Inhalable therapeutic agent

Abstract

To provide a therapeutic agent for treating airways of a subject.SOLUTION: The present invention provides a therapeutic agent comprising one or more types or sizes of particles, each particle comprising a biodegradable enclosure containing a mucolytic or another drug therein. A dispersing apparatus may be used to deliver metered doses of mucolytic and may be configured for self-administration by the subject. Encapsulation of the mucolytic in a liposomal formulation may prevent premature oxidation and maintain drug efficacy upon delivery to a target location in upper or lower respiratory tract.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross-reference data This patent application claims the benefit of the filing date of U.S. Provisional Patent Application No. 62809316, entitled "Specific Inhaled Formulations of Small and Large Molecules as Therapeutic Agents," filed on February 22, 2019, by the same inventor, which is hereby incorporated by reference in its entirety.

Background Art

[0002] Without limiting the scope of the present invention, its background related to inhalable therapeutic agents will be described. More specifically, the present invention describes inhalable particles containing a mucolytic agent contained within a biodegradable capsule, such as a liposomal formulation, for treating lung, airway, and respiratory diseases.

[0003] The main function of the respiratory system is to draw air into the lungs of a subject, circulate through the lung tissue, and effect gas exchange with the blood that perfuses it. The lungs are the most important respiratory organs of the body, where normal gas exchange of essential oxygen, carbon dioxide, and carbon monoxide occurs effectively and efficiently. The lungs perform their gas exchange function because this gas exchange occurs directly in contact with and is exposed to the outside air and environment. To perform this essential role, the epithelial lung tissue is kept moist with a thin film of mucus containing water, which mucus contains various proteins including mucin, physiological cations and anions maintained at an aqueous osmotic concentration, such as sodium ions, potassium ions, calcium ions, chloride ions, bicarbonate ions, carbonate ions, phosphate ions, in addition to other proteins and enzymes.

[0004] The mucus transport system is a basic defense of the airways against inhaled pieces of necrotic tissue, bacteria, and other infectious pathogens. Inhaled foreign particles are trapped in the mucus layer and subsequently pushed out of the lungs via mucociliary clearance. Sufficiently hydrated mucus facilitates such ciliary clearance of these foreign agents and keeps the respiratory tract protected. Mucociliary clearance (MCC) in a healthy and normal lung is promoted by the movement of cilia that removes the hydrated mucus / fluid and is also promoted by the cell's ion transport systems, such as the sodium ion and chloride ion transport systems. In the absence of sufficient mucus hydration and functioning cilia and ion transport systems, the mucus becomes overly viscous, adheres, and forms "mucus plugs." This results in airway obstruction, inadequate respiration (insufficient oxygen exchange), as well as recurrent lung, airway, and ear infections. Recurrent infections can cause permanent lung damage and lead to respiratory failure.

[0005] The initial causes of various respiratory diseases can be diverse. These include not only environmental exposures to various compounds, free radicals, reactive oxygen species (ROS), etc. (such as through smoking, toxic exposures, chronic respiratory infections, etc.), but also genetic etiologies, for example, mutations in functional proteins in cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). In various respiratory and lung diseases, it is widely established that common symptoms of the diseases are the absence or reduction of normal mucus clearance, and the formation of thick, viscous, and sticky mucus or sputum. The increasing viscosity and adhesiveness of mucus or sputum are thought to be caused by an increase in chronic "oxidative stress" and changes in the state of mucus brought about by the lack of water content and movement of mucus, and its common components are normal mucus proteins such as mucin and other proteins oligomerized through the formation of multiple intermolecular and intramolecular disulfide bonds. To this is added an increase in non-covalent protein-protein interactions, which further aggregates the protein(s) structure due to an increase in hydrogen bonds as well as hydrophobic intermolecular and intramolecular protein interactions. These molecular changes / interactions increase the elasticity and viscosity of the naturally maintained mucus, thereby reducing the efficiency of the natural mucus clearance mechanism and system. Mucus clearance is also hampered by the dysfunction of cilia (small hair-like structures lining the respiratory tract) and ion transport proteins caused by genetic mutations in the relevant proteins. In summary, the resulting intermolecular and intramolecular disulfide bonds between proteins, as well as various hydrogen bonds, hydrophilic and hydrophobic protein-protein interactions, cause changes in the normal mucus structure and the construction and maintenance of protein oligomerization, thereby resulting in a reticular protein network generally known as a "mucus plug". Furthermore, inflammatory processes, including the mobilization of neutrophils to the site of inflammation, toxic exposures, or infections, result in an increase in the oxidative environment with accompanying cell death, which in turn leads to the accumulation of necrotic tissue fragments including DNA, lipids, fibrin, and foreign particles, as well as pathogens, resulting in thick mucus that is too viscous and adhesive for normal flow and removal. The decrease in MCC in turn plays a role in exacerbating the mucus plug and provides a rich growth environment for bacterial growth in the respiratory tract.This cascade of molecular processes causes cumulative chronic respiratory disorders, recurrent airway, lung, and nasal infections, which are accompanied by persistence and progression to lung damage.

[0006] Structured, highly viscous mucus plugs are key signs in multiple lung diseases such as primary ciliary dyskinesia (PCD), cystic fibrosis, bronchiectasis, rhinosinusitis, paranasal sinusitis, and chronic obstructive pulmonary disease (COPD, an umbrella term used for a wide range of lung disorders such as emphysema and bronchitis). Aggregated mucus or sputum with a cohesive structure has a polymer composition and biophysical properties that vary according to the disease. The underlying causes of these diseases differ based on genetic and environmental factors, but a common feature in all these diseases is a decrease in mucus clearance, which leads to airway obstruction, capture of bacteria and pathogens, recurrent infections, and repeated inflammation. This in turn can gradually damage the lungs and ultimately cause respiratory failure and / or the need for lung transplantation.

[0007] Current standard treatments for most of these diseases (except for CF in certain populations) still focus on addressing symptoms and complications. These include: · Prevention, control, and treatment of lung, paranasal sinus, and ear infections (oral and IV antibiotics and anti-infectives) · Hydration and removal of thick, viscous mucus and sputum. (Humidifiers and bronchial lavage with saline) · Reduction of swelling and inflammation (corticosteroids and bronchodilators) · Dilation of the airways to facilitate breathing (bronchodilators) · Manual or device-assisted CPT (chest physical therapy). · Surgery (myringotomy, paranasal sinus surgery, lung transplantation)

[0008] Except for surgery, all of these methods show only slight or temporary relief and do not effectively address the underlying problems, which are the main causes, such as dyspnea, particulate necrotic tissue fragments and pathogens of trapped cells, recurrent infections, and irreversible progressive lung damage, of thick, viscous, and sticky mucus plugs.

[0009] Therefore, the compositions described in the present invention, which are safe, effective, and reliable therapeutic options, for example, to break the critical bonds that cause protein polymerization / mucus plug formation and thereby fluidize viscous mucus, are highly needed to address and alleviate the underlying problems in many rare and common lung and respiratory / lung diseases and to promote MCC. This should significantly improve the quality of life of patients with the above-mentioned diseases. It should, firstly, fluidize mucus, remove airway obstruction, improve gas exchange, and address respiratory disorders, and secondly, prevent recurrent infections by completely exposing pathogens to antibiotics (previously shielded by mucus plugs), thereby making other interventions more effective, and thirdly, prevent permanent lung damage.

[0010] There is also a need to protect the mucolytic agent from oxidation while it is being delivered to the site of treatment. Certain mucolytic agents may be easily oxidized before reaching their target, thereby potentially reducing their effectiveness. This can be explained by the inconsistent results in clinical trials. There is a need to protect the mucolytic agent from oxidation to maximize its potency. SUMMARY OF THE INVENTION

[0011] Accordingly, it is an object of the present invention to overcome these and other drawbacks of the prior art by providing a novel inhalable therapeutic agent that enables effective dissolution of mucus.

[0012] Another object of the present invention is to provide a novel inhalable therapeutic agent designed to provide effective treatment with lower doses of drugs, reduce possible side effects, and enable administration in repeated applications performed multiple times.

[0013] A further object of the present invention is to provide a novel inhalable therapeutic agent configured to be administered either by a medical professional or self-administration so as to be suitable for home delivery of such treatment.

[0014] Yet another object of the present invention is to provide a novel inhalable therapeutic agent configured to protect an active drug from oxidation and loss of mucolytic activity before directly delivering it to a target site in the airway, thereby maintaining its efficacy until it directly interacts at the target site.

[0015] In its most basic form, the present invention can be described as at least one or several inhalable particles. Each particle can contain a mucolytic agent or another suitable active therapeutic agent contained within one or several types of biodegradable capsules. The number and respective concentrations of therapeutic agents containing at least one type of mucolytic agent, the type of biodegradable capsule selected for each therapeutic agent, and the size of the inhalable particles can be adjusted according to the specific type of airway disorder so as to deliver the drug therapy intended to effectively treat the underlying condition to the intended location in the airway.

[0016] In an embodiment, inhalable particles of at least two types and / or sizes may be enclosed within a single nebulizer configured to be self-administered by a subject in repeated applications based on a predetermined schedule. At least one of such inhalable particles can contain a mucolytic agent within a biodegradable capsule such as a liposome formulation, microspheres, nanoparticles, or engineered spray particles.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The following description sets forth various examples along with specific details in order to provide a thorough understanding of the claimed subject matter. However, one of ordinary skill in the art will understand that the claimed subject matter may be practiced without one or more of the specific details disclosed herein. In addition, in some instances, well-known methods, procedures, systems, components, and / or circuits have not been described in detail so as not to unnecessarily obscure aspects of the claimed subject matter. The exemplary embodiments described in the detailed description and claims are not meant to be limiting. Other embodiments may be utilized and other changes may be made without departing from the spirit or scope of the subject matter presented herein. Aspects of the present disclosure, as generally described herein, can be arranged, replaced, combined, and designed in a variety of different configurations, all of which are clearly contemplated and will be readily understood to form part of the present disclosure.

[0018] The present invention aims to directly address the underlying conditions of respiratory diseases, namely, mucus plugs, reduced mucociliary clearance, and subsequent resultant events, using inhalable particles comprising a biodegradable enclosure containing a pharmaceutical composition of compounds consisting of amino acid derivatives, natural and synthetic peptides, small molecules, vitamins, and / or proteolytic and DNA-cleaving enzymes as hereinafter specified. These molecules can be designed and selected to cleave disulfide and other bonds, increase the concentration / potential of local antioxidants, aggregate, and cleave and disrupt hydrogen bonds and hydrophobic interactions in altered mucus proteins, as well as nucleic acids and lipids. Further, the inhaled biodegradable particles may optionally be formulated to contain a drug, molecular entity, or other agent, alone or in various combinations of two or more of these functional agents encapsulated within the same enclosure or separate enclosures of the same or different sizes. These separately formulated enclosures containing different drugs / agents can optionally be administered together or sequentially at different times to enhance their individual effectiveness in treatment.

[0019] The present invention encompasses therapeutic agents and methods for their direct pulmonary administration through any one or more of the routes including intranasal, intratracheal, and intrabronchial instillation. The particles of the present invention may be delivered by directly administering inhalable liposomes, microspheres, and nanoparticles to the lungs and respiratory tract. Further, the inhalable particles of the present invention may be placed by direct injection, inhalation, nebulized inhalation, aerosolized inhalation, or via the airway route by nebulization, or aerosolization, or inhalation. Methods for this direct delivery by inhalation or intranasal route envision the use of a dispenser capable of delivering drug-encapsulated particles via the inhalation and / or intranasal route, such as an aerosolized metered-dose inhaler, a handheld portable nebulizer, or a compressor-driven nebulizer inhalation device. Further, the particles of the therapeutic agents of the present invention may be stored in the form of a dry powder (such as for a metered-dose inhaler) or in the form of a liquid (such as for a nebulizer).

[0020] In embodiments, the dispenser includes a compressed / pressurized inhalable aerosol delivery device, which may optionally be equipped with a smart digital measurement function for monitoring patient compliance. Such devices include, but are not limited to, a pulsating membrane nebulizer, a vibrating mesh nebulizer, a small volume nebulizer, a pressurized metered-dose inhaler, a dry powder inhaler, and similar devices capable of delivering by inhalation a dry powder containing the particles of the present invention or a liquid containing these particles. Such a dispensing device may have one or more separate drug-containing chambers containing the inhaled particles as described hereinafter and configured to administer such particles simultaneously or sequentially according to a predetermined schedule.

[0021] For the purposes of this specification, the terms "enclosure", "capsule", "liposome", "formulation", and "coating" are used interchangeably to describe biodegradable particles containing a drug suitable for the treatment of the respiratory tract. The term "biodegradable" is used herein to describe a biocompatible material that degrades upon contact with the tissues of the respiratory tract and releases the drug contained therein. The release of the active drug from these enclosures may be an immediate release, controlled release, sustained release, and / or slow release process. Additionally, various particles may be combined together to effect slow release of the desired drug at predetermined intervals.

[0022] In embodiments, exemplary liposome delivery vehicles may include closed vesicles, colloids, bilayer structures formed by lipids, phospholipids, sphingolipids, glycolipids, long-chain fatty acids, and biologically acceptable surfactants that form liposomes of various sizes and compositions. Specific compositions may be inhalation liposome formulations, but encapsulating these molecules, compounds, agents, and / or enzymes may contribute to generating a physiologically compatible drug delivery vehicle for these drugs / agents.

[0023] Inhaled liposome formulations may be individually tailored to the target location of the diseased respiratory site and administered directly thereto, thereby avoiding the systemic drug exposure caused when the drug or agent is administered intravenously, intraarterially, intramuscularly, or in an oral formulation. This can consequently enable a significant reduction in the dosage of these agents, which in turn can alleviate many of the associated side effects.

[0024] Liposomes and nanoparticles are unique drug carriers that can deliver drugs site-specifically while protecting the drugs from interactions with the environment (such as blood, metabolism, exposure to air, etc.). As such, these vehicles are suitable for protecting mucolytics or other selected drugs from early oxidation and thereby maintaining their efficacy until the drugs are released at the target site. Specific to the structure / formulation of liposomes are certain phospholipids, surfactants, and other aqueous excipient molecules. When delivered to the targeted site, these components can liquefy mucus by disrupting the hydrophobic interactions within and between these proteins and further contribute to penetration of the mucus through the lipids.

[0025] The main functional drug to be contained within the biodegradable capsule is a mucolytic. Generally, such mucolytics can contain amino acid derivatives, peptides, peptide analogs, and / or small molecules as active agents, either alone or in combination with one or more of the agents. In embodiments, such mucolytics can be selected from the following compounds: · N-acetylcysteine at a concentration of about 5% to about 25%, such as 5%, 10%, 15%, 20%, 25%, or any concentration therebetween as the invention is not limited in this regard; · 2-mercaptoethanesulfonate at a concentration of about 5% to about 25%, such as 5%, 10%, 15%, 20%, 25%, or any concentration therebetween as the invention is not limited in this regard; · L-α-ureido-mercaptopropionic acid at a concentration of about 50 mg / ml to about 250 mg / ml, such as 50 mg / ml, 100 mg / ml, 150 mg / ml, 200 mg / ml, 250 mg / ml, or any other concentration within this range as the invention is not limited in this regard; · Bromhexine; · Ascorbic acid, such as vitamin-C (reduced ascorbic acid or its ascorbate); · N-butylcysteine; · Reduced glutathione, for example, the natural tri - peptide glutathione in its reduced form; · N - derivatives and C - derivatives of the amino acid cysteine; · Di - peptides of cysteine and glutamic acid; · Di - peptides of aspartic acid; · Ambroxol hydrochloride; · DNase, for example, recombinant DNase; and · DNA - cleaving agents.

[0026] In an embodiment, the active agent may comprise an amino acid derivative selected from D - and / or L - isomer derivatives according to the following formula:

Chemical formula

[0027] In a further embodiment of the present invention, the mucolytic agent may be an amino acid derivative, for example, D - and / or L - isomers of an amino acid derivative according to the following formula:

Chemical formula

[0028] In a further embodiment of the present invention, the mucolytic agent may be a peptide or a peptide analogue, for example, D - and / or L - isomers of an amino acid according to the following formula:

Chemical formula

[0029] In still a further embodiment of the present invention, the mucolytic agent may be a peptide or a peptide analogue, for example, D - and / or L - isomers of an amino acid in a peptide according to the following formula:

Chemical formula

[0030] In still other embodiments, the mucolytic agent may be vitamin-E, or small molecules such as sodium 2-mercaptoethanesulfonate or tris(2-carboxyethyl)phosphine hydrochloride.

[0031] Since mucus can serve as a form of bacterial covering, commonly used antibiotics may not be able to reach and attack these bacteria. Destroying the structured mucus and subsequently liquefying it may enable the antibiotics to reach the pathogens and bacteria and eliminate the infection. Therefore, the present invention further includes not only the inhalable liposomal formulation of the mucolytic agent but also the simultaneous or sequential administration of an antibiotic, antiviral, antifungal, or another anti-infective compound.

[0032] In embodiments, as anti-infective agents, quinolones (e.g., nalidixic acid, cinoxacin, ciprofloxacin, norfloxacin, etc.), sulfonamides (e.g., sulfanilamide, sulfadiazine, sulfamethoxazole, sulfisoxazole, sulfacetamide, etc.), aminoglycosides (e.g., streptomycin, gentamicin, tobramycin, amikacin, netilmicin, kanamycin, etc.), tetracyclines (e.g., chlortetracycline, oxytetracycline, methacycline, doxycycline, minocycline, etc.), para-aminobenzoic acid, diaminopyrimidines (e.g., trimethoprim (often used in combination with sulfamethoxazole), pyrazinamide, etc.), penicillins (e.g., penicillin G, penicillin V, ampicillin, amoxicillin, bacampicillin, carbenicillin, carbenicillin indanyl, ticarcillin, azlocillin, mezlocillin, piperacillin, etc.), penicillinase-resistant penicillins (e.g., methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin, etc.), first-generation cephalosporins (e.g., cephradroxil, cephalexin, cefradine, cephalothin, cephapirin, cefazolin, etc.), second-generation cephalosporins (e.g., cefaclor, cefamandole, cefonicid, cefoxitin, cefotetan, cefuroxime, efuroxime axetil, cefinetazole, cefprozil, loracarbef, ceforanide, etc.), third-generation cephalosporins (e.g., cefepime, cefoperazone, cefotaxime, ceftizoxime, ceftriaxone, ceftazidime, cefixime, cefpodoxime, ceftibuten, etc.), other beta-lactams (e.g., imipenem, meropenem, aztreonam, clavulanic acid, sulbactam, tazobactam, etc.), beta-lactamase inhibitors (e.g., clavulanic acid), chloramphenicol, macrolides (e.g., erythromycin, azithromycin, clarithromycin, etc.), lincomycin, clindamycin, spectinomycin, polymyxin B, polymyxins (e.g., polymyxin A, B, C, or D, E1 Colistin A), or E 2 , colistin B or C, etc.) colistin, vancomycin, bacitracin, isoniazid, rifampin, ethambutol, ethionamide, para - aminosalicylic acid, cycloserine, capreomycin, sulfonamides (e.g., dapsone, sodium sulfoxone, etc.), clofazimine, thalidomide, or any other antibacterial agent that can be encapsulated in lipids. As anti - infective agents, antifungal agents, for example, polyene antifungal agents (e.g., amphotericin B, nystatin, natamycin, etc.), flucytosine, imidazoles (e.g., miconazole, clotrimazole, econazole, ketoconazole, etc.), triazoles (e.g., itraconazole, fluconazole, etc.), griseofulvin, terconazole, butoconazole, ciclopirox, ciclopirox olamine, haloprogin, tolnaftate, naftifine, terbinafine, or any other antifungal agent that can be encapsulated in lipids or form a complex with lipids, and pharmaceutically acceptable salts thereof, and combinations thereof can be mentioned.

[0033] In embodiments, two or more biodegradable particles may be contained together in a single therapeutic agent. For example, the therapeutic agent of the present invention may contain a combination of a first inhalable particle and a second inhalable particle in a nebulizer. Each of the first inhalable particles may in turn contain a first mucolytic agent contained within a first biodegradable capsule as described above. Each of the second inhalable particles may in turn contain the same first or second mucolytic agent contained within a second biodegradable capsule. In other embodiments, the second particle may contain an anti - infective agent or another drug. As a result, the first mucolytic agent and / or the second mucolytic agent are protected from oxidation before being released from their respective first or second biodegradable capsules and subsequently absorbed at the target location in the subject's airway.

[0034] To ensure delivery to two or more target locations, the first particles may be sized differently from the second particles. In embodiments, the first particles may be sized from about 5 to about 50 microns for preferential delivery to the upper airway. In embodiments, the size of the first particles may be 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 microns, or any size therebetween as the invention is not limited in this regard.

[0035] The second particles may be sized from about 0.01 to about 6 microns to ensure preferential delivery to the lower airway. In embodiments, the second particles may be sized about 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6 microns, or any size therebetween as the invention is not limited in this regard.

[0036] In other embodiments, the drug concentration may also differ between the first and second particles. Exemplary concentrations of mucolytic for the first particles may be from about 5 mg to about 200 mg, and for the second particles may be from about 10 mg to about 100 mg.

[0037] In further embodiments, three or more types of particles may be provided and sized such that different particles preferentially deposit at different locations along the airway upon inhalation of the therapeutic agent by the subject. In embodiments, three, four, or more particle sizes may be provided to more uniformly cover desired portions of the airway with the therapeutic agent of the invention.

[0038] In addition to liposomal formulations having lipids, other biodegradable materials or surfactants may be used to generate the biodegradable enclosure of the present invention. This may be done for the purpose of sustained release. In one example, the first particles may be designed to release the drug immediately upon contact with the target site, while the second particles may be designed to release the drug with a predetermined delay. Combinations of two or more sustained-release particles having a predetermined drug release time may be used to create a schedule for the duration of drug release after a single or limited number of inhalations. This sustained or controlled release formulation should provide convenient dosing for the patient.

[0039] The particles may differ from each other not only in size but also in drug content. In an embodiment, the same mucolytic agent may be provided at two or more concentrations within biodegradable particles designed for different release times. In other embodiments, two different mucolytic agents may be used to form two or more types of particles of the present invention. In still further embodiments, the first particles may contain a mucolytic agent, while the second particles may contain an antibiotic or an antiviral agent.

[0040] In an embodiment, the total dose of the mucolytic agent delivered in a single application may vary from about 5 milligrams to about 200 milligrams, for example, 5, 10, 20, 30, 40, 50, 75, 100, 125, 150, 175, 200 milligrams, and can be delivered using any of the methods and devices described above.

[0041] The present invention as described above can be advantageously used to enable the enhancement of mucociliary clearance (MCC) and directly aims to alleviate and treat the common underlying problems and symptoms observed in lung and respiratory tract diseases. The list of conditions and diseases that can benefit from the present invention can include the following: · Primary ciliary dyskinesia (PCD), · Cystic fibrosis (CF), · Bronchiectasis (BE), · Sinusitis · Rhinosinusitis · Bronchiolitis obliterans (BO), · Emphysema, · Bronchitis, · Pneumonia, · Interstitial pneumonia, · COPD, · Other lung and airway diseases, · Other mucus obstructive diseases · Viral and bacterial infections of the lung, sinuses, and ears

[0042] Any embodiment contemplated herein can be carried out with respect to any method of the present invention, and vice versa is also contemplated. It will be understood that the specific embodiments described herein are presented by way of example and not as limitations of the present invention. The main features of the present invention can be used in various embodiments without departing from the scope of the present invention. One of ordinary skill in the art will recognize numerous equivalents to the specific procedures described herein and can confirm them using only routine experimentation. Such equivalents are within the scope of the present invention and are considered to be included in the claims.

[0043] All publications and patent applications mentioned herein represent the state of the art of those of ordinary skill in the art to which the present invention pertains. All publications and patent applications are hereby incorporated by reference into this specification as if each individual publication or patent application were specifically and individually indicated as being incorporated by reference. Incorporation by reference is limited such that no subject matter that conflicts with the explicit disclosure herein is incorporated, no claims of the document are incorporated by reference into this specification, and no definitions shown in the document are incorporated by reference into this specification unless explicitly included herein.

[0044] The use of the words "a" or "an" can mean "one" when used in conjunction with the term "comprising" in the claims and / or the specification, but is also consistent with the meanings of "one or more", "at least one", and "one or two or more". The use of the term "or" in the claims supports both a definition that refers only to alternatives and a definition that refers to "and / or", but is used to mean "and / or" unless it is clearly indicated that it refers only to alternatives or the alternatives are mutually exclusive. Throughout this application, the term "about" is used to indicate that a value includes the variability of errors inherent in the device, method used to determine that value, or variability that exists between the subjects of study.

[0045] As used in this specification and the claims (if any), the terms "comprising" (and any form of "comprising", such as "comprise" and "comprises"), "having" (and any form of "having", such as "have" and "has"), "including" (and any form of "including", such as "includes" and "include"), or "containing" (and any form of "containing", such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. In any embodiment of the compositions and methods provided herein, "comprising" may be replaced with "consisting essentially of" or "consisting of". As used herein, the phrase "consisting essentially of" requires not only the specified components or steps, but also those that do not materially affect the nature or function of the claimed invention. As used herein, the term "consisting of" is used to indicate the presence of only the recited components (e.g., features, elements, properties, characteristics, method / process steps, or limitations), or groups of components (e.g., features, elements, properties, characteristics, method / process steps, or limitations).

[0046] As used herein, the term "or combinations thereof" refers to all permutations and combinations of the listed items preceding that term. For example, "A, B, C, or combinations thereof" is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, BA, CA, CB, CBA, BCA, ACB, BAC, or CAB are also included. Continuing with this example, clearly included are combinations containing repetitions of one or more items or terms, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, etc. One of ordinary skill in the art will understand that, unless otherwise clear from the context, there is typically no limit to the number of items or terms in any combination.

[0047] As used herein, approximate terms, such as but not limited to, "about", "substantially", or "substantially the same", when modifying a state, are understood to not necessarily be absolute or complete, but rather to be a state that would be considered by one of ordinary skill in the art to be close enough to indicate the existence of that state. The degree of variability of the description will depend on how much change can occur and whether one of ordinary skill in the art would still recognize that the modified feature still has the properties and capabilities required of the unmodified feature. Generally, however, for the purposes of the foregoing discussion, numerical values in this specification that are modified by approximate terms such as "about" can vary by at least ±1, 2, 3, 4, 5, 6, 7, 10, 12, 15, 20, or 25% from the recited value.

[0048] All of the devices and / or methods disclosed and claimed in this specification can be made and executed without undue experimentation in light of this disclosure. Although the devices and methods of the present invention have been described from the perspective of preferred embodiments, it will be apparent to those skilled in the art that changes can be made to the devices and / or methods described herein, as well as to the steps or the order of steps of the methods, without departing from the concept, spirit, and scope of the present invention. All such similar substitutions and modifications that are apparent to those skilled in the art are considered to be included within the spirit, scope, and concept of the present invention as defined by the appended claims.

Claims

1. A therapeutic agent for treating the airways of a subject, the improvement being characterized by the therapeutic agent comprising a combination of first inhalable particles and second inhalable particles in a dispersion device configured to self-administer the therapeutic agent in repeated applications, each of the first inhalable particles comprising a first mucolytic agent contained within a first biodegradable capsule, and each of the second inhalable particles comprising the first or second mucolytic agent contained within a second biodegradable capsule; The therapeutic agent, wherein the first mucolytic agent and / or the second mucolytic agent are protected from oxidation prior to being released from the first biodegradable capsule or the second biodegradable capsule, respectively, and absorbed at a target location in the airways of the subject.

2. 2. The method of claim 1, wherein the first mucolytic agent or the second mucolytic agent is selected from the group of compounds consisting of N-acetylcysteine, 2-mercaptoethanesulfonate, L-α-ureido-mercaptopropionic acid, bromhexine, ascorbic acid, N-butylcysteine, reduced glutathione, N- and C-derivatives of the amino acid cysteine, di-peptides of cysteine ​​and glutamic acid, di-peptides of aspartic acid, ambroxol hydrochloride, DNase, and DNA cleaving agents.

3. The method of claim 1 , wherein at least one of the first biodegradable capsules comprises a liposomal formulation.

4. the first particles are sized from about 5 microns to about 50 microns and the second particles are sized from about 0.01 microns to about 6 microns; 2. The therapeutic agent of claim 1, wherein the first particles are configured to be predominantly absorbed at a first target location in the airways and the second particles are configured to be predominantly absorbed at a second target location in the airways.

5. The method of claim 4 , wherein the first target location of the airway is the upper airway and the second target location of the airway is the lower airway.

6. 5. The therapeutic agent of claim 4, further comprising additional particles of a mucolytic drug contained in a biodegradable capsule, said additional particles sized to be absorbed preferentially at additional locations in the airways upon inhalation of said therapeutic agent by the subject.

7. 2. The therapeutic agent of claim 1, wherein the first biodegradable capsule is configured to immediately release the first mucolytic agent upon inhalation of the therapeutic agent by the subject and the second biodegradable capsule is configured to release the second mucolytic agent with a predetermined delay, providing a sustained release mucolytic agent therapy to the subject.

8. 8. The method of claim 7, further comprising additional particles comprising a mucolytic agent contained within a biodegradable capsule configured to release the mucolytic agent with an additional predetermined delay.

9. The method of claim 1 , wherein the first inhalable particles and the second inhalable particles are stored in the form of a solution or in the form of a dry powder.

10. 10. The method of claim 1, wherein the dispenser is configured to provide each dose of the therapeutic agent, upon actuation, containing from about 5 mg to about 200 milligrams of the first mucolytic agent.

Images