MX2007014468A - Formulations for alteration of biophysical properties of mucosal lining - Google Patents

Abstract

Conductive formulations containing conductive agents, and methods of use, have been developed. Active agents, such as antivirals, antimicrobials, anti-inflammatories, proteins or peptides, may be included with the formulation. When applied to mucosal lining fluids, the formulation alters the physical properties such as the surface tension, surface elasticity, and bulk viscosity of the mucosal lining. The formulations may be administered for several different purposes:reducing the spreading of infectious diseases, both viral and bacterial, such as SARS, influenza, tuberculosis, and RSV in humans and hoof and mouth disease in cloven-footed animals;minimizing ambient contamination due to particle formation during breathing, coughing, sneezing, or talking which is particularly important in the clean room applications;decreasing or preventing the occurrence of obstructive sleep apnea and some cases of irritable bowel syndrome;and controlling the uptake kinetics of drug molecules and pathogens.

Description

FORMULATIONS FOR THE ALTERATION OF THE BIOPHYSICAL PROPERTIES OF MUCOSAL COATING i FIELD OF THE INVENTION The present invention is in the field of formulations and methods for controlling the arrangement of particles from mucosal surfaces, and altering the absorption kinetics of drug and pathogen molecules. BACKGROUND OF THE INVENTION Many organs have a liquid mucosal lining! whose biophysical properties may facilitate or impede normal function. A wide array of adverse health effects have been associated with the properties of a mucosal lining, for example particles "diffused" from the fluid of the mucosal lining of the upper airways (UAL), during normal exhalation. bacterial or viral, infectious, viable pathogens, such as Acute Respiratory Syndrome! ("SARS", for its acronym in English), influenza, tuberculosis, capable of spreading to healthy individuals, through inhalation; the surface tension of the UAL has shown that it plays a role in the obstructive sleep apnea syndrome; and the alteration of mucosal lining of the intestinal tract by virus / mycobacteria can REF "§187SS7 lead to inflammatory bowel disease over time .; The controlled alteration of the biophysical properties of the mucosal lining can effectively treat / prevent many of these adverse health effects. Further,! the biophysical properties of the mucosal coating may affect the uptake of pathogen and drug molecule uptake into the body and therefore the manipulation of these properties may be used to block the absorption of pathogens or improve the absorption / bioavailability of pharmacological molecules. Airborne transmission is one of the main routes of infection by pathogens. Aerosols composed of mucus droplets that originate in the lungs and labial nasal cavities are produced when a human or animal coughs or simply breathes. These bioaerosols may contain pathogens that transmit the disease after inhalation by humans or exposed animals. In addition, respirable pathogenic bioaerojols produced in the upper respiratory tract can be breathed again by the host, leading to a parenchymal infection with exacerbated results of the disease. Bacterial and viral infections are often highly contagious, especially when they are dispersed with the breath. Reports to SARS, you know! are caused by a coronavirus, are proof of what An infection can spread so quickly when it is transmitted through air contact. Other diseases such as influenza are dispersed by contact with air, and rapidly reach epidemic proportions, with high numbers of fatalities in populations of the elderly and immunocompromised persons. Epidemics of respiratory infections are not limited to humans. The foot and mouth disease virus (FMDV) is the etiologic agent of foot and mouth disease (FMD), which is a disease of livestock, pigs and others. animals with pesuñas. FMD is characterized by the formation of vesicles on the tongue, nose, snout and coronary bands of infected animals. Several unique characteristics make the virus one of the most economically rewarding diseases in the world today. The ease with which it can be transmitted by contact and aerosol, and combined with its increased ability to initiate infections, virtually ensures that most, if not all, animals in a herd will contract FMD. The long-term survival of FMDV in tissues and organs of infected animals, especially when refrigerated, creates an opportunity for their national and international transmission through the food chain. Multiple serotypes and numerous subtypes reduce the effectiveness and Conflability of vaccines. The possible development of carriers in vaccinated animals and those that have recovered from FMD provides additional potential sources of new outbreaks. These characteristics create a disease that can have a greater economic impact on livestock operations around the world. The FMD epidemic in IDE cattle is still a growing cause of problems, with new cases still emerging in previously unaffected areas (Ferguson, et al., Nature 2001 414 (6861): 329). The estimated parameters obtained in a dynamic model of the spread of the disease show that the extended selection programs were essential for the control: of the epidemic to the extent achieved, but show that the epidemic could have been substantially reduced in scale if they had been carried out. more efficient methods more early in the outbreak. In addition to reducing or preventing the "dispersion or diffusion" of the contagious aerosol agents of UAL, the alteration of the biophysical properties of the mucosal coatings within the body can achieve several other purposes. One is the control over the appearance of apnea and obstructive sleep (OSA). OSA occurs during sleep ! and refers to frequent closure and reopening of the upper respiratory tract. OSA is triggered by relaxed throat muscles in sleep that allows the throat is completely constricted during inhalation 1 and is especially prevalent in people with narrow throats (either hereditary or due to external factors such as swelling, fat deposits, etc.). Certain medications for allergy such as antihistamines, as well as alcohol consumption can also relax the throat leading to OSA. Chronic OSA is observed in approximately 4% of the general population and leads to frequent breakouts and increased breathing work throughout the night, which causes fatigue and sudden sleep intervals during normal activities. A study on anesthetized rabbits showed that UAL surface tension influenced the lack of obstruction of the rabbit upper respiratory tract, and it was presumed that the surface properties of UAL probably played a role in the appearance of OSA (Kirkne; ss, JP et al. J Physiol 2003, 547.2 pp. 603-611). Another region of the body where the mucosal lining plays an important role is in the gastrointestinal system. Irritable bowel syndrome (IBS) is inflammation of the intestines and can develop for several different reasons (although the exact cause remains unknown). In many cases the development of IBS seems to be a genetic susceptibility to the disease, but recent studies have suggested that certain viruses of bacteria can alter the mucosal lining of the intestines and that over time this alteration can lead to the development of IBS (A.D.A.M., http://adam.about.com/reports/000069_l.htm, May 12, 2005). Studies have reported a link between the development of IBS in children and an increased frequency of childhood infections, such as measles, which has been I specifically identified. Other infectious agents capable of altering the mucosal lining properties that are under investigation are Escherichia Coli (E. coli) and Cyto egalovirus (CMV). An IBS study reported that more than 43% of enrolled patients were infected with CMV. The mucosal lining is the first mechanism of selection of the immune system in many areas of the body, selectively allowing the beneficial components through the underlying epithelial layer and from there, into the bloodstream, and preventing the absorption of pathogens and dangerous allergens. . The main component of the mucus that I protected against harmful absorption is the secretory immunoglobulin A (igA), which shows antiviral, antibadterine, anti-inflammatory and anti-allergenic activity (Williams, J. E., Alternative Medicine Review Vol. 8, Number 9, 2003). This chemically inhibits pathogens / allergens from passing through the mucosal layer, trapping them at or near the surface where they are sooner or later washed through. of the tissue and expelled in the faeces, the urine or in the respiratory system, through the action of the ciliadajs cells. However, many pathogens have developed sophisticated chemical transport systems to penetrate the mucosal layer, and the immunocompromised individual, the normal mechanism to prevent the absorption of pathogens to be impaired or disabled. Alteration of the biophysical properties of the mucosal lining (for example, increased gelification on the surface of the mucus) could reduce or prevent the pathogen's ability to physically entrain the mucosal lining. One side effect of the immune response of the mucosal lining is that the beneficial drugs can be picked up because they are dangerous in the body and blocked so that they do not pass through the mucosal lining. The alteration of the biophysical properties of the mucosal coating can increase the permeability of a pharmacological molecule through the coating, and improve the absorption of pharmacological molecules. There have been various methods / formulations introduced to effectively distribute the antibiotics and peptides poorly absorbed through the mucosal membranes. Ionic surfactants, such as sodium lauryl sulfate and chelating agents such as ethylenediamine tetraacetic acid (EDTA), have been found to increase intestinal absorption of such molecules Unfortunately, a large amount of this substance has been found to be dangerous for the mucosal membrane. The document WO03 / 092654 to David Edwards et al. describe a method to decrease the dispersion of inhaled infections by the distribution of materials such as surfactants that suppress the expiration of the aerosol. This technique works based on the alteration of the surface or other physical properties of the endogenous surfactant fluid in the lungs, and with this they favor that less aerosol particles are exhaled. WO 2005/084638 to Pulmatrix et al describes a non-surfactant solution which, by dilution of the endogenous surfactant fluid, alters the physical properties such as surface tension, surface elasticity and volume viscosity of the fluid i Lung mucus lining. The aerosolized material may be an isotonic saline solution, a hypertonic saline solution, or another solution containing osmotically active materials. The formulation can be administered as a powder where the particles consist essentially of a sa or an osmotically active substance that dilutes the endogenous surfactant fluid. The aerosol can be a solution, a suspension, dew, mist, vapor, droplets, particles or a dry powder. The typical concentrations of I salts or sugars are in the range of up to 5 or 6% solute. The formulation is administered in an amount effective to decrease surface instabilities in the liquid coating lining the airways and lung without causing expectoration. It would be desirable to have additional means to limit the formation of the bioaerosol and / or the dispersion of the infection. An objective of the present invention is therefore to provide methods for altering the biophysical properties of the mucosal coatings present within the body. A further objective of the present invention is to provide the compositions for altering the biophysical properties of the mucosal coatings present within the body. BRIEF DESCRIPTION OF THE INVENTION Conductive formulations containing conductive agents, such as salts, ionic isurfactants, or other substances that are in an ionized or easily ionized state in an aqueous or organic solvent environment and the method of use have been developed. One or more active agents, such as antivirals, antimicrobials, anti-inflammatories, proteins or peptides, may optionally be included with the formulation. The active agent it can be administered with or incorporated into the formulation, or it can be administered after the conductive formulation is administered. When the mucosal lining fluids are applied, the formulation alters the physical properties such as the gel characteristics at the air / liquid interface, the surface tension, the surface viscosity, the surface elasticity, and the apparent viscoelasticity of the mucosal lining. The formulation is administered in an amount sufficient to alter the biophysical properties in mucosal coatings of the body. The formulations can be administered for several different purposes: the reduction of the spread of infectious, viral and bacterial diseases, such as SARS, influenza, tuberculosis and RSV in humadnos, and the disease of hoof and mouth in animals with lit leg; relief of respiratory tract irritation and congestion due to respiratory conditions that include acute infection (eg, common cold), asthma, chronic bronchitis, emphysema, bronchiectasis; the minimization of environmental pollution due to the formation of particles during respiration, cough, | sneezing or conversation that is particularly important in the application of clean rooms; the decrease or prevention of obstructive sleep apnea in some cases of irritable bowel syndrome; and the control of the absorption kinetics of drug molecules and pathogens. BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a schematic view of the simulated respiratory machine apparatus (SRM) used in the examples. Figure 2 is a bar chart of the cumulative particle counts (> 300 nm) after administration of different aerosolized formulations on the mucus mimic layer, as measured in vitro, using the SRM apparatus 0.21 kg / cm2 (3 psi air pressure, 2 mm mimetic height (6.4 ml of total mimetic volume), | 15 minutes of crosslinking time, and 2 minutes of j time of aerosolization of the formulation). Figure 3 is a bar chart of cumulative particle counts (> 300 nm) after administration of different aerosolized formulations in water and in saline) on the mucus mimic layer, as measured in vitro, using the SRM apparatus (in water and in saline) 0.21 kg / cm2 (air pressure 3 psi, mimetic height of 2 mm (6.4 ml of total mimetic volume), 2 minutes of aerosolization time of the formulation, and 15 minutes of crosslinking time). Figure 4 is a graph of the conductivity of the anchoring (μe /? P?) As measured by a zetasizer apparatus (ZetaPAS) (Brookhaven Instruments Corp, Holtsville, Y) versus cumulative particle counts (> 300 nm) as measured in vitro using the SRM apparatus. t Figure 5 is a graph of the surface loss tangent ("Tan d") as measured by the Rheometer Interfacial surface versus cumulative counts at i from (> 300 nm) as measured in vitro using the SRM apparatus. Figure 6A is a bar chart of the cumulative particle counts after administration of different aerosolized formulations on the mucus mimetic layer, as measured in vitro using the SRM apparatus 0.28 kg / cm2 (4 psi air pressure) , (0.2812 Kg / Cm2) mimetic height of 2 mm (6.4 ml of total mimetic volume), 2 minutes of aerosolization time of the formulation and 15 minutes of crosslinking time). Figure 6B is a bar graph of the percentage suppression of particle counts in comparison to the mimetic of untreated mucus for the same formulations under the same conditions as described in Figure 6A. DETAILED DESCRIPTION OF THE INVENTION A wide range of adverse health effects are associated with the properties of a mucosal lining !. Consequently, the ability to alter the biophysical properties of the mucosal lining is a valuable tool for the treatment or prevention of the spread of the disease. In addition, the alteration of the physical properties for the mucosal lining can be used to control the uptake and absorption of drugs as well as pathogens. The mucosal lining consists of complex substances. The mechanism of crosslinking that occurs in the mucosal lining can be altered by the alteration by the load and the distribution of charge on the surface of the lining. This subsequently causes the biophysical alteration of the mucosal lining that is beneficial for the prevention and treatment of various diseases; the suppression and formation of bioaerosol during breathing / conversation / coughing / sneezing (thereby, minimizing the distortion of airborne respiratory infectious diseases, such as influenza, SARS, etc.); the relief of irritation and congestion of the respiratory tract due to conditions Respiratory I include acute infection (eg, common cold), asthma, chronic bronchitis, emphysema, bronchiactasis; increased absorption / bioavailability of the drug molecules; and blocking the absorption of pathogens through the mucosal lining. The biophysical properties, such as viscoe¾asticity and apparent viscosity, for the i mucosal lining can be determined using the experiments in vi tro. The viscoelastic module, G *, is written as a complex number involving the real elastic modulus, storage, G ', and the imaginary viscous modulus (loss) G. "This relationship can be expressed as G * = G '+ zG "or | G * | = ^ (G') 2 + (G") 2 (Equation 1) where G | * is the viscoelastic module, also known as the mechanical impedance, G 'is the elastic module or the storage module, and G "is the viscous module or the loss module.

The tangent of the phase interval (written as d) between the applied force (tension) and the measured response (traction) is equal to the ratio of the viscosity modulus to the elastic modulus. This is commonly referred to as the "tangent of loss" or "Tan d", and may be expressed as follows: Tan d = G "/ G '(Equation 2) The loss tangent is used as a measure of system damping. For a viscoelastic sample, 0S < d < 902. For a semi-liquid sample, d > 45s and G "> G '. For a semi-solid sample, d < 45a and G '> G "For example, the greater is Tan d, the greater is G" with relativity to G '; and therefore, the more viscosity less able s the material to store energy. In a completely elastic solid, Tan d equal to zero (eg, G '> G). In order to measure the viscoeastric properties of a material, a sinusoidal voltage is applied and a response is developed sinusoidal (traction) (delaying the voltage by some amount) (see Example 4) The magnitude of the response and the delay can be measured, and from these measurements G 'and G "can be determined. 1 Pulmonary mucociliary clearance is the main mechanism by which the airways are kept clean of particles present in the liquid film that covers them. The conductive airways are lined with the ciliated epithelium that strikes to push a layer of mucus into the larynx, clearing the airways of the lower ciliated region within 24 hours, j The fluid coating consists of water, sugar ^ , proteins, glycoproteins and lipids. This is generated in the epithelium of the respiratory tract and in the submucosal glands, and the thickness of the layer is in the range of several micra in the trachea to approximately 1 micrometer in the distal respiratory tracts in humans, rats and guinea pigs. A second important mechanism to keep the pulmoneis clean is by means of the moment transfer from the air that flows through the lungs to the mucus coating. Cough increases moment transfer and is used by the body to help eliminate excess mucus. It becomes important when the mucus can not be adequately removed by ciliary beating only, as occurs in mucus hypersecretion associated with many disease states. High air velocities as high as 200 m / second can be generated during a forced cough. The onset of unstable sinus disturbances of the mucus layer has been observed at such air velocities. This disturbance results in increased momentum transfer from the air to the mucus and consequently accelerates the speed of clearance of the mucus from the lungs. Experiments have shown that this disturbance is initiated when the air velocity exceeds some critical value that is a function! of film thickness, surface tension and viscosity (M. Gad-El-Hak, R.F. Blackwelder, J.J. Riley, J.

Fluid Mech. (1984) 140: 257-280). The predictions and theoretical experiments with mucus-like films suggest that the critical velocity to initiate wave perforations in the lungs is in the range of 5-30 m / second. Papineni and Rosenthal (J. Aerosol Med., 1997, 10 (2): 105-116) have shown that during standard breathing with the jboca and the nose or during cough, the human subjects Normally tens to hundreds of liquid bioaerosol droplets with a preponderance of exhaled bioaerosol droplets having a smaller diameter of one micron expire. It was shown that cough gives rise to the greatest number of particles, although the size of the exhaled particle must remain significantly less than one miera. Most of these particles are larger than most of the 1 inhaled pathogens, for example, greater than 150 nm.

For example, some common inhaled pathogens have characteristic sizes in this range: tuberculosis, 1,000-5,000 nm; influenza at 80-120 nm; measles, 100-250 nm; Chicken pox, 120-200 nm; and FMD, 27-30 nm. I, Formulations The formulations described herein are effective in altering the biophysical properties of the mucosal lining. These properties include, for example, the increase in gelification on the surface of the mucus, the surface tension of the mucosal lining, the surface elasticity of the mucosal lining, and the apparent viscoelasticity of the mucosal lining. Preferred formulations for altering the biophysical properties of the pulmonary lining fluid are formulations that contain certain concentrations of charge and mobility, and thus the conductivity of the liquid. Suitable formulations include solutions or Aqueous suspensions that are conductive (also referred to herein as "conductive formulations"). Suitable conductive formulations typically have conductivity values greater than 5,000 pS / cm, preferably greater than 10,000 pS / cm, and more preferably greater than 20,000 pS / cm. In a preferred embodiment, the formulation has a specific conductivity that is j greater than the specific conductivity of the saline solution! isotonic These formulations are particularly useful when administered to a patient to suppress exhalation of particles. The conductivity of the solution is a product of ionic strength, concentration and mobility (the last two contribute to the conductivity of the formulation as a whole). Any form of the ionic components (anionic, cationic or amphoteric) can; be used. These conductive materials can alter the mucosal coating properties by acting, for example, as a cross-linking agent within the mucus. The ionic components in the formulation described herein may interact with the strongly bound anionic glycoproteins within the normal tracheobronchial mucus. These interactions can influence the state of the air / liquid surface of the airway lining fluid, and transiently the nature of the physical entanglements due to the interactions covalent and non-covalent, including hydrogen bonds, hydrophobic and electrostatic interactions (Dawsonj, M., et al., The Journal of Biological Chemistry, Vol. 21 ^, No. 50, pp. 50393-50401 (2003) ). Optionally, the formulation includes mucoactive or mucolytic agents, such as mucins MUC5AC and i MUC5B, DNA, N-acetylcysteine (NAC), cysteine, nacysteline, dornase alfa, gelsolin, heparin, heparin sulfate, agonistjas of P2Y2 (for example UTP, INS365), and nedocromil? sodium: The formulations can be designed for specific applications. In some embodiments, the formulation is administered to a mucosal surface to make the mucosal lining more liquid-like, while in others the formulation is administered to make the mucosal lining more like a solid. For example, to minimize the absorption of pathogens and reduce the exhalation of particles, the formulation is designed to increase the solidity of the mucosal lining, for example where d is less than 45 ° (see Equation 2 above). In contrast, to increase the absorption of the drug, the formulation is designed to increase the liquidity of the mucosal lining, i for example where d is greater than 45 ° (see Equation 2 above). to. Conducting Agents Formulations containing substances that are easily ionized in an aqueous or anorganic solvent environment (also referred to herein as "conductive agents") / such as salts, ionic surfactants, I charged amino acids, loaded proteins or peptides, or charged materials (cationic, anionic or amphoteric). Suitable salts include any salt form of the elements sodium, potassium, magnesium, calcium, aluminum, silicon, scandium, titanium, vanadium, chromium, cobalt, nickel, I copper, manganese, zinc, tin and similar elements. Ingredients include sodium chloride, sodium acetate, sodium bicarbonate, sodium carbonate, sodium sulfate, sodium stearate, sodium ascorbate, sodium benzoate, sodium bisphosphate, sodium phosphate, sodium bisulfite, citrate sodium, sodium borate, sodium gluconate, calcium chloride, calcium carbonate, calcium acetate, calcium phosphate, calcium alginate, calcium stearate, calcium sorbate, calcium sulfate, calcium gluconate, magnesium carbonate, sodium sulphate magnesium, magnesium stearate, magnesium trisilicate, potassium bicarbonate, potassium chlorurq, potassium citrate, potassium borate, potassium bisulfate, potassium bisphosphate, potassium alginate, potassium benzoate, magnesium chloride, sulfate cúpricq, Chromium chloride, stannous chloride, and metasilicate of sodium and similar salts. Suitable ionic surfactants include sodium dodecylsulfate (SDS) (also known as sodium lauryl sulfate (SLS)), magnesium lauryl sulfate, polysorbate 20, polysorbate 80 and similar surfactants. Suitable charged amino acids include L-lysine, L-arginine, histidine, aspartate, glutamate, glycine, cystein, tyrosine. Suitable charged proteins or peptides include proteins and peptides that contain the I charged amino acids, carmodulin (CaM), and troponin C. The charged phospholipids, such as triflate of 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (EDOPC) and alkyl-phospho-choline trimesters, can be used. The negatively charged phospholipids include phosphatidylinositol, phosphatidylserine, phosphatidylglycerol and phosphatidic acid, cardioljipins, dialkanoyl-phosphatidyl glycerols (dipalmitoyl-phosphatidyl-glycerol and dimyristoyl-phosphatidyl-glycerol), 4-phosphatidylinositol phosphate (PIP), 4,5-biphosphite phosphatidylinositol (PIP2), and phosphatidylethanolamines. Positively charged phospholipids include dioleyltrimethylammoniumpropane, esters of phosphatidic acids, such as dipalmijtoylphosphatidic acid and distearoylphosphatidic acid with aminoalcohols such as hydroxyethylene diamine. Preferred formulations are formulations containing salts, such as saline solution (sodium chloride 0. 15 or 0.9%), CaCl 2 solution, CaCl 2 in saline, or saline containing ionic surfactants, such as SDS or SLS. In the preferred embodiment, the formulation contains saline and calcium chloride. Suitable concentration ranges of the salt or other conductive / charged compounds may vary from about 0.01% to about 20% (weight of the conductive charged compound / total weight of the formulation), preferably from 0.01% to about 10% (weight of the cpmpuesto conductor or loaded / total weight of the formulation), more preferably between 0.1 to 7% (weight of the loaded conductive compound / total weight of the formulation). In a preferred embodiment, the formulation contains a hypertonic saline solution (e.g., sodium chloride concentration greater than 0.9% by weight). ! Saline solutions have been widely chronically distributed to the lungs with small amounts of therapeutically active agents, such as beta agonistias, corticosteroids or antibiotics. For example;, VENTOLIN® Inhalation Solution (GSK) is a solution of albuterol sulfate used in the chronic treatment of asthma and symptoms of bronchospasm induced by exercise. A solution of VENTOLIN® for nebulization is prepared (for the patient) by mixing 1.25-2.5 mg of sulphate! of albuterol (in 0.25 to 0.5 ml of aqueous solution) in sterile normal saline solution to achieve a total volume1 of 3 ml. No adverse effects have been found that are associated with the distribution of saline solution to the lungs by nebulization with VENTOLIN®, even though the nebulization times can range from 5 to 15 minutes.

The saline solution is distributed in more significant amounts to induce expectoration. Often these salt solutions are hypertonic (sodium chloride concentrations greater than 0.9% by weight, often as high as: 5% by weight) and in general these are distributed for up to 2.0 minutes. b. Active Ingredients jj The formulations described herein can be used by any route for the distribution of a variety of organic or inorganic molecules, especially small molecule drugs such as antiviral and antibacterial drugs which include antibiotics, antihistamines, bronchodilators, suppressants of Lactose, anti-inflammatories, vaccines, adjuvants and expectorants. Examples of macromolecules include protein and large peptides, polysaccharides and oligosaccharides, and nucleic acid molecules of DNA and RNA and their analogs having therapeutic, prophylactic or diagnostic activities. Nucleic acid molecules include genes, anti-sense molecules that bind to complementary DNA 2 to inhibit transcription and ribozymes. The preferred agents are antivirals, steroids, bronchodilators, antibiotics, inhibitors of mucus production and vaccines. In the preferred embodiment, the concentration of the active agent is in the range of about 0.01% to about 20% by weight. In a more preferred embodiment, the condentration of the active agent is in the range of from 0.1% to about 10%. II. Carrier and Aerosols for Administration. The formulation can be distributed in a solution, a suspension, a spray, a mist, a foam, a gel, a vapor, droplets, particles or a dry powder form (eg, using a metered dose inhaler including soap). the HFA propellant, a metered-dose inhaler with the non-HFA propellant, a nebulizer, a pressurized can, or a continuous sprayer). The carriers can be divided into those for administration via solutions or suspensions (liquid formulations) and those for administration via the particles (powder formulations sieco). . Dosage forms for administration to different mucosal surfaces i For administration to mucosal surfaces in the respiratory tract, the formulation is typically in the form of solution, suspension or dry powder. Preferably, The fornulation is aerosolized. The formulation can be generated via any aerosol generators, such as the dry powder inhaler (DPI), nebulizers or pressurized metered dose inhalers (pMDl). The term "aerosol" as used herein refers to any preparation of a fine mist of particles, typically less than 10 micrometers in diameter. The preferred average diameter for the aerosol particles of aqueous formulation is about 5 micrometers, for example between 0.1 and 30 micrometers, more preferably between 0.5 and 20 micrometers and most preferably between 0.5 and 10 micrometers. For administration to the oral mucosa, including the buccal mucosa, the formulation can be administered as a solid which dissolves after administration to the mouth and / p adheres to the mucosal surface or a liquid. For administration to the vaginal mucosa, the formulation is preferably in the form of a viscous solution or suspension, gel, foam, ointment, cream, lotion or I supositprio. Optionally, the formulation can be placed in a device for insertion, such as a ring. { vaginal. For administration to the gastrointestinal mucosa, the formulation is typically in the form of solution, suspension, solid dose form (e.g. capsule or tablet) or dry powder. Optionally, the formulation is bioadhesive, and may contain one or more bioadhesive polymers or other excipients. B, Formulated formulations 1 Aerosols for the distribution of therapeutic agents to the respiratory tract have been developed. See, for example, Adjei, A. and Garren, J. Pharm. Res., 7: 565-569 (l ^ O); and Zanen, P. and Lamm, J.-W. J. Int. J. Pharm., 114: 111-115 (1995). These are typically by atomizing the solution or suspension under pressure through a nebulizer or through the use of a metered dose inhaler ("MDI"). In the preferred embodiment, these are I solutions or aqueous suspensions. C. Dry powder foundations The geometry of the airways is a major barrier to the dispersion of drugs within the lungs. The lungs are designed to trap particles of foreign matter that are breathed in, such as I the pol † o. There are three basic mechanisms of deposition: impaction, sedimentation and Brownian movement (J.M. Padfieljd, 1987. in: D. Ganderton &T. Jones eds, Drug Deliverjy to the Respiratory Tract, Ellis Harwood, Chicherjster, United Kingdom). Impaction occurs when the particles are unable to remain within the current of airjs, particularly in branches of the tracks It breathes These are adsorbed on the layer of mucosa that covers the bronchial walls and cleansed by the mucosiliar action. Impaction occurs mainly with particles larger than 5 pm in diameter. Smaller particles (< 5 μ ??) can remain within the air stream and be transported deep into the lungs. Sedimentation often occurs in the lower respiratory system where air flow is slower. Very small particles (<0.6 μp?) Can be deposited by the Bro nian movement. This regimen is undesirable because the deposition can not be directed to the alveoli (N. Worakul and J.R. Robinson, 2002. in: Polymeric Biomaterials, 2nd ed. S. Dumitriu ed. Marcel Dekker.

York) The preferred average diameter for aerodynamically light particles for inhalation is at least? about 5 micrometers, for example between about 5 and 30 micrometers, most preferably between 3 and 7 micrometers in diameter. The particles can be manufactured with appropriate material, surface roughness, diametrix and bulk density of the powder for localized distribution to selected regions of the respiratory tract such as the deep lung or airways. For example, higher density or larger particles can be used for the distribution of airways superiors Similarly, a mixture of different particle sizes, provided with the same or different therapeutic agent may be administered to the different lung target regions in one administration. As used herein, the phrase "aerodynamically light particles" refers to particles having an average or apparent density of the powder of less than about 0.4 g / cm 3. The apparent density of the particles of a dry powder can be obtained by measuring the powder density after releasing the content, standard of the USP. The apparent density of the powder is a standard measurement of the density of the envelope mass. The envelope mass density of an isotropic particle is defined as the mass of the particle divided by the minimum volume of the envelope of the sphere in which it can be enclosed. The characteristics that contribute to the low apparent density of the powder include the irregular superfijcial texture and the porous structure. ! Dry powder formulations ("DPFs") with large paticle size have improved flow characteristics, such as less aggregation (Visser, J., Powder Technoljogy 58: 1-10 (1989)), easier aerosolization and less phagocytosis phagocytosis . Rudt, S. and R. H. Muller, J. Contjrolled Reeléase, 22: 263-272 (1992); Tabata, Y., and Y. Ikada, 1 J. Biomed Mater. Res., 22: 837-858 (1988). The French, D.L., Edwards, D.A. and Niven, R.W., J. Aerosol iSci., 7: 769-783 (1996). Particles with degradation and release times in the range of seconds to months can be designed and manufactured by methods established in the art. The particles can consist of or of the conductive agents, alone or in combination with drug, agents? antivirals, antibacterials, antimicrobials, surfactants, proteins, peptides, polymers, or combinations thereof! Representative surfactants include L-alpha-phosphatijdilcholine-dipalmitoyl ("DPPC"), diphosphatidyl-glycerol i (DPPG), | 1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine (DPPS), 1,2-dipalmitoyl-sn-glycero-3-phosphochol (DSPC), 1,2- distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), 1-palmit > il-2-oleoylphosphatidylcholine (POPC), fatty alcohols,? ether ij > olioxyethylene-9-lauryl, active fatty acids of Surface, sorbitan trioleate (Span 85), glycocholate, surfactjine, poloxomers, fatty acid esters of sorbitan, thiloxane, phospholipids, and alkylated sugars. Polymers can be tailored to optimize particle characteristics including: i) the interactions between the agent to be distributed and the polymer, to provide agent stabilization and retention of activity after distribution; ii) rate of degradation of the polymer and thus profile of drug release; iii) surface characteristics and targeting capabilities through chemical modification; and iv) porosity of the particle. Polymeric particles can be prepared using solvent evaporation in single and double emulsion, spray drying, solvent extraction, solvent evaporation, phase separation, simple and complex preservation, interfacial polymerization, and other methods well known to those of experience. ordinary in the art. The particles can be processed using methods for making microspheres or microcapsules known in the art. The preferred manufacturing methods are by spray drying and freeze-drying, which involves the use of a solution that it contains the conductive / charged materials, the spray of the solution on a substrate to form droplets of the desired size, and the elimination of the solvent. III. Uses for conductive formulations Formulations capable of altering the biophysical properties of the mucosal coating within the body have been developed for distribution by any of the available routes and can be used for several different purposes: the reduction of the dispersion of infectious diseases ( viral and bacterial) such as SARS, influenza, tuberculosis and RSV in humans and the hoof and mouth disease in cloven leg animals; relief of respiratory tract irritation and congestion due to respiratory conditions that include acute infection (eg, common cold), asthma, chronic bronchitis, emphysema, bronchiectasis; minimization of environmental pollution due to particulate formation during breathing, coughing, sneezing or conversation (which is particularly important in clean room applications); the decrease or prevention of the appearance of obstructive sleep apnea, some cases of irritable bowel syndrome, chronic obstructive pulmonary disease (COPD), cystic fibrosis, and dysentery; and control of the absorption kinetics of drug molecules and pathogens.

, Administration of Drug Distribution Formulations I In one modality, the conductive formulation I have a suitable drug and conductivity to increase the viscoelasticity of the mucosal membrane at the site (ie the administration of the formulation), the drug may be a conductive agent, or the formulation may contain a drug and a conductive agent. conductive formulation can be administered via inhalation to interact with the air / liquid interface of the tracheobronchial mucus layer to modify the biophysical properties of the mucus layer and increase drug distribution and diffusion through airway cells Alternately, the formulation can be administered parenterally, orally, rectally, vaginally or topically, or by administration to the ocular space to interact with other mucosal surfaces. In some cases, it has been noted that the high viscoeljasticity of the sputum causes a more macropowder transport of the particles (Sanders, N.N., De Smedt, S.C., Rompaey, E.V., Simoens, P., De Baets, F. &; Demeester, j. (2000) Am J Respir Crit Care Med. 162, 1905-1911. ). Therefore, these formulations can cause a net force or gradient of the air / liquid interface to the cells for increased absorption of the drug. lisaistratio of Formulas lati-aes Pre-Treatment of Drug Distribution Conductive formulations can be used as a! "pre-treatment" of drug distribution. In one embodiment, a conductive formulation is distributed, and then a drug formulation is distributed to the patient. The drug can be any of a wide range of drugs including anti-viral, siRNA formulations, and liposomal formulations. When the conductive formulation is administered via inhalation, the conductive formulation is designed to alter the interfacial biophysical properties for the airway lining fluid by increasing or distributing its elasticity, depending on the desired result, to improve the subsequent distribution. of the drug Alternatively, the formulation can be administered parenterally, orally, rectally, vaginally, or topically, or by administration to the ocular space to interact with other mucosal surfaces. In some cases, it has been noted that the induction of large gradients in biophysical properties (surface tension) and viscoelastic properties) improve the transport or depth of immersion of submicron tefjLon particles (Im Hof, V., Gehr, P. , Gerber, V., Lee, M M. & Schurch, S. (1997) Respir. Physiol. 109, 81-93. and Schurch, S., Gehr, P., Im Hof, V., Geiser, M. & Green, F. (1990) j Respir Physiol. 80, 17-32. ). C Administration of Conducting Formulations to alter) Transport and Absorption of Pathogens In another embodiment, the conductive formulation has adequate conductivity to increase the viscoel'asticidad or alter the load gradient of the mucous membrane at the site of the administration of the formulation, to prevent or reduce the kinetics of absorption of the pathogens in the body. In some cases, it has been noted that the induction of large loading gradients improves the transport and adhesion of microbial agents (see Goldber ^, S, et al, J Bacteriology 172, 5650-5654 (1990)) and may alter the virus entry (Davis, HE, et al, Biophysi J, 86, 1234-1242 (2004)). The conductive formulation is designed to alter the interfacial biophysical properties for the airway lining fluid by increasing or decreasing its elasticity, depending on the desired result, or by altering the charge interaction in the fluid interface of the lining of the airways. Respiratory tract / torn from the respiratory tract. The formulation may contain cationic or anionic molecules to achieve this effect. This change in charge gradient subsequently prevents or retards the absorption and transport of a pathogen intracellularly or alters the liberation of the pathogen replicated again in the extracellular space. Alternatively, the loading gradient may alter the adhesion and immunogenicity of a pathogen. The conductive formulation is typically administered by inhalation. However, the formulation can also be administered parenterally, orally, rectally, vaginally, or topically, or mediated administration to the ocular space to interact with other mucosal surfaces. o Administration of the conductive formulations to reduce the amount of exhaled particles. In yet another embodiment, the conductive formulation contains a suitable conductivity to increase the viscoelasticity of the mucous membrane at the site of administration of the formulation, to suppress or reduce the formation of bioaerosol particles during breathing, coughing, sneezing and / or conversation. Preferably, the formulation is administered to one or more individuals who have bacterial or viral infections to decrease or limit; the spread of pulmonary infections to other animals or humans, especially viral or bacterial infections. Alternatively, the formulation can be administered to healthy individuals, or immunocompromised individuals to prevent or reduce the absorption of pathogens by the body.

Administration to the Respiratory Tract The respiratory tract is the structure involved in the exchange of gases between the atmosphere and the bloodstream. The lungs are branched structures that eventually end up in the alveoli where gas exchange occurs. The area of the alveolar surface is the largest in the respiratory system and is where drug absorption occurs. The alveoli are covered by an eciliate thin epithelium or a mucus layer and secrete phospholipids and surfactants. J. S. Patton & R. M. Platz 1992 Adv. Drug Del.

The respiratory tract includes the upper respiratory tract, including the oropharynx and larynx, followed by the lower respiratory tract, which includes the trachea, followed by bifurcations to the bronchi and bronchioles. The upper and lower airways are called the conductive airways. The terminal bronchioles are then divided into respiratory bronchioles that ultimately lead to the final respiratory zone, 1 the alveoli or the deep lung. The deep lung, or alveoli, is the main objective of inhaled therapeutic aerosols for the distribution of systemic drugs. The formulations are typically administered to an individual to distribute an effective amount for alter! physical properties such as surface tension and viscosity of the endogenous fluid in the upper respiratory tract, thereby increasing the distribution to the lungs and / or suppressing cough and / or improving clearance from the lungs. The effectiveness can be measured using a system as described below. For example, saline can be administered! in a volume of 1 gram to a normal adult. The exhalation of the particles is then measured. The distribution is then optimized to minimize the dose and j the number of particles. The formulations can be administered using a metered dose inhaler ("MDI"), a nebulizer, or using a dry powder inhaler. Suitable devices are commercially available and described in the literature. The aerosol dose, the formulations and the distribution systems can 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 i Reviews in Therapeutic Drug Carrier Systems, 6: 273-313, 1990; and in Moren, "Aerosol dosage forms and formulations," in: Aerosolis in Medicine, Principies, Diagnosis and Therapy, Moren,! et al., Eds. Esevier, Amsterdam, 1985 The distribution is achieved by one of several methods, for example, using a metered-dose inhaler that induces the HFA propellant, a metered-dose inhaler with non-HFA projpellant, a nebulizer, a pressurized can, I or a continuous sprayer. For example, the patient can mix a dry powder of the pre-suspended therapeutic product with solvent, and then nebulize it. It may be more appropriate to use a pre-nebulized solution, regulating the dose administered and avoiding the possible loss of suspension.

After the nebulization, it may be possible to pressurize the aerosol and have it administered through an inhaled dose inhaler (ID). Nebulizers create a fine mist from a solution or suspension, which is inhaled by the patient. The devices described in U.S. Patent No. 5,709,202 to Lloyd, et al., Can be used. An MDI typically includes a pressurized container having a metering valve, wherein the container is filled with the solution or suspension and a propellant. The solvent itself can function as the propellant, or the composition can be combined with a propellant, such as FREON® (E. I. Du Pont De Nemours and Co. Corp.). The composition is a fine mist when it is released from the container due to release in the pressure. The propellant and the solvent can evaporate completely or partially due to the decrease in pressure.

In an alternative embodiment, the formulation is in the; form of one or more salts or other conductive materials that are dispersed on or in the excipients.

The excipient is preferably a safe (harmless) and biodiable material. Typical excipients include dextran, lactose and mannitol. Individuals to be treated include those at risk of infection, those with a bacterial viral infection, patients with allergies, patients with asthma, and individuals who work with immunocompromised patients and infected patients. The formulation can be administered to humans or animals such as race horses, breeding cattle, or endangered captive animals to protect these animals from infection by viral diffusion. This can be achieved by placing a nebulizer system near the water stations triggering the production of the aerosol as the animals approach or leave the station. The formulation can be sprayed on animals as they walk through gutters or pens, or sprayed from spray trucks or even sprinkling the crop with airplanes. The individual battery powder rojciadores that are currently used to spray the insecticides can be adapted for use in the administration of the solutions to animals to minimize the formation of bioaerosol and / or dispersion. The formulation can be administered to humans or animals at the beginning of the viral or bacterial outbreak to prevent the spread of the disease to epidemic levels. Animals within a 10-kilometer radius of an FMD outbreak are currently considered to be infected. These animals are subsequently slaughtered and disinfected. This aerosol system can be administered immediately to the animals within this area of 10 km radius and an additional prescribed buffer zone outside this area to ensure the containment of the outbreak. The aerosol can then be administered for as long as necessary to ensure success, for example beyond the normal period between the first infection and the expression of the symptoms. The formulation can be administered to humans or animals by creating an aqueous environment in which humans and animals move or remain for a sufficient period of time to sufficiently treat the lungs. This atmosphere can be created by the use of a nebulizer or even a humidifier. Although it is described primarily with reference to pulmonary administration, it is understood that the formulations can be administered to individual or human animals at through [inhalation; parenteral, oral, rectal, administration! vaginal or topical; or by administration to the eye space I Other Methods for Altering the Load of the Mucosal Coating The alteration of the biophysical properties for the mucosal coating can also be achieved by alternative methods. In one method, the electrodes or patches are placed on the body of the individual to be treated and an electric field is stored. This can result in alteration of the charge location, ion concentration or ionic strength of the mucosal coating, and thus its biophysical properties are modified. The present invention will be further understood by reference to the following non-limiting examples. Examples Immune formulation of mucus and methods used was in vitro studies Mucus Mucus Formulation Weak polymer gels with rheological-mucosal properties similar to tracheobronchial mucus were prepared in a manner similar to those described by King et al. al, Nurs Res. 31 (6): 324-9 (1982) using locust bean gum (LBG) (ÍFluka BioChemika) in solutions that were cross-linked with sodium tetraborate (Na2B07) (J.T. Baker). LBG at 2% w / v was dissolved in boiling Milli-Q distilled water. HE I prepared a concentrated solution of sodium tetraborate in Milli-Q distilled water. After the LBG solution was cooled to room temperature, small amounts of the sodium tetraborate solution and the mixture were added.

I was rotated slowly for 1 minute (also referred to herein as "mucus mimetic"). A specific volume of the aqueous mucus mimetium was then placed on a trachea model 1 (a machined throat), creating a mimetic depth based on the geometry of the throat. The mimetic layers of mucus were left to crosslink 15 minutes before the beginning of the in vi tro experiments. The final concentrations of sodium tetraborate were in the range of 1 to 3 njM. Methods The following in vitro method was used to test the effectiveness of different formulations, such as saline or calcium chloride in saline. As described above, the mucus mimic was applied to a model trachea (throat) and allowed to reticulate 15 minutes. The throat was connected to a simulated breathing machine (a modification of a "coughing" machine by King et al. (M.

King, > jr. . Zahm, D. Pierrot, S. Vaquez-Girod, E. Puchelle, Biorheology (1989) 26: 737-745)). A respiratory event of the flow c.e prescribed air on the surface of the mimetic was initiated through the throat model (this simulated respiration on the mucus layer within the trachea). The Figure 1 is a schematic view of the simulated breathing machine that was used in the studies. The shear stress experienced on the mimetic surface caused the formation of aerosol particles that were trapped in the air stream and carried downstream. An optical particle counter (OPC) (number 20 in Fig. 1) (CLiMET Instruments, Redlands, CA) was placed downstream of the throat to count and measure the size of the aerosol particles generated. ? The entire in vitro test system is shown in Figure 1. The components are as follows: Pressure regulator Compressed air tank - Provides pressurized air I al | 10 nm Teflon membrane Filltro system - Filter the air I cushioned to ensure low particle counts before the air enters the Bijo-bell Baker system - Prevents the addition of particles from the atmosphere . Safety air relief valve - Prevents system pressurization 6. Air-tight 6.2 liter pressurized container - Provides controlled release of pressurized air to the system (mimics the capacitance function of lungs) 7. Pressure gauge LED 8. Two-way solenoid valve Asco- Electromechanical switch to control the distribution of pressurized air to the throat 9. Open / closed switch for the solenoid valve i 10. Fleisch pneumotach No. 4- Provides laminar air flow 1 pressure transducer 11. Validyne pressure transducer DP45 - Measures the head loss through the p12 pneuotachograph. Pall Conserve filter - Prevents particles generated from the mechanical action of the solenoid valve from entering the system 13. Demodulator / amplifier of signals Validyne CD15 Manipulates the electrical signal received from the transmission transducer for the system a of data acquisition 14. Trachea model (throat) - Machined acrylic of 30 cm x: 1.6 cm x 1.6 cm (L x W x H) to simulate the trachea 15. Adjustable platform - Level the throat lajs aerosol droplets by means of laser diffraction.

The OPC CLiMET extracts a current of air through the path of a laser beam at 1 CFM. The particles inside the air stream cause the laser light to diffract when they are hit by the beam, and the intensity of the diffracted light is measured. The intensity and frequency of the diffraction are then used to calculate the total number of particles as well as their physical size. ! An alternative method can be used that uses' labeled nanoparticles that are incorporated into the miniature, then carried downstream into the aerosol droplets and collected from the use of a filter. placed at the exit of the throat for later analysis. A variety of formulations were tested to determine their appearance on the biophysical properties of the mucosal coating, such as surface viscoelasticity and surface tension. Each formulation was introduced onto the mucus layer by aerosolization of the formulation using an appropriate aerosolization method. For solutions / suspensions, an Aeroneb Go nebulizer (Aerogen, Mountain View, CA) was used. The Aeroneb Go nebulizer uses vibrating screen technology to air-ionize the solution. The aerosolization time was established for 2 minutes for all tests. The mimetic was placed at the entrance to the throat and the air pressure was set at 0.21 kg / cm2 (3 psi), mimicking a coughing event. These conditions were selected based on the optimized tangent and the normal stresses that occur on the bulk mimic i to minimize the movement of the mimetic inside the liquid valve / trap and the spatter of the bulk mimic on the walls of the throat. Example ls Study? N Vitro using the SWl apparatus on the Effect of Different Formulations on the Number of Particle Counts Four formulations were tested in vi tro using the SRM apparatus described above and compared against the mucus mimic alone (simulated) that was used as a reference. The production of the mucus mimetic and the SRM method described above were used in each e > waste. The following formulations were tested: (1) 0.9% isotonic saline, (2) 1.29% calcium chloride (CaCl2) dissolved in 0.9% isotonic saline, (3) 0.1% sodium dodecyl sulfate (SDS) dissolved in solution I saline isotonic 0.9%, and (4) 1% dextran dissolved in 0.9% isotonic saline. The height of the mimetic applied to the throat was maintained at a constant height of 2 mm (total mimetic volume of 6.4 ml) for all tests. The mimetic was cross-linked for 15 minutes and each formulation was then aerosolized on the mimetic using Aeroneb Go (Aerogen, Mountain View, CA) for 2 minutes before the test. Each test was repeated at at least three times and the cumulative particle counts averaged and the standard deviation values were then calculated. These results are graphically described in Figure 2. As shown in Figure 2, each formulation demonstrated the suppression of particles of an order of magnitude or greater. Isotonic saline solution containing CaCl2 shows the highest suppression of particles, for example, three orders of magnitude.

Example 2% Effect of the Formulations (in Aqueous Solution Saline Solutions) on the Reduction of the Particles Sprayed Aerosol as Measured in Vitro using the SMR Apparatus To further understand the mechanism underlying the suppression of particles, formulations were prepared in deionized water (DI) and in saline. The production of mucus mimetic and the SRM method described above were used in each experiment. The height of the mimetic applied to the throat was kept constant at 2 mm (6.4 ml total mimetic volume) for all tests. The mimetic was cross-linked for 15 minutes and each formulation was aerosolized on the mimetic using Aeroneb Go (Aerogen, Mountain View, CA) for 2 minutes before the test. Each test was repeated at least three times and the cumulative particle counts, average and standard deviation values were then i! calculated. The results are graphically described in Figure 3. As shown in Figure 3, when the saline solution used in a given formulation is replaced with deionized water (DI), the operation of particle suppression of the given formulation decreases. For calcium chloride, the ability of the formulation to suppress particle formation decreased only slightly when the saline solution was replaced with DI water, and the DI water and the saline formulations containing calcium chloride were better at particle suppression than the saline solution alone. However, for formulations containing SDS or dextran, the amount of suppression becomes negligible when the saline solution is replaced with DI water. These results indicate that the salts (sodium chloride and calcium chloride) play a key role in the suppression of particle formation. The 3s Conductivity Values of the Different Formulations and the Effect of the Conductivity of the Formulation on the Cumulative Particle Accounts as Measured in Vitro using the SRM Apparatus To determine the effect of the charge / ductuctivity of a formulation on the suppression of the particle formulation, the conductivity of different formulations was measured and graphically plotted against the cumulative particle counts. The following ten formulations were tested: (1) 0.45% saline, (2) 0.9% isotonic saline, (3) 1.45% saline, (4) calcium chloride in isotonic saline (1.29%), (5) calcium chloride in DI water (1.29%), (6) calcium chloride in DI water (1.87%), (7) SDS in isotonic saline solution (0.1%), (8) SDS in DI water (0.1%), (9) Dextran in isotonic saline solution (1%), and (10) Dextran in water DI (1%). The conductivity value for each of the different formulations and for the mucus mimic was measured using the zetaizer device Brookhaven ZetaPALS (Brookljtaven Instruments, Holtsville, NY). This instrument measures the zeta potential of a given solution / formulation by first measuring its conductivity (to determine the strength of the applied electric field) and then optically measuring the mobility of the solution. Conductivity is reported t before the start of the zeta potential measurement, and this value is reported in Table 1. Conductivity is the reciprocal j of the electrical resistance of a given sample, and is dependent on force / concentration. of the load inside the sample, as well as the mobility of the load. A geometric correction factor is applied (called the constant of the measurement cell, I determined by dividing the length of the cell between the electrode area) which results in the j conductivity being reported as the specific conductivity with micro-Sieraens units per centimeter Table L Conductivity of Ten formulations and mucus mimic Specimen Specific Conductivity Moco 528 Salina 0.45% 12,232 Saline Isotonica 0.9% 23,829! Salina 1.45% 33,989? C Cl2 1.29% (Saline Isotonica) 37, 586: CaCl2 1.29% (DI Water) 24,931 t I CaCl2 1.87% (DI Water) 30, 187 I SDS 1% (Isotonic Solution) 24, 045 SDS 0.1% (DI Water ) 103 lj) extrano 1% (Saline Solution 20, 689 Isotonic) 1 Dextran 1% (DI Water) 60 i The SRM test and mucus mimic production described above were used in this study.

CA) pojr 2 minutes before the test. Each test was repeated at least three times and the particle counts, average cumulative values and the values of the standard deviation were then calculated. Figure 4 is a graph of the conductivity of that formulation versus the exhaled particle counts for that formulation (from the SRM in vi tro tests). As shown in Figure 4, a strong correlation between conductivity and exhaled particle counts is evident, for example, the greater the conductivity, the lower the total particle count. In this way, formulations with higher conductivities result in greater suppression of the aerosol droplets. Example s Comparison of the conductivity and loss tangent values (measured by an interfacial tension factor) The values for G ', G ", G * and Tan d were obtained using an interfacial tension rheometer (ISR) for eg mucus mimic as well as the mimetic with one of several formulations (0.9% sodium chloride in water (isotonic saline), 1.29% calcium chloride in saline, i 0.1% SDS in saline and 1.0% dextran in saline) aerosolized on surfaces The ISR used a magnetized rod with a small proportion of diameter to length (in order to obtain data in an interface and limit the effects of the volume.) The rod was placed on the surface of the sample that was contained in a small gargantuan. An oscillating magnetic field (with a frequency of 0.25 Hz to simulate respiration) was applied through j of the sample as the tension, causing the rod to move along the length direction.

An optical camera captured the movement, and the image recognition software was used to calculate the response (the distance the rod moved or the tension moved). G ', G ", G * and the loss tangent (Tan d) were then determined from this information, Figure 5 is a graph showing the tangent of loss versus conductivity versus each formulation, a correlation can be observed. where the smaller the loss tangent (indicating a more elastic sample), the greater the conductivity.When these idates are compared with the correlation found between the conductivity and the exhaled particle count (Example 3), this demonstrates a relationship in where the count of exhaled particles decreases as the conductivity (increased resistance / concentration and load mobility) increases and the loss tangent decreases (increasing the elasticity in relation to the viscosity) .This suggests a potential mechanism by which the exhaled particle count is suppressed: the addition of the charge through the application of an aerosolized formulation on the surface of the mimetic alters the viscoelasticity of the mimetic, decreasing the loss tangent and increasing the mechanical rigidity of the surface (G *) through the increased cross-linking and chemical bonding on the surface of the mimetic. Example 5s Effectiveness of Different Formulations with Different Conductivity Values on the Suppression of Particle Formation when Subjected to Shear Effort at 0.28 kg / cm2 (4 psi) i To further distinguish the effect of conductivity / charge on particle suppression For different formulations, the pressure used in the SRM test was increased from 0.21 kg / cm2 to 0.28 kg / cm2 (3 to 4 psi). Four formulations, saline and isotonic, calcium chloride at 1.29%, dissolved in isotonic saline, calcium chloride at 1.29% dissolved in DI water and 1.8% saline, were used in the tests. The conductivity values of the four formulations are tabulated in Table 2. The conductivity value i for each of the different formulations was measured! using the Brookhaven ZetaPAiLS zetasizer apparatus (Brookhaven Instruments, Holtsville, NY) as described above in Example 3.

Table 2s Conductivity values of the formulations Sample Specific Conductivity (pS / caa) Saline 0.9% 23829 Saline 1.8% 42201 Ca | ci2 1.29% (Saline Isotonic) 37586 CaCl2 1.29% (Water DI) 24931 The production of the mucus mimic and the method < of SRM described above were used in each experiment. The height of the mimetic applied on the throat was kept constant at 2 mm (6.4 ml total mimetic volume) for all the tests. The mimetic was reticulated for 15 minutes and each of the formulations was then aerosolized on the mimetic using Aeroneb.

Go (A rogen, ountain Vie, CA) for 2 minutes before the test. Each test was repeated at least three times j and the cumulative particle counts, average and percentage suppression compared to the standard mucus mimic were then calculated and summarized in Figures 6A and 6B, respectively. As shown in Figures 6A and 6B, the higher the value of the conductivity of the formulation, the greater its capacity for particle suppression. It is noted that with respect to this date the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (21)

CLAIMS Having described the invention as above, the contents of the following claims are claimed as property:

1. A conductive biocompatible formulation, which comprises a charged compound, characterized in that the conductive formulation when administered to the mucosal lining fluid or to the mucosal lining of a human or other animal, alters the surface viscoelastic properties of the mucosal lining fluid as defined by tangent loss (Tan d), surface tension or viscosity.

2. The formulation according to claim 1, characterized in that it is selected from the group consisting of aqueous solutions, dry powders, vapors, aqueous suspensions, non-toxic solutions or suspensions, and different dry solid dosage forms.

3. The formulation according to claim 1, characterized in that it is formulated for administration to a region selected from the group consisting of the respiratory tract, the gastrointestinal tract, the reproductive organs, the ocular region i and the otopharynx or the nasal cavities.

4. The formulation according to claim 1, characterized in that the charged compound is selected from the group consisting of salts, ionic surfactants, charged amino acids, charged proteins or peptides, charged nucleic acids, and combinations thereof.

5. The formulation according to claim 1, characterized in that it also includes an active agent selected from the group consisting of nucleic acids, proteins, carbohydrates, amino acids, inorganic substances and organic substances.

The formulation according to claim 4, characterized in that the charged compound is a salt selected from the group consisting of sodium chloride, sodium acerate, sodium bicarbonate, sodium carbonate, sodium sulfate, sodium stearate, ascorbate sodium, sodium benzoate, sodium bisphosphate, sodium phosphate, sodium bisulfite, sodium citrate, sodium borate, calcium chloride, calcium carbonate, calcium acetate, calcium gluconate, calcium phosphate, alginate calcium, calcium stearate, calcium sorbate, calcium sulfate, magnesium carbonate, magnesium sulfate, magnesium stearate, magnesium trisilicate, potassium bicarbonate, potassium chloride, potassium citrate, potassium borate, bisulfide or potassium, potassium bisphosphate, potasip alginate, potassium benzoate, magnesium chloride, sulfate cupric, chromium chloride, stannous chloride, and sodic metasilicate and combinations thereof.;

7. The formulation according to claim 4, characterized in that the compound cargadb is an ionic surfactant selected from the group consisting of sodium dodecylsulphite (SDS), magnesium lauryl sulfate, polysorbate 20, pol i soir ato 80 , triflate of 1,2-dioleoyl-sn-glycero-3-ethyljf osf ocolina (EDOPC) and alkyl-phosphocbline trimesters.

8. The formulation according to claim 1, characterized in that it comprises saline solution and calcium chloride.

9. The formulation according to claim 1, characterized in that the formulation i has a conductivity greater than 5,000 pS / cm.

10. The formulation according to claim 9, characterized in that the formulation has a conductivity moon greater than 10,000 pS / cm.

11. The formulation according to claim 10, characterized in that the formulation has a conductivity greater than 20,000 i μ = / cm.

12. The formulation according to claim 1, characterized in that the formulation is capable of altering the viscoelasity of the mucosal lining, so that d is greater than 45 ° and less than 90 °.

13. The formulation according to claim 1, characterized in that the formulation is capable of altering the viscoelasticity of the mucosal lining, so that d is greater than 0o and menoi: from 45 °.

14. A method for decreasing particle exhalation or reducing intracellular transport of pathogens in an individual, characterized in that it comprises administering to a mucosal coating in the individual, an effective amount of a biocompatible formulation comprising a charged compound, wherein the formulation is administered in an effective amount to increase the strength of the mucosal lining and modify the viscoelasticity of the mucosal lining, so that Tan d is less

15. The method according to claim 14, characterized in that the formulation has a conductivity greater than 5,000 yS / cm.

16. A method for increasing drug absorption in an individual, characterized in that comprises administering to a mucosal lining in an individual, an effective amount of a first biocompatible formulation comprising a charged compound, wherein the absorptive and diffusive properties of the mucosal lining and to modify the viscoelasticity of the mucosal lining, ijie Tan d is greater than 1.0

17. The method according to claim 16, characterized in that the formulation also comprises an active ingredient.

18. The method according to claim 16, characterized in that it further comprises administering a second formulation to the mucosal coating after administration of the first formulation, wherein the second formulation comprises an active agent.

19. A method for reducing or preventing the occurrence of obstructive sleep apnea, irritable bowel syndrome, chronic obstructive pulmonary disease (COPD), cystic fibrosis, or dysentery in an individual, characterized by the purchase of a mucosal lining. in? the individual, an effective amount of a biocompatible formulation comprising a charged compound -

20. The method according to any of claims 14 to 19, characterized in that the formulation is administered to the respiratory tract in the form of an aerosol.

21. The method according to any of claims 16-18, characterized in that the first formulation is administered parent erally e, orally, rectally, vaginatly, topically, or by inhalation. SUMMARY OF THE INVENTION: Conductive formulations are described which contain conductive agents, such as salts, ionic surfactants or other substances that are in an ionized or easily ionized state in an aqueous or organic solvent environment, and methods of use. One or more active agents such as antivirals, antimicrobials, anti-inflammatories, proteins and peptides, may optionally be included with the formulation. The active agent can be administered with or incorporated into the formulation, or it can be administered after the conductive formulation is administered. When applied to mucosal lining fluids, the formulation alters the physical properties such as surface tension, surface elasticity and apparent viscosity of the mucosal lining. The formulation is administered in an amount sufficient to alter the biophysical properties in coatings and mucosal membranes of the body. The formulation can be administered for a number of different purposes: reduce the spread of infectious, viral and bacterial diseases, such as SARS, influenza, tuberculosis and RSV in humans, and hoof and mouth disease in hoofed animals; minimize the environmental pollution due to the formation of particles during breathing, coughing, sneezing or conversation, which is particularly important in clean room applications; the reduction or prevention of the appearance of obstructive sleep apnea and some cases of irritable bowel syndrome; and the control of the absorption kinetics of the drug molecules and pathogens.