic or diagnostic effect or efficacy. The actual effective amounts of bioactive agent may vary from. according to the specific bioactive agent or combination thereof that is used, the particular composition formulated, the mode of administration, and the age, weight, condition of the patient, and severity of the symptoms or condition being treated. Dosages for a particular patient can be determined by one of ordinary skill in the art using conventional considerations, for example, by means of an appropriate conventional pharmacological protocol. In one embodiment, the bioactive agent is coated on the nanoparticle. Although described primarily with reference to pulmonary administration, it is understood that the particles can be administered nasally, orally, vaginally, rectally, topically or by injection. The formulations are administered to a patient in need of treatment, prophylaxis or diagnosis. Administration of the particles to the respiratory system may be by means such as are known in the art. For example, particles (agglomerates) can be supplied from an inhalation device. In a preferred embodiment, the particles are administered via a dry powder inhaler (DPI). Metered dose inhalers (MDI), nebulizers, or instillation techniques can also be used. Preferably, the delivery is to the alveolar region of the pulmonary system, the central airways, or the upper respiratory tract. Various suitable inhalation devices and methods that can be used to deliver particles to the patient's respiratory tract are known in the art. For example, suitable inhalers are disclosed in U.S. Patent Nos. 4,995,385, and 4,069,819 to Valentini et al., U.S. Pat. No. 5,997,848 to Patton. Other examples include but are not limited to, the Spinhaler® (Fisons, Loughborough, U.K.), Rotahaler® (Glaxo-Wellcome, Research Triangle Technology Park, North Carolina), FlowCaps® (Hovione, Loures, Portugal), Inhalator. RTM. (Boehringer-Ingelheim, Germany), the Aerolizer® (Novartis, Switzerland), the diskhaler (Glaxo-Wellcome, RTP, NC) and others known to those skilled in the art. Preferably, the particles are administered as a dry powder by way of a dry powder inhaler. In one embodiment, the dry powder inhaler is a simple, powered breathing device. An example of a suitable inhaler that can be employed is described in U.S. Patent No. 6,766,799.

A receptacle is used to enclose or store particles and / or breathable pharmaceutical compositions comprising the particles for subsequent administration. The receptacle is filled with the particles using methods known in the art. For example, vacuum filling or tamping technologies can be used. Generally, the filling of the receptacle with the particles can be carried out by methods known in the art. In one embodiment, the particles that are enclosed or stored in a receptacle have a mass of at least about 5 milligrams to about 100 milligrams. In another embodiment, the mass of the particles stored or enclosed in the receptacle comprises a mass of bioactive agent of at least about 1.5 mg to at least about 200 milligrams. In one embodiment, the volume of the inhaler vessel is at least about 0.37 cm3 to 0.95 cm3. Alternatively, the receptacles may capsules, for example, capsules designed with a particular capsule size, such as 2, 1, 0, 00 or 000. The. Suitable capsules can be obtained, for example, from Shionogi (Rockville, Md.). The ampoules can be obtained, for example, from Hueck Foils, (Wall, N.J.). Other receptacles and other volumes thereof suitable for use in the above invention are also known to those skilled in the art.

Preferably, the particles administered to the respiratory tract travel through the upper respiratory tract (oropharynx and larynx), the lower respiratory tract including the trachea followed by the bifurcations in the bronchi and bronchioles and through the terminal bronchioles which in turn They are divided into the respiratory bronchioles that lead them to the final respiratory zone, the alveoli or the deep lung. In one embodiment, the majority of the mass of particles is deposited in the deep lung. In another modality, the supply is mainly to the central airways. The supply to the upper respiratory tract can also be obtained. The aerosol dosage, formulations and delivery systems can also be selected for a particular therapeutic application, as described, for example, in Gonda, I. "Aerosols for delivery of therapeutic and diagnostic agents to the respiratory tract," in Critical Reviews in Therapeutic Drug Carrier Systems, 6: 273-3 13, 1990; and in Moren, "Aerosol dosage forms and formulations, in: Aerosols in Medicine, Principles, Diagnosis and Therapy, Moren et al., Eds, Elsevier, Amsterdam, 1985. The release rates of the bioactive agent from the particles can be described in terms of release constants The first order release constant can be expressed using the following equations: Where k is the first order release constant? (8) e -the total mass of the bioactive agent in the agent delivery system bioactive, eg dry powder, and • M (t) is the amount of the mass of bioactive agent released from dry powders at time T. Equation (1) can be expressed either in quantity (ie, mass ) of the released bioactive agent or the concentration of bioactive agent released in a specified volume of release medium For example, equation (1) can be expressed as: C (t) = C (oo) * (lel * t) or Liberation (t) = Liberation ( _8) * (1-e ek * t *) (2) Where k is the first order release constant. C8) is the maximum theoretical concentration of the bioactive agent in the release medium, and C t) is the concentration of bioactive agent that is released from the dry powders into the release medium at time t. The release rates of the drug in terms of first order release constant can be calculated using the following equations: K = -ln (M (8) -M (t)) / M (ro) / t (3) The proportions of release of bioactive agents from. The particles can be controlled or optimized by adjusting the thermal properties or transitions of the physical state of the particles. The particles can be characterized by their matrix transition temperature. As used in this, the term "matrix transition temperature" refers to the temperature at which the particles are transformed from the vitreous or rigid phase with less molecular mobility to a more amorphous, rubbery or molten state or fluid-like phase. Corns is used herein, "matrix transition temperature" is the temperature at which the structural integrity of a particle is decreased in a manner that imparts more rapid release of the bioactive agent from the particle. Above the matrix transition temperature, the particle structure changes so that the mobility of the bioactive agent molecules increases resulting in faster release. In contrast, below the matrix transition temperature, the mobility of the bioactive agent particles is limited, resulting in a slower release. The "matrix transition temperature" can be related to the different phase transition temperatures, for example, melting temperature (Tm), crystallization temperature (Tc) and glass transition temperature (Tg) representing changes in mobility of order and / or molecular within the solids. Experimentally, matrix transition temperatures can be determined by methods known in the art, in particular by differential scanning calorimetry (DSC). Other techniques for characterizing the matrix transition behavior of dry particles or powders include synchrotron X-ray diffraction and freeze fracture electron microscopy. As used herein, the term "nominal dose" means the total mass of the bioactive agent that is present in the mass of particles targeted for administration and presents the maximum amount of bioactive agent available for administration. Patients to be Treated: Effective Dosages The formulations described herein are particularly suitable for the treatment of respiratory diseases such as TB. SAR, meningococcal meningitis, RSV, influenza and smallpox. In the preferred embodiment, patients treated have chronic or long-term infection, or drug-resistant infection. In the case of an antibiotic such as capreomycin, a dosage equivalent to a dosage in the range of 30-100 mg, more preferably 30-60 mg, given orally, is administered once or twice daily for rapid release, and once one week for slow release. Leucine is the preferred excipient. The present invention will be further understood by reference to the following non-limiting examples. Example 1: Large Porous Particles Containing Capreomycin Multi-drug resistant tuberculosis (MDR-TB) is emerging as a significant public health threat, which creates an unmet medical need that requires the development of new treatment procedures. Direct topical delivery of antibiotics to infected lungs is used to obtain the primary objective of directing high-dose drug doses to the site of primary infection for rapid sterilization of the lung mucosa and reduction of RD-TB therapy . Dry powder aerosols containing 50-80% capreomycin have been made, which exhibit similar physical and aerosolization properties. The aerosols with geometric diameters that vary from 2-10 μp? and aerodynamic diameters in the range of 5-6 μp? they were formed by spray dehydration. The optimization of the increased powder of the processing parameters produces up to 60% before the large batch ascent. The aerosols show excellent storage capacity at refrigerated room temperature, and accelerated conditions (40 ° C), with both chemical and physical properties that remain stable for up to two months of parking. EXPERIMENTAL METHODS Preparation of Dry Powder Sprays Aerosols were prepared by heating a solution of capreomycin: leucine 80:20 (36 g in 5000 mL of 50% ethanol) at 60 ° C and by spray drying the solution using a dehydrator Niro sprinkling in a feed flow gas of 80 mL / min, an atomizer flow rate of 28-31 g / min and a process gas flow rate of 79-82 kg / hr. The inlet temperature varied from 189-192 ° C to achieve an exit temperature of ~ 65 ° C. In a second example, a solution containing 28.8 g of capreomycin sulfate (Lilly, No, Control 7RT71R) and 7.2 g L-leucine (Sigma L-8912, Lot 044K0381) in 2500 mL of Milli-Q water and 2500 mL of 200 test ethanol (PharmCo 11 1ACS200, Lot 04259-14, Lot 0409144) was heated to 60 ° C and dehydrated by spray using a Niro spray drier at a feed flow rate of 80 mL / min, a Atomizer flow rate of 28-31 g / min and a process gas flow rate of 79-82 kg / hr. The inlet temperature was varied from 189-192 ° C to achieve an exit temperature of ~ 65 ° C. Yield: 17.5149 g = > 48.7% Physical Aerosol Characterization Each spray-dried powder was initially characterized by morphology, geometric size, and aerosolization properties. Particle morphology was observed by scanning electron microscopy with an Electron Field Scanning Electron Microscope LEO 982 (SEM) (Zeiss). The particle size was measured by laser diffraction using a HELOS diffractometer and a dry powder dispersant of variable shear stress RODOS (Sympatec) at applied regulatory pressures of 0.5, 1, 2, and 4 bar. The aerodynamic properties of the dispersed powders of an inhaler device were estimated with cascade impact using gravimetric analysis via an 8-stage Mark II Andersen Cascade Impactor (ACI-8, Thermo Electron, aitham, MA) to measure the fraction of fine particles of the total dose (FPFTD). The FPFTD reported the measurements of the aerosol fraction with aerodynamic diameters less than 3.3 or 5.8 μ ??. A FPFTD <; 3.3 μp? represents the percentage of aerosols that must deposit in the lower respiratory tract, while a FPFTD < 5.8 μp? represents the percentage of aerosols that must be deposited in the middle of the lower respiratory tract. The volume density of the particles was determined by the blow density measurements. Briefly, the particles were loaded into 0.3 ml sections of a 1-ml plastic pipet, capped with NMR tube lids, and tapped approximately 300-500 times until the volume of the powder did not change. The density of the stroke was determined from the difference between the weight of the pipette before and after loading, divided by the volume of powder after tapping. Characterization of the Chemical Aerosol The content of capreomycin in the powders was determined by HPLC. The content of Capreomycin in each powder was determined by HPLC analysis in 22:78 methanol: phosphate buffer with 0.3% by weight of heptafluorobutyric acid using a C18 reverse phase column (Agilent ZORBAX® Eclipse XDB-C18) in 1.0 mL / min and 25 ° C. Stability Test The powder was formed in aliquots in 15 glass scintillation flasks (-200 mg each) and a glove box at 10.5% RH, then tightly capped. Each of 3 bottles was placed in 4 dry plastic chambers containing drierite. The chambers were stored at room temperature under dark conditions, at room temperature exposed to sunlight, at 4 ° C (refrigerated), and at 40 ° C and 75% RH in a humidity chamber as a condition of accelerated stability. The final 3 flasks were placed uncovered at 40 ° C and 75% RH in a humidity chamber. The time points are 0, 1, 2 and 6 weeks, 2 months, and 3 months. At each time point, the physical and chemical properties of the powder were characterized. RESULTS AND DISCUSSION Dry powder aerosols containing various percentages of capreomycin and leucine were formed by spray dehydration. The average mass diameter of each formulation, as determined using a HELOS / RODOS laser diffraction system at a pressure of 1.0 bar, is shown in Table 2. No significant difference in diameter was observed with a change in the regulatory pressure. This suggests that the aerosol flight characteristics for these powders are independent of a patient's inspiratory flow rate. The SEM images of the dry powder aerosols containing 80% and 90% of capreomycin show that as the percentage of capreomycin in the dry powder aerosols was increased up to 80%, a decrease in the average diameter was observed - (Table 2) . In 90% capreomycin, an aerosol containing two-diameters of spheres was observed by laser diffraction and SEM. This double population led to an increase in the average diameter of the powder. The FPFTD for aerosols containing 50-80% capreomycin was not significantly different. However, the 90% capreomycin spray showed approximately a 30% decrease in the FPFTD. Since aerosols containing the largest amount of capreomycin possible, but with good flight properties, are needed, aerosols containing 80% capreomycin were used for further studies. Table 2: Average size and FPFTD of dry powder aerosols containing capreomycin The initial escalation of dust production resulted in a yield of 48.7%. These aerosols, used for stability and pharmacokinetic studies, had an average geometric diameter of 4.2 μp ?, with a range of aerodynamic diameter of 4-6 micras. A geometric standard derivation (GSD) of 1.8 μ? T? was determined from W. C. Hinds. Spray Teclmology. John Wiley & Sons, Inc., New York, 1999: GSD = (d84% / d16%) 0-5 equation (1) where dn is the diameter in the nth percentile of the cumulative distribution, and showed that the aerosol was almost monodisperse. No significant difference in diameter was observed with a change in the regulating pressure. This suggests that the aerosol flight characteristics for these powders are independent of a patient's inspiratory flow rate. The resulting particles had high drug loads. Repeated spray dehydration on different days showed good reproductive capacity with respect to particle size and morphology. The total visual stability tests at room temperature, 4 ° C and 40 ° C showed no changes in size or morphology after 2 and a half weeks. The FPFTD of the aerosols stored at 40 ° C for 6 weeks decreased by 40%. However, the FPFTD under other storage conditions remained stable for up to 2 months. The content of capreomycin in the formulations stored in closed vials at 4 ° C, RT, and 40 ° C remained stable for up to three months. When placed in direct contact with an atmosphere of 40 ° C and 75% RH, the aerosols adsorbed significant amounts of water, leading to a decrease in the capreomycin content per aerosol mass. A three-month physical and chemical stability analysis of aerosols containing 80% capreomycin was conducted under refrigerated room temperature (4 ° C), (RT, approximately 25 ° C), and accelerated conditions (40 ° C). Figures 1A, IB, and 1C show the stability of the geometrical diameter of the aerosol, the fraction of fine particles (FPFTD), and the chemical content over time. No significant change in geometric diameter was observed under all conditions (Figure 1A). The FPFTD of the aerosols stored at 40 ° C for 6 weeks was decreased by 40% (Figure IB). However, the FPFTD under other storage conditions remained stable for up to three months. The content of capreomycin and the formulations stored in the closed vials at 4 ° C, RT, and 40 ° C remained stable for up to 3 months (Figure 1C). When placed in direct contact with an atmosphere at 40 ° C and 75% RH, the aerosols adsorbed significant amounts of water, leading to a decrease in the capreomycin content per aerosol mass. Briefly, an injectable hydrophilic TB drug molecule, capreomycin, was formulated into an aerosol form of dry powder for inhalation. Due to the large storage doses required for the treatment, a powder spray with high drug loading (80% capreomycin) was prepared which exhibits excellent aerosolization properties ((FPFTD < 5.8 μp? 48%). Significant difference in geometric diameter was observed with a change in applied regulatory pressure, which suggests that the aerosol flight characteristics for these powders are independent of a patient's respiratory flow expenditure Significantly, these aerosols show excellent storage capacity at ambient temperature, refrigerated, and accelerated conditions (40 ° C), with both chemical and physical properties that remain stable up to three months of storage It is understood that the disclosed invention is not limited to the methodology, protocols, and particular reagents described since These may vary, and it will also be understood that the terminology used here is for the purpose of describing particular modalities only and is not proposed to limit the scope which will be limited only by the appended claims.

Claims (20)

1. CLAIMS 1. A formulation for the treatment of a respiratory infection, characterized in that it comprises a therapeutic, diagnostic or prophylactic agent for the treatment of a respiratory infection in a dry powder suitable for administration by inhalation in the dry lung; which comprises microparticles or aggregates of nanoparticles having a particle or aggregate diameter between one and 30 microns and a FPFTD less than 3.3 μp? for particles or aggregates that are deposited in the lower respiratory tract and a FPFTD less than 5.8 μp? for particles or aggregates that are deposited in the middle of the lower respiratory tract.
2. 2. The formulation according to claim 1, characterized in that it comprises an agent for the treatment of a disease selected from the group consisting of tuberculosis, severe acute respiratory syndrome (SARS), meningococcal meningitis, respiratory syncytial virus (RSV), influenza and smallpox.
3. 3. The formulation according to claim 1, characterized in that it is for the treatment of a chronic respiratory infection or drug resistant.
4. 4. The formulation according to claim 1, characterized in that it is for the treatment of tuberculosis, especially multidrug-resistant tuberculosis.
5. 5. The formulation according to claim 1, characterized in that it comprises aggregates of nanoparticles.
6. 6. The formulation according to claim 1, characterized in that it comprises bioactive agents selected from the group consisting of antibiotics, antivirals and vaccine.
7. The formulation according to claim 6, characterized in that it comprises antibiotic selected from the group consisting of capreomycin, PA-824 rifapicin, rifapentine, quinolones), aparfloxacin, gatifloxacin, CS-940, Du-6859a, sitafloxacin, HSR-903 , levofloxacin, WQ-3034, ciprofloxacin and levofloxacin.
8. 8. The formulation according to claim 7, characterized in that it comprises caprepreomycin at a high load of greater than 50%, more preferably greater than 60% to 80% by weight.
9. 9. The formulation according to claim 8, characterized in that it comprises leucine as the excipient.
10. The formulation according to claim 6, characterized in that it comprises an antiviral selected from the group consisting of amantadine, rimantadine, zanamavir and oseltamivir.
11. The formulation according to claim 6, characterized in that it comprises a vaccine alone or in combination with antibiotic or antiviral.
12. 12. The formulation according to claim 1, characterized in that it is in a device or dosage form for pulmonary delivery.
13. The formulation according to claim 11, characterized in that it is in a dry powder for delivery by inhalation.
14. 14. The formulation in accordance with. claim 1, characterized in that the particles have an aerodynamic range of between four and six microns.
15. 15. The formulation according to claim 14, characterized in that the particles comprise capreomycin and leucine.
16. 16. The formulation according to claim 1, characterized in that it is in a form selected from the group consisting of tablets, capsules, pills, powders,. emulsions, aerosols, suspensions and solutions.
17. 17. A method of treatment, characterized in that it comprises administering to a patient an effective amount of the formulation of any of claims 1-16.
18. 18. The method according to claim 17, characterized in that the formulation is administered once or twice a day and is a rapid release formulation.
19. 19. The method according to claim 17, characterized in that the formulation is administered once a week and is a slow release formulation. The method according to claim 17, characterized in that the formulation comprises capreomycin and is administered to a person in need thereof in an equivalent dosage of 30 to 100 mg of capreomycin supplied orally. * SUMMARY OF THE INVENTION Formulations have been developed to treat or reduce the diffusion of respiratory infections, especially chronic or drug resistant infections, particularly tuberculosis (TB), severe acute respiratory syndrome (SARS), meningococcal meningitis, Respiratory syncytial virus (RSV). , influenza, smallpox. The formulations include a drug or vaccine in the form of a microparticle, nanoparticle, or aggregate of nanoparticles, and, optionally, a carrier, which can be delivered by inhalation. By giving the drugs through an inhaler, the problems associated with oral or injectable drugs are avoided by not going through the stomach and liver, and by delivering the medication directly into the lungs. In one embodiment, the particle containing the agent is a large porous aerosol particle (LPPs). In another embodiment, the particles are nanoparticles, which can be administered as aggregates of porous nanoparticles with micron diameters that are dispersed in nanoparticles after administration. Optionally, the nanoparticles are coated, such as with a surfactant or protein coating. The formulation can be administered as a powder or administered as a solution or via a non-pulmonary enteral or parenteral route of administration. The formulation is preferably administered as a pulmonary formulation. In the preferred embodiment for the treatment of TB, the vaccine is a BCG vaccine which is stable at room temperature, or is an antibiotic effective against TB, such as capreomycin or PA-824, loaded at a very high percentage in the microparticles or nanoparticles. In one embodiment, a patient is treated with formulations that supply both the antibiotic and the vaccine.