WO2023028364A1 - Compositions ciblées et leurs utilisations - Google Patents

Compositions ciblées et leurs utilisations Download PDF

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Publication number
WO2023028364A1
WO2023028364A1 PCT/US2022/041877 US2022041877W WO2023028364A1 WO 2023028364 A1 WO2023028364 A1 WO 2023028364A1 US 2022041877 W US2022041877 W US 2022041877W WO 2023028364 A1 WO2023028364 A1 WO 2023028364A1
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composition
antibiotic
cell
linker
targeting moiety
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PCT/US2022/041877
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English (en)
Inventor
Tomasz Glinka
Emil Samara
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Sepelo Therapeutics, Llc
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Publication of WO2023028364A1 publication Critical patent/WO2023028364A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/552—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being an antibiotic

Definitions

  • Figure 1 shows the structure of a targeting moiety (in this case a macrolide antibiotic), linker, a therapeutic moiety (in this case a fluoroquinolone antibiotic), and the first and second attachments of the linker.
  • a targeting moiety in this case a macrolide antibiotic
  • linker in this case a linker
  • therapeutic moiety in this case a fluoroquinolone antibiotic
  • Figure 2 shows possible cleavage and/or noncleavage patterns for a prodrug.
  • Figure 3 shows a generalized structure of one form of macrolide antibiotics and potential attachment sites for a linker.
  • Figure 4 shows another generalized structure of one form of macrolide antibiotics and potential attachment sites for a linker.
  • Figure 5 shows another generalized structure of one form of macrolide antibiotics and potential attachment sites for a linker.
  • Figure 6 shows structures of various linkers.
  • Figure 7 shows structures of various linkers.
  • Figure 8 shows structures of various linkers.
  • Figure 9 shows structures of various linkers.
  • Figure 10 shows structures of various linkers.
  • Figure 11 shows structures of various linkers.
  • Figure 12 shows steps in the preparation of azithromycin conjugate without protection of azithromycin.
  • Figure 13 shows steps in the preparation of azithromycin conjugate without protection of azithromycin.
  • Figure 14 shows steps in the preparation of azithromycin conjugate without protection of azithromycin.
  • Figure 15 shows steps in the preparation of azithromycin conjugate without protection of fluoroquinolone.
  • Figure 16 shows steps in the preparation of azithromycin conjugate without protection of fluoroquinolone.
  • Figure 17 shows steps in the preparation of azithromycin conjugates at multiple positions on azithromycin.
  • Figure 18 shows steps in the preparation of azithromycin conjugates at multiple positions on azithromycin.
  • Figure 19 shows steps in the preparation of azithromycin conjugates at multiple positions on azithromycin.
  • Figure 20 shows steps in the preparation of azithromycin conjugates at multiple positions on azithromycin.
  • Figure 21 shows steps in the preparation of azithromycin conjugates at multiple positions on azithromycin.
  • compositions using a targeting moiety linked via a linker to a therapeutic moiety where the linker forms a first attachment to the targeting moiety and a second attachment to the therapeutic moiety ( Figure 1), and where the composition provides the therapeutic moiety in active form at the target site or sites.
  • This can occur by cleavage of the first attachment, the second attachment, cleavage at both attachments, cleavage in between the first and second attachments, or no cleavage (original prodrug remains intact or substantially intact), so long as the therapeutic moiety retains sufficient activity for its intended purpose at the target site or sites (Figure 2).
  • the second attachment is cleaved at the target site or sites of the targeting moiety; in some cases, the first attachment is cleaved at the target site or sites of the targeting moiety. In some cases, both the first and second attachments are cleaved at the target site or sites of the targeting moiety.
  • the first and/or second attachments can be covalent attachments.
  • the target of the targeting moiety is generally a structure, such as a cell and/or and organelle of a cell, that is involved in the body’s response to a pathological condition, and is not a structure, such as a cell, that is causative of the pathological condition, e.g., not a cancer cell.
  • the target site or sites are the sites to which the target, e.g., cell, is drawn and/or concentrated due to the presence of a pathological condition at the site or sites, and can include the intracellular and/or extracellular environment of, e.g., a cell.
  • the first and/or second attachments can be cleaved by exposure to reactive oxygen species released in an oxidative burst of an immune cell.
  • the target is lysosomes, especially lysosomes present in infection healing cells, and, in some of these cases, the first and/or second attachments are cleaved in the environment of the lysosome.
  • the targeting moiety is taken up by a target cell, e.g., an infection healing cell such as an immune cell or a fibroblast and, in some cases, further taken up by one or more organelles in the target cell, e.g., lysosomes.
  • a target cell e.g., an infection healing cell such as an immune cell or a fibroblast
  • organelles in the target cell e.g., lysosomes.
  • the targeting moiety itself has therapeutic activity, e.g., a therapeutic activity such as a therapeutic activity that complements the therapeutic activity of the therapeutic moiety.
  • the therapeutic moiety comprises an antibiotic.
  • the targeting moiety comprises a moiety that is itself therapeutic.
  • the targeting moiety comprises an antibiotic.
  • the targeting and therapeutic moieties both comprise antibiotics, which can be the same or different antibiotics.
  • the targeting moiety linked via the linker to the therapeutic moiety is referred to herein as the “prodrug.” See, e.g., Figure 1, showing a prodrug where the targeting moiety is a macrolide antibiotic and the therapeutic moiety is a fluoroquinolone antibiotic; these structures are merely exemplary and the targeting and therapeutic moieties may be any suitable moieties, such as those described herein.
  • the therapeutic moiety not be in active form in sufficient amounts and/or for sufficient time at sites that are not the target site or sites, e.g., in the systemic circulation, to cause significant adverse effects in the individual to which it is administered, e.g., not in sufficient amount and/or sufficient time to cause adverse effects that necessitate halting or significantly decreasing treatment with the prodrug.
  • the prodrug is used to treat a condition in an individual through administration of the prodrug to the individual.
  • the prodrug is taken up by a target, e.g., cell or cells at the site or sites of the condition, or that travel to the site or sites of the condition, and/or one or more organelles of the cell or cells, and the therapeutic moiety is active at the site of the condition, for example, it can be released at the site of the condition.
  • the condition is an infection, e.g., a bacterial infection
  • the therapeutic moiety is an antibiotic that reduces or eliminates one or more bacteria responsible for the infection.
  • compositions and methods provided herein are effective by engaging the body’s own infection fighting cells (immune cells) or healing cells (fibroblasts) for targeted delivery of antimicrobials to the site of infection.
  • the second attachment has sufficient lability to release the therapeutic moiety at the target site at a rate and in an amount to be therapeutically effective.
  • the first attachment also has sufficient lability to release the targeting moiety at the target site, e.g. , if the targeting moiety is also a therapeutic agent, at a rate and in an amount to be therapeutically effective.
  • the first and second attachments remain sufficiently stable in environments encountered by the prodrug after administration that a sufficient amount of intact prodrug reaches its target, such as target cells, e.g., target infection healing cells, and is taken up by the cells and/or organelles of the cells and, in some cases, transported by the cells to a site of a condition, e.g., a site of infection, that a therapeutically effective amount of the therapeutic moiety can be released at the site of the condition, e.g., infection.
  • target cells e.g., target infection healing cells
  • the second attachment is such that the therapeutic moiety, when exposed to the environment of the cytosol and/or organelle of the target cell, is released at the site of the condition at a rate and in an amount that provides a therapeutically effective dose at the site of the condition.
  • the prodrug is removed from systemic circulation and concentrated at target cells such that adverse effects due to one or both of the targeting moiety and the therapeutic moiety are reduced or eliminated.
  • a relatively small amount of prodrug is administered but it concentrates to an effective level in the target cells; in these cases, the amount of prodrug in circulation before it is taken up can be low enough that adverse effects are not significant.
  • the attachments need not be highly stable in that environment, so long as a sufficient amount of prodrug remains intact to be effective at the site of the condition and, in some cases, so as not to incur adverse effects or significant adverse effects from release of the therapeutic moiety before being taken up by target cells.
  • This can be especially the case for, e.g., inhaled therapeutics, which are brought directly to the site of a condition, e.g., infection, and bypass plasma, but can also be the case for prodrugs exposed to plasma after administration so long as uptake into target cells is present.
  • route of administration e.g., oral administration results in exposure to the digestive environment (e.g., stomach, and/or small intestine, and/or large intestine) then blood plasma; administration by injection will result in exposure to intramuscular or subcutaneous environment, in the case of intramuscular or subcutaneous administration, and ultimately to plasma, for all types of injection and directly for intravenous injection.
  • intravenous administration results in exposure to blood plasma but not directly to the digestive environment (although in some cases a drug eliminated in, e.g., bile, will reach portions of the digestive tract); topical administration results in exposure to skin then plasma; administration by inhalation bypasses plasma, etc., and exposure is to the environment in the airways and alveoli.
  • target destination e.g., cytosol or organelle, such as lysosome; in some cases, both cytosol and organelle, e.g., lysosome
  • the second attachment of the linker to the therapeutic moiety is cleaved at such a rate that the therapeutic moiety is released at the site of the condition, e.g., infection site at a rate that allows a therapeutically effective amount of the therapeutic moiety to be released at the site of the condition, e.g. , infection site, and to achieve a therapeutically effective concentration, for a desired amount of time.
  • a dose of the prodrug in the case of an antibiotic as a therapeutic, moiety, retains prodrug structure until at the site of infection, and then is released at such a rate to provide a concentration of the antibiotic sufficient to reduce or eliminate the bacteria at the site of the infection to which it is directed.
  • the first moiety i.e., the targeting moiety, which in some embodiments also has therapeutic activity
  • the first attachment of the linker to the targeting moiety is cleaved at such a rate that the targeting moiety is released at the site of the condition, e.g., infection site at a rate that allows a therapeutically effective amount of the targeting moiety to be released at the site of the condition, e.g., infection site and to achieve a therapeutically effective concentration, for a desired amount of time.
  • the second attachment and, in some cases, the first attachment may be susceptible to cleavage by, e.g., hydrolysis, where the hydrolysis can be assisted by enzymes, e.g., esterases (e.g., enzymes such as esterases present intracellularly and/or in a target organelle), assisted by an acidic environment (e.g., if the prodrug travels to lysosomes), and/or relatively prone to hydrolysis in an aqueous environment (e.g., if the time for the prodrug to travel to the target site, e.g., target cells, and be taken up is relatively short).
  • enzymes e.g., esterases (e.g., enzymes such as esterases present intracellularly and/or in a target organelle)
  • an acidic environment e.g., if the prodrug travels to lysosomes
  • relatively prone to hydrolysis in an aqueous environment e.g., if the time for
  • the second attachment need not be cleaved for the therapeutic moiety to be active; in these embodiments, the second attachment may remain intact while the first attachment is cleaved to produce a therapeutic moiety-linker and a free targeting moiety; or neither attachment may be cleaved. In these cases, so long as the active therapeutic moiety, either as prodrug or as therapeutic moiety-linker, does not reach systemic levels that cause significant adverse effects before being taken up by target cells. The same may also be true if the targeting moiety is itself a therapeutic moiety — cleavage of the first attachment may not be necessary for it to retain sufficient therapeutic action to be effective.
  • the type of cell targeted by the targeting moiety may be any suitable type of cell.
  • the type of cell targeted is an infection healing cell.
  • the target can comprise an organelle of a cell, such as lysosomes and/or granules, that is abundant in a cell or cells that are drawn to and/or concentrate at the target site; thus, in certain embodiments, the targeting moiety may be, e.g., a lysosomotropic moiety, i.e., a moiety that becomes concentrated in lysosomes, for example, in lysosomes of infection healing cells.
  • compositions and methods provided herein are used to target one or more targets, e.g., cell types, in order to concentrate the therapeutic moiety, e.g., antibiotic, at the site or sites where those targets, e.g., cells, are concentrated and/or active; in the case of an antibiotic therapeutic moiety, this will be at a site of infection.
  • targets e.g., cell types
  • the therapeutic moiety e.g., antibiotic
  • compositions are targeted to a site or sites of infection.
  • targeting is achieved by a composition that comprises a targeting moiety that is preferentially taken up by a cell or cells that participate in infection healing.
  • a cell may be an immune cell that is involved in actively fighting infection, and/or it may be a tissue repair cell that is involved in tissue repair and rebuilding at the site of infection.
  • the therapeutic moiety such as an antibiotic
  • concentrations in the rest of the body are lower; thus, therapeutic levels may be reached at site of the condition, e.g. , infection site that would otherwise produce unacceptable adverse effects if distributed throughout the body.
  • a therapeutic moiety e.g., an antibiotic
  • concentrations in the site of the body e.g., an antibiotic
  • concentrations in the rest of the body are lower; thus, therapeutic levels may be reached at site of the condition, e.g. , infection site that would otherwise produce unacceptable adverse effects if distributed throughout the body.
  • a therapeutic moiety e.g., an antibiotic
  • a specific site of action e.g., an infection site
  • the targeted concentration is a concentration that is therapeutic at the site of action, e.g., infection site, in some cases a concentration that may be toxic if distributed throughout the body.
  • compositions and methods provided herein result in an improved therapeutic index and therapeutic window; that is, the ratio of effective dose to toxic dose is greater than for the therapeutic agent administered alone; in certain cases, the therapeutic index of the prodrug compared to the therapeutic index of the therapeutic agent alone is increased at least 1.2, 1.4, 1.6, 1.8, 2.0, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 15, 20, 30, 40, or 50-fold; in certain embodiments, the therapeutic index in increased at least 1.5 -fold, in some cases at least 2-fold.
  • the target comprises a cell or cells that is/are immune cells. Any suitable type of immune cell, such as immune cells that are attracted to a site of infection, may be targeted.
  • the immune system is comprised of cells and proteins that work together to provide defense against infection. These cells and proteins do not form a single organ like the heart or liver. Instead, the immune system is dispersed throughout the body to provide rapid responses to an infection. Cells travel through the bloodstream or in specialized vessels called lymphatics. Lymph nodes and the spleen provide structures that facilitate cell-to-cell communication.
  • the cells of the immune system can be categorized as lymphocytes (T-cells, B-cells and NK cells), neutrophils, eosinophils, basophils, and monocytes/macrophages. These are all types of white blood cells.
  • the major proteins of the immune system are predominantly signaling proteins (often called cytokines), antibodies, and complement proteins.
  • Innate immune responses are those that rely on cells that require no additional “training” to do their jobs. These cells include neutrophils, monocytes, natural killer (NK) cells and a set of proteins termed the complement proteins. Innate responses to infection occur rapidly and reliably. Adaptive immune responses involve T-cells and B-cells, two cell types that require “training” or education to learn not to attack our own cells. The advantages of the adaptive responses are their long-lived memory and the ability to adapt to new infections.
  • the target cells include one or more types of phagocytic cells.
  • Phagocytic cells are part of the immune system that are commonly found in the bloodstream.
  • Phagocytes are one of the first responders that migrate to the site of infection and are responsible for clearing infections by eradicating bacteria and, along with fibroblasts, repairing the surrounding tissue damage. Phagocytes selectively accumulate some type of antibiotics. The accumulation is dependent on the class of antibiotics with limited to no accumulation of betalactam, mild accumulation for tetracyclines and fluoroquinolones and extensive accumulation for azithromycin.
  • antibiotics may accumulate in any manner, e.g., active transport, passive transport (trapping of form inside cell or organelle), or a combination thereof.
  • Phagocytic cells include neutrophils, monocytes, macrophages, mast cells, and dendritic cells. These cells engulf pathogenic microbes and localize them in intracellular vacuoles, where they are exposed to toxic effector molecules, such as nitric oxide, superoxide, and degradative enzymes in an effort to destroy the invading organism.
  • the target cells include neutrophils.
  • Neutrophils or polymorphonuclear leukocytes are the most numerous of all the types of white blood cells, making up about half or more of the total. They are also called granulocytes because they contain granules in their cytoplasm. They are found in the bloodstream and can migrate into sites of infection within a matter of minutes. They are the cells that leave the bloodstream and accumulate in the tissues during the first few hours of an infection and are responsible for the formation of “pus.” Their major role is to ingest bacteria or fungi and kill them. Their killing strategy relies on ingesting the infecting organisms in specialized packets of cell membrane that then fuse with other parts of the neutrophil that contain toxic chemicals that kill the microorganisms.
  • Monocytes are closely related to neutrophils and are found circulating in the bloodstream. They make up 5-10 percent of the white blood cells. They also line the walls of blood vessels in organs like the liver and spleen. Here they capture microorganisms in the blood as the microorganisms pass by. When monocytes leave the bloodstream and enter the tissues, they change shape and size and become macrophages. Macrophages are essential for killing fungi and the class of bacteria to which tuberculosis belongs (mycobacteria). Like neutrophils, macrophages ingest microbes and deliver toxic chemicals directly to the foreign invader to kill it. [0043] T-cells (sometimes called T-lymphocytes) are another type of immune cell.
  • T-cells directly attack cells infected with viruses, and they also act as regulators of the immune system.
  • An important aspect of the T-cell arm of the immune system is to recognize host cells that are infected by viruses, intracellular bacteria, or other intracellular parasites.
  • T cells have evolved an elegant mechanism that recognizes foreign antigens together with self-antigens as a molecular complex.
  • T-cells perform the actual destruction of infected cells.
  • Killer T-cells protect the body from certain bacteria and viruses that have the ability to survive and even reproduce within the body’s own cells. The killer cell must migrate to the site of infection and directly bind to its target to ensure its destruction.
  • B-cells (sometimes called B-lymphocytes) are specialized cells of the immune system whose major function is to produce antibodies (also called immunoglobulins or gammaglobulins). When B-cells encounter foreign material (antigens), they respond by maturing into another cell type called plasma cells. B-cells can also mature into memory cells, which allows a rapid response if the same infection is encountered again. Plasma cells are the mature cells that actually produce the antibodies.
  • NK cells Natural killer (NK) cells are so named because they easily kill cells infected with viruses. NK cells kill virus-infected cells by injecting it with a killer potion of chemicals. They are particularly important in the defense against herpes viruses.
  • An immune cell can be targeted by using a targeting moiety that is preferentially taken up by the immune cell or cells to be targeted.
  • the target cell comprises a phagocytic cell
  • the targeting moiety is a moiety that is preferentially taken up by the phagocytic cell.
  • Phagocytic cells include neutrophils, monocytes, macrophages, mast cells, and dendritic cells.
  • the target cell comprises a neutrophil and the targeting moiety is a moiety that is preferentially taken up by neutrophils.
  • the targeting moiety is lysosomotropic, that is, it is taken up by lysosomes to accumulate in a form that cannot re-cross the lysosomal membrane at a significant rate, thus trapping the moiety inside the lysosomes.
  • the targeting moiety comprises a weak base; in the extracellular or cytosolic environment, such a moiety may be uncharged and thus pass through the lysosomal membrane, but in the acidic environment of the lysosome it becomes charged and cannot easily re-cross the lysosomal membrane to escape.
  • the lysosomotropic moiety comprises a macrolide antibiotic, such as azithromycin, clarithromycin, or erythromycin; use of such a targeting moiety has the advantage that it may be therapeutic itself, in addition to the therapeutic moiety to which it is attached, e.g., as an antibiotic and/or as an anti-inflammatory agent and/or as an antiviral agent.
  • a macrolide antibiotic such as azithromycin, clarithromycin, or erythromycin
  • Tissue repair cells such as connective tissue cells, then proliferate and repair and replace the damaged tissue.
  • Tissue repair cells e.g., connective tissue cells
  • connective tissue cells that may be targeted in the compositions and method of the inventions include dendritic cells and fibroblasts.
  • a fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (stroma) for body tissues.
  • Fibroblasts play an important role in tissue repair, a primary site of a trauma induced site of infection.
  • the target cell comprises a fibroblast and the targeting moiety is preferentially taken up by fibroblasts. Fibroblasts are the workhorse of the most important tissue that holds the human body together — connective tissue.
  • Connective tissue joins and supports all other tissues, including the parenchymal tissues of organs.
  • This connective tissue is made of fibroblasts widely spaced in a vast extracellular matrix (ECM) of fibrous proteins and gelatinous ground substance.
  • ECM extracellular matrix
  • Fibroblasts produce the ECM’s structural proteins and play various additional roles in ECM maintenance and reabsorption, tissue repair, inflammation, angiogenesis, cancer progression, and in physiological as well as pathological tissue fibrosis.
  • Fibroblasts are ubiquitous mesenchymal cells derived from the embryonic mesoderm tissue, and they are not terminally differentiated. They can be activated by a variety of chemical signals that promote proliferation and cellular differentiation to form myofibroblasts with an up-regulated rate of matrix production. Ancillary to these various biological roles, fibroblasts produce and respond to a broad array of paracrine and autocrine signals, such as cytokines and growth factors.
  • the ground substance of ECM is a hydrated gel of proteo- glycans that is interspersed among the structural proteins.
  • the ground substance forms a final pathway for nutrient flow beyond the reach of blood vessel transport into tissues as well as a pathway for intercellular communication.
  • This cell-free medium forms an avenue for cell migration of immune cells, fibroblasts, and myofibroblasts.
  • Fibroblasts have a pivotal role in tissue repair in response to tissue injury. First and foremost, fibroblasts respond to tissue repair by proliferating and by chemotaxing to the sites of tissue injury to rebuild the ECM as a scaffold for tissue regeneration. Fibroblast to myofibroblast transitioning enables the contraction of the matrix to seal an open wound in the event of the loss of tissue.
  • Fibroblasts serve roles in inflammation and immune cell recruitment to sites of tissue injury. Furthermore, fibroblasts produce and are responsive to many inflammatory cytokines. Fibroblasts are responsive to cytokines such as TGF01, IL-10, interleukin-6 (IL-6), IL-13, IL-33 as well as prostaglandins and leukotrienes. Fibroblasts are stimulated chemically by inflammatory agents to differentiate into myofibroblasts that have a greatly up-regulated rate of matrix production (discussed in more detail below). In turn fibroblasts produce and secrete cytokines such as TGF01, IL-10, IL-33, CXC, and CC chemokines, as well as reactive oxygen species.
  • cytokines such as TGF01, IL-10, IL-33, CXC, and CC chemokines
  • fibroblasts allow fibroblasts to assist in the activation and migration of resident immune cells such as macrophages. Moreover, the recruitment of non- resident immune cells is facilitated by the fibroblast-mediated production and maintenance of the relatively spacious, non-solid ground substance of the extracellular matrix, which plays an important role as a thoroughfare for the extravasation of immune cells into connective tissue.
  • These tools endow fibroblast roles in chemical(non-specific) and cell-mediated immunity, acute and chronic inflammation, and inflammation resolution. Fibroblasts can contribute to chronic inflammation, and reciprocally, inflammatory cytokines promote fibroblast to myofibroblast transition, facilitating fibrosis.
  • fibroblasts are chemotactic and can migrate and accumulate in new areas in response to secreted cytokines, a behavior well characterized in the tissue repair response after tissue injury. Fibroblasts are not a terminally differentiated cell type and retain the potential to be activated for differentiation into subtypes of fibroblast-like cells. Myofibroblasts are rarely found in healthy human physiology; they become vastly up regulated after injury and play a critical role in the tissue repair response.
  • a targeting moiety targets differentiated fibroblasts, e.g., myofibroblasts and/or other differentiated fibroblasts that are up regulated at a target site, such as an infection site, for example alveolar differentiated fibroblasts present at an infection site and/or in a condition such as cystic fibrosis.
  • differentiated fibroblasts e.g., myofibroblasts and/or other differentiated fibroblasts that are up regulated at a target site, such as an infection site, for example alveolar differentiated fibroblasts present at an infection site and/or in a condition such as cystic fibrosis.
  • Targeting fibroblasts or other tissue repair cells also has the advantage that these cells can be in areas where perfusion is low, either as part of normal physiology, such as at the otitis media or in gingivitis, and/or as a result of a pathological condition such as cystic fibrosis or diabetes.
  • methods and compositions provided herein provide a means whereby a therapeutic moiety, such as an antibiotic, can be accumulated even with poor circulation, because when the composition does reach the site with, e.g., a fibroblast, it is retained there, thus allowing the therapeutic moiety to accumulate at the site.
  • a therapeutic moiety such as an antibiotic can be accumulated in such cells and not exposed to conditions that inactivate the antibiotic, then released unchanged into the circulation, thus, in effect, extending the half-life of the antibiotic.
  • Any suitable targeting moiety may be used.
  • the targeting moiety is an antibiotic, such as an antibiotic that is preferentially taken up by one or more target cells, e.g., one or more infection healing cells such as phagocytic cells, and/or one or more organelles of target cells, e.g., lysosomes.
  • the antibiotic is an antibiotic whose concentration is increased at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 300, 400, 500, 700, 1000, or 1500-fold, such as at least 20-fold, for example at least 50-fold, in some cases at least 100-fold in the target cell compared to plasma at equilibrium.
  • the antibiotic is an antibiotic whose concentration is increased at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 300, 400, 500, 700, 1000, or 1500-fold, such as at least 20-fold, for example at least 50-fold, in some cases at least 100-fold, in one or more types of phagocytic cells compared to plasma at equilibrium.
  • Phagocytic cells include neutrophils, monocytes, macrophages, mast cells, and dendritic cells.
  • the antibiotic is an antibiotic whose concentration is increased at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 300, 400, 500, 700, 1000, or 1500-fold, such as at least 20-fold, for example at least 50-fold, in some cases at least 100-fold, in neutrophils compared to plasma at equilibrium.
  • the mechanism for the target moiety to be taken up by the target cell may be any suitable mechanism, such as passive transport or active transport, or a combination thereof.
  • the target moiety is taken up by passive transport. Without being bound by theory, it is thought that passive accumulation for an antibiotic such as azithromycin can be driven by its basicity and ability to bind to lysosomes.
  • the targeting antibiotic comprises a macrolide antibiotic.
  • macrolide antibiotics include but are not limited to erythromycin, clarithromycin, fidaxomicin, spiramycin, telithromycin, carbonmycin A, josamycin, kitsamycin, midecamycin, oleandomycin, solithromycin, troleandomycin, tylosin, roxitromycin or azithromycin.
  • the targeting antibiotic comprises erythromycin, clarithromycin, or azithromycin.
  • the targeting antibiotic comprises azithromycin.
  • the targeting antibiotic comprises clarithromycin.
  • the targeting antibiotic comprises erythromycin.
  • Azithromycin a macrolide, with potent gram-positive and anti-inflammatory activity, is known to extensively accumulate in phagocytes. Intra- to extra-cellular concentration ratio of greater than 500-fold has been reported in phagocytes. After administration of azithromycin to healthy volunteers and patients with cystic fibrosis, CF, up to 100-fold higher and sustained concentrations of azithromycin are observed in the phagocytes relative to plasma. Without being bound by theory, it is though that inside phagocytes, azithromycin is captured within the acidic environment of the lysozymes and slowly released into the phagosomes during bacterial phagocytosis. As such, azithromycin can be used to enhance the accumulation and residence time of other antimicrobials.
  • Azithromycin is active against Gram-positive bacteria. It also possesses anti-inflammatory effects that can be useful especially in inflamed wounds and lungs. Thus, in certain embodiments, e.g., treating infections, azithromycin can act as both a targeting moiety and a secondary therapeutic moiety, due to its anti-inflammatory activity, antiviral activity, and/or anti-Gram-positive bacterial activity.
  • a prodrug that links azithromycin to a therapeutic moiety such as another antibiotic, for example a fluoroquinolone such as an antipseudomonal fluoroquinolone, is expected to increase both the Cmax and the AUG with both being important for increasing the activity of the antibiotic, especially against resistant bacteria, e.g. , resistant P. aeruginosa.
  • composition comprising a targeting moiety comprising a macrolide antibiotic attached via a first attachment to a linker, the linker, and a therapeutic moiety that is attached to the linker via a second attachment.
  • the macrolide antibiotic comprises erythromycin, clarithromycin, or azithromycin.
  • the targeting moiety comprises azithromycin.
  • the therapeutic moiety comprises an antibiotic.
  • the antibiotic is a tetracycline, beta-lactam, or fluoroquinolone.
  • the antibiotic is a fluoroquinolone antibiotic.
  • the fluoroquinolone antibiotic comprises ciprofloxacin, levofloxacin, or gemifloxacin.
  • the first and/or second attachments are covalent bonds.
  • a method of treating an infection comprising administering to an individual suffering from an infection a therapeutically effective amount of one of the above compositions.
  • the infection comprises antibiotic-resistant bacteria.
  • the infection comprises P. aeruginosa, in some cases antibiotic-resistant P. aeruginosa.
  • the infection is in Cystic Fibrosis patients caused at least partially by P. aeruginosa, in some cases antibiotic-resistant P. aeruginosa.
  • Any suitable therapeutic moiety can be used so long as it can be attached to the targeting moiety via a linker with requisite properties and is effective in treating the condition for which it is used.
  • the therapeutic moiety comprises an antibiotic.
  • any suitable antibiotic may be used; in some cases, two antibiotic moieties are linked, where the targeting moiety is itself an antibiotic. It is desirable that the antibiotic used be effective against the bacterial agent or agents causing an infection.
  • the antibiotic is a broad-spectrum antibiotic.
  • the antibiotic is most effective against Gram-negative bacteria.
  • the antibiotic is most effective against Gram-positive bacteria.
  • the antibiotic is one that is effective, or has some effect, on antibiotic-resistant bacteria, which can depend on the particular type of antibiotic-resistant bacteria.
  • the targeting moiety is an antibiotic that is effective against Gram-positive bacteria
  • the therapeutic moiety is an antibiotic that is effective against Gram-negative bacteria.
  • An “antibiotic,” including all specific types described herein, includes all forms of the antibiotic suitable for formulation into a composition, and for administration, as described herein including salts, esters, and other pharmaceutically acceptable forms, as known in the art.
  • the antibiotic is a beta-lactam, such as a carbapenem, a cephalosporin, a monobactam, or a penicillin; an aminoglycoside; a quinolone such as a fluoroquinolone; a glycopeptide or lipoglycopeptide, such as vancomycin; a macrolide, such as clarithromycin, erythromycin or azithromycin; an oxazolidinone, such as linezolid or tedizolid; a polypeptide; a rifamycin; a sulfonamides, a streptogramin such as quinupristin or dalfopristin; chloramphenicol; clindamycin; daptomycin; fosfomycin; lefamulin; metronidazole; mupirocin; nitrofurantoin; or tigecycline; or
  • the therapeutic moiety comprises a beta-lactam, tetracycline, or fluroquinolone antibiotic. In certain embodiments the therapeutic moiety comprises a fluoroquinolone antibiotic.
  • the antibiotic is a fluoroquinolone.
  • Any suitable fluoroquinolone may be used.
  • Exemplary fluoroquinolones include acorafloxacin, amifloxacin, antofloxacin, avarofloxacin, balofloxacin, benofloxacin, besifloxacin, cadroflocacin, chinfloxacin, ciprofloxacin, clinafloxacin, danofloxacin, delafloxacin, ecenofloxacin, enoxacin, enrofloxacin, esafloxacin, fandofloxacin, finafloxacin, fleroxacin, gatifloxacin, gemifloxacin, grepafloxacin, irloxacin, lemefloxacin, levofloxacin, levonadifloxacin, lomefloxacin, marbofloxacin
  • the fluoroquinolone antibiotic comprises ciprofloxacin, moxifloxacin, gemifloxacin, levonadiflocacin or delafloxacin. In certain embodiments the fluoroquinolone antibiotic comprises ciprofloxacin. In certain embodiments the fluoroquinolone antibiotic comprises moxifloxacin. In certain embodiments the fluoroquinolone antibiotic comprises gemifloxacin. In certain embodiments the fluoroquinolone antibiotic comprises levonadifloxacin. In certain embodiments the antibiotic comprises fluoroquinolone delafloxacin.
  • fluoroquinolones that may be useful in compositions and methods provided herein include acorafloxacin, amifloxacin, antofloxacin, avarofloxacin, balofloxacin, benofloxacin, besifloxacin, cadroflocacin, clinafloxacin, dalofloxacin, danofloxacin, ecenofloxacin, enoxacin, enrofloxacin, esafloxacin, finafloxacin, fleroxacin, gatifloxacin, grepafloxacin, irloxacin, lemefloxacin, levofloxacin, lomefloxacin, marbofloxacin, merafloxacin, motifloxacin, nadifloxacin, orbifloxacin, pazufloxacin, pefloxacin, pradofloxacin, premafloxacin
  • the antibiotic is a beta-lactam.
  • Any suitable beta-lactam may be used, e.g., a carbapenem, a cephalosporin, a monobactam, or a penicillin.
  • the beta-lactam is a carbapenem, such as imipenem, meropenem, panipenem, biapenem, ertapenem, or tebipenem.
  • the beta-lactam is a cephalosporin, such as a third- or fourth-generation cephalosporin.
  • the beta-lactam is a penicillin, such as an aminopenicillin, e.g., ampicillin, amoxicillin; an antipseudomonal penicillin, e.g., carbenicillin, piperacillin, ticarcillin; a natural penicillin, e.g., penicillin G, procaine penicillin G, penicillin V, benzathine; a penicillinase resistant penicillin, e.g., oxacillin, dicloxacillin, nafcillin.
  • the beta-lactam is a monobactam, such as aztreonam, tigemonam, carumonam, nocardicin A, tabtoxin.
  • a betalactam antibiotic is used in combination with a beta-lactamase inhibitor, for example, a betalactamase inhibitor that is itself linked to a linker.
  • the antibiotic is a tetracycline antibiotic.
  • Any suitable tetracycline antibiotic may be used, such as tetracycline, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, methacycline, minocycline, rolitetracycline, doxycycline, or tigecycline, or a combination thereof.
  • Any suitable linker may be used so long as it provides a first point of attachment for the targeting moiety and a second point of attachment for the therapeutic moiety, where the first and second attachments have sufficient stability to travel to the site of the condition sufficiently intact and, in some cases, sufficient lability to release the therapeutic moiety and, in some cases, also the targeting moiety e.g., when the targeting moiety is also a therapeutic agent) at the site of the condition to be treated at a rate and in an amount to be therapeutically effective.
  • the first and second attachments remain sufficiently stable in environments encountered by the prodrug after administration that a sufficient amount of intact prodrug reaches its target cells, such as target infection healing cells and is taken up by the cells and/or organelles of the cells and, in some cases, transported by the cells to a site of a condition, e.g., a site of infection, that a therapeutically effective amount of the therapeutic moiety can be present, e.g. , at the site of the condition, e.g., infection.
  • the second attachment is cleaved at the target, e.g., infection healing cell or organelle thereof.
  • the second attachment can be such that the prodrug, when exposed to the environment of the cytosol and/or organelle of a target cell, such as an infection healing cell, releases the therapeutic moiety at the site of the condition at a rate and in an amount that provides a therapeutically effective dose of the therapeutic moiety at the site of the condition.
  • the first attachment is cleaved at the target, e.g., infection healing cell or organelle thereof.
  • both the first and second attachments are cleaved at the target, e.g., infection healing cell or organelle thereof.
  • neither the first nor the second attachment is cleaved at the target, e.g., infection healing cell or organelle thereof.
  • the liner is cleaved between the first and second attachment at the target, e.g., infection healing cell or organelle thereof.
  • the amount of therapeutic moiety and/or targeting moiety released before the prodrug reaches the site of the condition is also such that adverse effects due to one or both of the targeting moiety and the therapeutic moiety are reduced or eliminated. It will be appreciated that if the exposure to the environment prior to the prodrug being taken up by target cells is brief, the linkage need not be highly stable in that environment, so long as a sufficient amount of prodrug remains intact to be effective at the site of the condition and, in some cases, so as not to incur adverse effects or significant adverse effects from release of the therapeutic moiety before being taken up by target cells.
  • prodrugs which are brought directly to the site of a condition, e.g., lung infection, and bypass plasma, but can also be the case for prodrugs exposed to plasma or other environments after administration so long as uptake into target cells is present/adequate.
  • the targeting moiety may be directly covalently linked to the therapeutic moiety.
  • the first and second attachments are a single attachment, and both the targeting moiety and the therapeutic moiety are released when the attachment is cleaved.
  • the “linker” is simply the covalent bond between the targeting moiety, e.g., macrolide antibiotic, and the therapeutic moiety, e.g., another antibiotic.
  • the first and second attachments may be covalent or noncovalent. In certain embodiments, the attachments are covalent.
  • the first attachment of the linker, to the macrolide antibiotic can be at any suitable group on the macrolide antibiotic, such as at a hydroxy group.
  • the linker forms a first attachment with a hydroxy of a macrolide antibiotic comprising erythromycin or azithromycin at position -6, -11, -12, -2’ or -4” ( Figures 3 and 4), or comprising clarithromycin at position -11, - 12, -2’ or -4” ( Figure 5), where the numbering is conventional numbering.
  • the therapeutic moiety is a therapeutic moiety, e.g., antibiotic, comprising a carboxy group, and the site of attachment to the linker is the carboxy group.
  • the therapeutic moiety is a therapeutic moiety, e.g., antibiotic, comprising an amino group, and the site of attachment to the linker is the amino group.
  • the therapeutic moiety is a therapeutic moiety, e.g., antibiotic, comprising a hydroxy group, and the site of attachment to the linker is the hydroxy group.
  • the second attachment of the linker, to the fluoroquinolone antibiotic can be at any suitable group on the fluoroquinolone antibiotic, such as an amine, carboxy group, or hydroxy group (in certain fluoroquinolones).
  • the linker is attached to the fluoroquinolone antibiotic at the carboxy group, e.g., a carboxy group at the 3-position of lH-pyridin-4-one ring.
  • the linkage is direct, i.e., a direct covalent bond between the macrolide antibiotic and the fluoroquinolone antibiotic.
  • the linkage is via a linker and the composition comprises a targeting moiety comprising a macrolide antibiotic linked at a first attachment to a linker that is linked by a second attachment to a therapeutic moiety comprising a fluoroquinolone antibiotic.
  • the first attachment can be at any suitable hydroxy of the macrolide antibiotic, such as, with erythromycin or azithromycin at position -6, -11, -12, -2’ or -4” ( Figures 3 and 4), or with clarithromycin at position -11, -12-2’ or -4” ( Figure 5).
  • the second attachment can be at any suitable group of the fluoroquinolone, such as an amine, carboxy group, or hydroxy group. In certain embodiments the second attachment is at a carboxy group of the fluoroquinolone.
  • Any suitable linker can be used, so long as the first and second attachments have the requisite stability (for both attachments in the environments to which the prodrug is exposed before it reaches the interior of the target cell) and lability (for at least the second attachment, and in some cases also the first attachment, in the environment within the target cell or at the site where the target cell releases the therapeutic moiety).
  • the linker comprises a linker as shown in Figure 6; note that the linkers in Figure 6 are shown attached to a hydroxy on the targeting moiety and to a carboxy on a fluoroquinolone moiety, these are merely exemplary and do not limit the linkers. Also note that the top left hand structure shows direct linkage with no intermediate linkage.
  • the linker comprises -C(O)O-C(RI)(R.2)- wherein Ri and R2 are independently selected from H, Me, Et, z-Pr, CH2NH2, CEENHMe, CH2NHC(O)Me, CH2NmeC(O)Me, CEENHMe, CH2Nme2, Ome.
  • the linker comprises a linker as shown in Figure 7; note that the linkers in Figure 7 are shown attached to a hydroxy on the targeting moiety and to a carboxy on a fluoroquinolone moiety, these are merely exemplary and do not limit the linkers.
  • the linker comprises -CH2OC(O)O-C(RI)(R2)-, wherein Ri and R2 are independently selected from H, Me, Et, z-Pr, CH2NH2, CEENHMe, CH2NHC(O)Me, CH2NmeC(O)Me, CEENHMe, CH2Nme2.
  • the linker comprises a linker as shown in Figure 8; note that the linkers in Figure 8 are shown attached to a hydroxy on the targeting moiety and to a carboxy on a fluoroquinolone moiety, these are merely exemplary and do not limit the linkers.
  • the linker comprises a linker as shown in Figure 9; note that the linkers in Figure 9 are shown attached to a hydroxy on the targeting moiety and to a carboxy on a fluoroquinolone moiety, these are merely exemplary and do not limit the linkers.
  • the linker comprises a linker as shown in Figure 10; note that the linkers in Figure 10 are shown attached to a hydroxy on the targeting moiety and to a carboxy on a fluoroquinolone moiety, these are merely exemplary and do not limit the linkers.
  • the linker comprises a linker as shown in Figure 11; note that the linkers in Figure 11 are shown attached to a hydroxy on the targeting moiety and to a carboxy on a fluoroquinolone moiety, these are merely exemplary and do not limit the linkers.
  • compositions comprising a targeting moiety and a therapeutic moiety linked by a linker, where the linker forms a first attachment with the targeting moiety and the linker forms a second attachment with the therapeutic moiety, and wherein the targeting moiety accumulates at a target that is present at and/or accumulates at and/or is activated at a target site, and the therapeutic moiety is active at the target site.
  • the second attachment is cleavable at the target of the targeting moiety.
  • “at the target of the targeting moiety” includes, in the case of a cell, intracellularly and/or in the local environment of the cell (e.g.
  • the “local environment” of a cell includes the environment that immediately surrounds the Cell, e.g., within 1, 10, 100, or 1000 microns of the cell, or within 1, 2, 5, 10, or 20 mm of the cell.
  • the first attachment is cleavable at the target of targeting moiety.
  • both the first and second attachments are cleavable at the target of targeting moiety.
  • neither the first nor the second attachment is cleavable at the target of targeting moiety.
  • the linker is cleavable between the first attachment and the second attachment at the target of targeting moiety.
  • the first and second attachments are covalent bonds.
  • one or both of the covalent bonds are susceptible to hydrolysis at the target, e.g., assisted by esterases or other enzymes, assisted in the environment at the target (e.g., where the composition accumulates in lysosomes with an acidic environment), or simply unstable in aqueous environment.
  • a target of the targeting moiety is a cell or cells and the targeting moiety preferentially accumulates in the cell or cells, e.g., accumulates to a level that is at least 2, 3, 5, 7, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 250, 300, 400, or 500-fold its level in plasma and/or not more than 3, 5, 7, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 250, 300, 400, 500 or 1000-fold its level in plasma, for example, at least 5-fold, in some cases at least 20-fold, or even at least 100-fold or at least 200-fold.
  • the preferential uptake by the target cell or cells can be ascertained by any suitable method, e.g., incubating the cell or cells in plasma containing a known concentration of the targeting moiety for a suitable amount of time, e.g. , a time to reach equilibrium, then measuring the concentration of the targeting moiety in the cell or cells and in the plasma, and determining the ratio.
  • a suitable amount of time e.g. , a time to reach equilibrium
  • the target of the targeting moiety comprises a cell or cells that participate in infection healing, and the targeting moiety preferentially accumulates in the cell or cells, e.g., accumulates to a level that is at least 2, 3, 5, 7, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 250, 300, 400, or 500-fold its level in plasma and/or not more than 3, 5, 7, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 250, 300, 400, 500 or 1000-fold its level in plasma, for example, at least 5-fold, in some cases at least 20-fold, or even at least 100-fold or at least 200-fold.
  • the cells or cells that participates in infection healing comprises an immune cell or cells.
  • the immune cell comprises a phagocytic cell, such as neutrophils, monocytes, macrophages, mast cells, and/or dendritic cells.
  • the cell comprises a neutrophil.
  • the cell or cells that participates in infection healing comprises a fibroblast; in certain cases the fibroblast comprises a differentiated fibroblast, such as a myofibroblast.
  • the target cell or cells can be cells that accumulate at the site of a condition to be treated by the therapeutic moiety. These are cells that accumulate to modulate the condition, and not cells causing the condition, e.g., in the case of cancer the target cells would not be cancer cells themselves.
  • the targeting moiety-linker-therapeutic moiety also referred to as the “prodrug,” is administered to an individual who has the condition, travels to the target, e.g., target cell or cells of the targeting moiety, and is taken up by the target, e.g., the cells and/or an organelles of the cells.
  • the first and second attachments, and the linker are stable enough during the travel to the target cell or cells that a sufficient amount of the prodrug is taken up by the target cell or cells that a therapeutically effective amount of the therapeutic moiety can be present at the site of the condition.
  • the first and second attachments, and the linker are stable enough during the travel to the target cell or cells that the amount of targeting moiety, linker, and/or therapeutic moiety present in the time before the prodrug is taken up by the target cell or cells does not cause an adverse effect in the individual to which it is administered, or does not cause a significant adverse effect, e.g. , an adverse effect of sufficient severity that treatment must be halted or significantly decreased.
  • a prodrug administered orally must be stable enough in at least the digestive tract and plasma for the time that it takes to travel to and be taken up by its target, e.g.
  • target cells which will be considerably longer than that necessary for, e.g., a prodrug used to treat a pulmonary infection that is administered by inhalation that may come immediately or very quickly into contact with its target, e.g., target cell or cells, e.g., immune cells and/or fibroblasts at the site of the pulmonary infection, and that does not necessarily substantially come in contact with plasma or other bodily fluids besides those encountered in the airways and alveoli.
  • target cell or cells e.g., immune cells and/or fibroblasts at the site of the pulmonary infection
  • at least some of the targeting moiety is taken up by lysosomes in the target cell or cells.
  • condition to be treated is a microbial infection and the therapeutic moiety comprises an antimicrobial, such as an antifungal, antiviral, antiparasitic, or antibiotic.
  • condition comprises a bacterial infection and the therapeutic moiety comprises an antibiotic.
  • the targeting moiety can be any suitable targeting moiety.
  • the targeting moiety has a therapeutic action, that can be the same or different than the therapeutic action of the therapeutic moiety.
  • it is desirable that the first attachment also is sufficiently labile in the target cell or cells or organelles thereof that it is released at a therapeutically effective rate and amount, and/or that the targeting moiety has sufficient therapeutic activity while still attached to the linker.
  • the targeting moiety comprises an antibiotic, such as a macrolide antibiotic.
  • the macrolide antibiotic comprises erythromycin, clarithromycin, fidaxomicin, spiramycin, telithromycin, carbonmycin A, josamycin, kitsamycin, midecamycin, oleandomycin, solithromycin, troleandomycin, tylosin, roxitromycin or azithromycin.
  • the macrolide antibiotic is erythromycin, clarithromycin, or azithromycin.
  • the macrolide antibiotic comprises azithromycin.
  • the macrolide antibiotic comprises clarithromycin.
  • the macrolide antibiotic comprises erythromycin.
  • the first attachment, between the linker and the macrolide may be at any suitable site on the macrolide antibiotic, such as a hydroxy group; for erythromycin and azithromycin these include a hydroxy group at position -6, -11, -12, -2’ or -4”; for clarithromycin these include a hydroxy group at position -11, -12, -2’ or -4”.
  • the therapeutic moiety can be any suitable therapeutic moiety.
  • the therapeutic moiety comprises an antibiotic.
  • the targeting moiety comprises a first antibiotic and the therapeutic moiety comprises a second antibiotic, different from the first. Any suitable antibiotic may be used as the therapeutic moiety.
  • the therapeutic moiety comprises a tetracycline, beta-lactam, or fluoroquinolone antibiotic.
  • the fluoroquinolone antibiotic comprises acorafloxacin, amifloxacin, antofloxacin, avarofloxacin, balofloxacin, benofloxacin, besifloxacin, cadroflocacin, chinfloxacin, ciprofloxacin, clinafloxacin, danofloxacin, delafloxacin, ecenofloxacin, enoxacin, enrofloxacin, esafloxacin, fandofloxacin, finafloxacin, fleroxacin, gatifloxacin, gemifloxacin, grepafloxacin, irloxacin, lemefloxacin, levofloxacin, levonadifloxacin, lomefloxacin, marbofloxacin, merafloxacin, motifloxacin, nadifloxacin, nemonoxacin (
  • the fluoroquinolone comprises ciprofloxacin, moxifloxacin, gemifloxacin, levofloxacin, levonadifloxacin or delafloxacin, or a combination thereof. In certain embodiments the fluoroquinolone comprises ciprofloxacin. In certain embodiments the fluoroquinolone comprises moxifloxacin. In certain embodiments the fluoroquinolone comprises gemifloxacin. In certain embodiments the fluoroquinolone comprises levonadifloxacin. In certain embodiments the fluoroquinolone comprises delafloxacin. In certain embodiments the fluoroquinolone comprises levofloxacin.
  • the second attachment, between the linker and the antibiotic is at a carboxy group of the antibiotic, for example a carboxy group of a fluoroquinolone; e.g., an ester linkage.
  • the second attachment, between the linker and the antibiotic is at an amino group of the antibiotic, for example an amino group of a fluoroquinolone.
  • the second attachment, between the linker and the antibiotic is at a hydroxy group of the antibiotic, for example a hydroxy of a fluoroquinolone, if available.
  • the therapeutic moiety comprises one of the following structures:
  • the therapeutic moiety comprises one of the following structures: [0086] In certain embodiments, the therapeutic moiety comprises an antibiotic effective for treating a non-tuberculosis mycobacterial (NTM) infection. In certain embodiments, the antibiotic comprises an antibiotic effective for treating Mycobacterium avium complex (MAC). In certain embodiments, MAC comprises Mycobacterium avium and Mycobacterium intracellulare . Any suitable antibiotic can be used to target the NTM infection and/or MAC infection.
  • NTM non-tuberculosis mycobacterial
  • MAC Mycobacterium avium complex
  • MAC comprises Mycobacterium avium and Mycobacterium intracellulare . Any suitable antibiotic can be used to target the NTM infection and/or MAC infection.
  • the antibiotic comprises a macrolide, such as azithromycin or clarithromycin, rifampin, ethambutol, aminoglycoside, inhaled amikacin, clfazimine, rifabutin, ciprofloxacin, moxifloxacin, or amikacin, or combinations thereof.
  • a targeting moiety comprises a macrolide, e.g., azithromycin, and a therapeutic moiety comprises a fluoroquinolone, such as ciprofloxacin or moxifloxacin; it will be appreciated that in such cases, the tarteting moiety also acts as a therapeutic moiety.
  • the antibiotic is an antibiotic that has been approved for use in humans (e.g., approved in the United States), as known in the art. In certain embodiments, the antibiotic is an antibiotic that has been approved for use in animals but not humans (e.g., in the United States), as known in the art.
  • the therapeutic moiety comprises a compound that inhibits one or more transporters (efflux pumps) involved in a drug resistance mechanism.
  • a composition comprising a targeting moiety and a transporter inhibitor linked by a linker, where the linker forms a first attachment with the targeting moiety and the linker forms a second attachment with the transporter inhibitor, and wherein the targeting moiety accumulates at a target that is present at and/or accumulates at and/or is activated at or near a target site, and the transporter inhibitor is active at the target site.
  • the transporter inhibitor can inhibit any suitable transporter.
  • the transporter inhibitor inhibits, or at least partially inhibits, one or more efflux pumps of the resistance-nodulation-division (RnD family, such as AcrAB-TolC (E. coli and S. typhimurium), which can export chloramphenicol, fluoroquinolone, tetracycline, novobiocin, rifampin, fusidic acid, anidixic acid, and beta-lactam antibiotics; MexAB-OprM, MexXY-OprM (P. aeruginosa), which can export fluoroquinolones, tetracycline, and chloramphenicol, AdeABC (A.
  • RnD family such as AcrAB-TolC (E. coli and S. typhimurium)
  • MexAB-OprM MexXY-OprM (P. aeruginosa)
  • AdeABC AdeABC
  • MFS multidrug and toxic compound extrusion
  • the tranporter inhibitor inhibits P -glycoprotein (P-gp), breast cancer resistance protein (BCRP), LmrA, ABC transporter, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, MATE-2K, OCT2, AdeABC, AmeABC, AmrAB, BpeAB, CmeABC, Bmr, Bit, AcrAB, AcrD, AcrEF, CusCFBA, EmrAB, EmrKY, MdtABC, MdtEF, FarAB, MtrCDE, MexAB, MexCD, MexEF, MexXY, ArpAB, SrpABC, TtgABC, TtgDEF, TtgGHI, AcrAB, AcrD, AcrEF, MacAB, MdsABC, MdtABC, MepA, QacA, SmeABC, SmeDEF, NorA, PmrA, OprM, or OqxAB or
  • the transport inhibitor inhibits a transporter involved in biofdm formation/maintenance, as known in the art. See, e.g., transporters and inhibitors described in Alav et al., J Antimicrob Chemother 2018 73: 2003-2020, for example one or more of the inhibitors CCCP, l-(l-napthylmethyl) piperazine (NMP), PABN, thioridazine, 4’,5’-O- dicaffeoylquinic acid, reserpine, chlorpromazine, or MP-601205, or a combination thereof.
  • a transporter involved in biofdm formation/maintenance as known in the art. See, e.g., transporters and inhibitors described in Alav et al., J Antimicrob Chemother 2018 73: 2003-2020, for example one or more of the inhibitors CCCP, l-(l-napthylmethyl) piperazine (NMP), PABN, thioridazine
  • the transporter inhibitor is MP-601205, for example, formulated in a composition suitable for inhalation, thus providing high local concentrations in the lungs and lower systemic exposure; thus such a composition can be used to treat bacterial infections of the lungs, e.g., in cystic fibrosis patients, generally in combination with one or more antibiotics or antibiotic conjugates, as described herein.
  • the transporter inhibitor inhibits, or at least partially inhibits, P-gp and/or BRCP, more preferably P-gp, even more preferably BRCP.
  • the transporter inhibitor inhibits, or at least partially inhibits, a transporter comprising P- glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP).
  • the transporter inhibitor inhibits, or at least partially inhibits, a transporter comprising P-glycoprotein (P-gp).
  • the transporter inhibitor inhibits, or at least partially inhibits, a transporter comprising breast cancer resistance protein (BCRP).
  • Any suitable transporter inhibitor can be used, such as benzylpenicillin, bromosulfopthalein, cimetidine, clofazimine, clonidine, cyclosporine, elacridar, estrone-3- sulfate, fumitremorgin C, ketoconazole, K0- 143, novobiocin, probenecid, pyrimethamine, quinidine, rifampicin, rifamycin SV, valspodar, verapamil, chloroquinolone, Ikoxyquinolone, alkylaminoquinolone, pyrridoquinolone, thioalkoxy quinolone, pheophorbide a, 3 -arylpiperidine, EA-371a ,EA-3718, Naphthylpiperazines, genistein, spinosan A, Tiliroside, phenylalanyl- arginyl-b-naphth
  • any suitable linker can be used, so long as the first and second attachments have the requisite stability (for both attachments in the environments to which the prodrug is exposed before it reaches the interior of the target cell) and lability (for attachments or linker between the attachments, in embodiments in which one or both attachments, or the linker between attachments is cleaved, in the environment within the target cell or in the environment of the target cell).
  • the linker comprises a linker as shown in Figure 6; note that the linkers in Figure 6 are shown attached to a hydroxy on the targeting moiety and to a carboxy on a fluoroquinolone moiety, these are merely exemplary and do not limit the linkers. Also note that the top left hand structure shows direct linkage with no intermediate linkage.
  • the linker comprises -C(O)O-C(RI)(R2)-, wherein Ri and R2 are independently selected from H, Me, Et, z-Pr, CH2NH2, CEENHMe, CH2NHC(O)Me, CH2NmeC(O)Me, CEENHMe, CH2Nme2, Ome.
  • the linker comprises a linker as shown in Figure 7; note that the linkers in Figure 7 are shown attached to a hydroxy on the targeting moiety and to a carboxy on a fluoroquinolone moiety, these are merely exemplary and do not limit the linkers.
  • the linker comprises -CH2OC(O)O-C(RI)(R2)-, wherein Ri and R2 are independently selected from H, Me, Et, z-Pr, CH2NH2, CEENHMe, CH2NHC(O)Me, CH2NmeC(O)Me, CEENHMe, CH2Nme2.
  • the linker comprises a linker as shown in Figure 8; note that the linkers in Figure 8 are shown attached to a hydroxy on the targeting moiety and to a carboxy on a fluoroquinolone moiety, these are merely exemplary and do not limit the linkers.
  • the linker comprises a linker as shown in Figure 9; note that the linkers in Figure 9 are shown attached to a hydroxy on the targeting moiety and to a carboxy on a fluoroquinolone moiety, these are merely exemplary and do not limit the linkers.
  • the linker comprises a linker as shown in Figure 10; note that the linkers in Figure 10 are shown attached to a hydroxy on the targeting moiety and to a carboxy on a fluoroquinolone moiety, these are merely exemplary and do not limit the linkers.
  • the linker comprises a linker as shown in Figure 11; note that the linkers in Figure 11 are shown attached to a hydroxy on the targeting moiety and to a carboxy on a fluoroquinolone moiety, these are merely exemplary and do not limit the linkers.
  • both the targeting moiety and the therapeutic moiety comprise antibiotics, e.g. , different antibiotics, such as a targeting moiety that comprises an antibiotic active against Gram positive bacteria and a therapeutic moiety that comprises an antibiotic that is active against Gram negative bacteria.
  • a composition comprising a first antibiotic, such as a first antibiotic comprising a macrolide antibiotic; a second antibiotic, which can be the same as or different from the first antibiotic; and a linker that is attached to the first antibiotic at a first attachment and to the second antibiotic at a second attachment.
  • a first antibiotic such as a first antibiotic comprising a macrolide antibiotic
  • a second antibiotic which can be the same as or different from the first antibiotic
  • a linker that is attached to the first antibiotic at a first attachment and to the second antibiotic at a second attachment.
  • the second antibiotic is a tetracycline, beta-lactam, or fluoroquinolone
  • the second antibiotic is a fluoroquinolone.
  • Any suitable first antibiotic e.g., macrolide antibiotic, may be used.
  • the macrolide antibiotic comprises erythromycin, clarithromycin, fidaxomicin, spiramycin, telithromycin, carbonmycin A, josamycin, kitsamycin, midecamycin, oleandomycin, solithromycin, troleandomycin, tylosin, roxitromycin or azithromycin.
  • the macrolide antibiotic is erythromycin, clarithromycin, or azithromycin.
  • the macrolide antibiotic comprises azithromycin.
  • the macrolide antibiotic comprises erythromycin.
  • the macrolide antibiotic comprises clarithromycin.
  • the first attachment, between the linker and the macrolide may be at any suitable site on the macrolide antibiotic, such as a hydroxy group; for erythromycin and azithromycin these include a hydroxy group at position -6, -11, -12, -2’ or -4”; for clarithromycin these include a hydroxy group at position -11, -12, -2’ or -4”.
  • the second antibiotic comprises a beta-lactam, such as a carbapenem, a cephalosporin, a monobactam, or a penicillin.
  • the beta-lactam comprises a carbapenem, such as imipenem, meropenem, panipenem, biapenem, ertapenem, or tebipenem.
  • the beta- lactam comprises a cephalosporin, such as a third- or fourth-generation cephalosporin.
  • the beta-lactam comprises a penicillin, such as an aminopenicillin, e.g., ampicillin, amoxicillin; an antipseudomonal penicillin, e.g., carbenicillin, piperacillin, ticarcillin; a natural penicillin, e.g., penicillin G, procaine penicillin G, penicillin V, benzathine; a penicillinase resistant penicillin, e.g., oxacillin, dicloxacillin, nafcillin.
  • the betalactam comprises a monobactam, such as aztreonam, tigemonam, nocardicin A, tabtoxin.
  • a beta-lactam antibiotic is used in combination with a beta-lactamase inhibitor.
  • Any suitable form, dosage, and route of administration of beta-lactamase inhibitor may be used, for example, a beta-lactamase inhibitor linked to the first antibiotic, which is also linked to the second antibiotic in a single composition, or a beta-lactamase inhibitor linked to the first antibiotic as a separate composition, or a beta-lactamase inhibitor linked to the second antibiotic, or administered alone, or in any other suitable form.
  • the second antibiotic comprises a tetracycline antibiotic.
  • the second antibiotic comprises a fluoroquinolone, such as acorafloxacin, amifloxacin, antofloxacin, avarofloxacin, balofloxacin, benofloxacin, besifloxacin, cadroflocacin, chinfloxacin, ciprofloxacin, clinafloxacin, danofloxacin, delafloxacin, ecenofloxacin, enoxacin, enrofloxacin, esafloxacin, fandofloxacin, finafloxacin, fleroxacin, gatifloxacin, gemifloxacin, grepafloxacin, irloxacin, lemefloxacin, levofloxacin, levonadifloxacin, lomefloxacin, marbofloxacin, merafloxacin, motifloxacin, nadifloxacin,
  • the second antibiotic comprises a fluoroquinolone that is ciprofloxacin, moxifloxacin, gemifloxacin, levofloxacin, levonadifloxacin or delafloxacin. In certain embodiments the second antibiotic comprises a fluoroquinolone that is ciprofloxacin. In certain embodiments the second antibiotic comprises a fluoroquinolone that is moxifloxacin. In certain embodiments the second antibiotic comprises a fluoroquinolone that is gemifloxacin. In certain embodiments the second antibiotic comprises a fluoroquinolone that is levofloxacin. In certain embodiments the second antibiotic comprises a fluoroquinolone that is levonadifloxacin.
  • the second antibiotic comprises a fluoroquinolone that is delafloxacin.
  • the first antibiotic comprises an antibiotic active against Gram positive bacteria and second antibiotic an antibiotic active against Gram negative bacteria. Any suitable linker between the first antibiotic and the second antibiotic may be used.
  • the linker is covalently bonded to a hydroxy group of the first antibiotic, such as a hydroxy group of a macrolide antibiotic.
  • the linker is covalently bonded to a hydroxy of azithromycin or erythromycin at position -6, -11, -12, -2’ or -4”; in certain embodiments the linker is covalently bonded to a hydroxy of clarithromycin at position -11, -12, -2’ or -4”.
  • the linker is covalently bonded to a carboxy group of the second antibiotic, such as a carboxy group of a fluoroquinolone. In certain embodiments, the linker is covalently bonded to an amino group of the second antibiotic, such as an amino group of a fluoroquinolone. In certain embodiments, the linker is covalently bonded to a hydroxy group of the second antibiotic, such as a hydroxy group of a fluoroquinolone.
  • the linker comprises -C(O)O-C(RI)(R2)-, wherein Ri and R2 are independently selected from H, Me, Et, z- Pr, CH2NH2, CH 2 NHMe, CH 2 NHC(O)Me, CH 2 NmeC(O)Me, CH 2 NHMe, CH 2 Nme2, Ome; exemplary linkers and linkages are shown in Figure 7.
  • the linker comprises -CH2OC(O)O-C(RI)(R2)-, wherein Ri and R2 are independently selected from H, Me, Et, z-Pr, CH2NH2, CH 2 NHMe, CH 2 NHC(O)Me, CH 2 NmeC(O)Me, CH 2 NHMe, CH 2 Nme2; exemplary linkers and linkages are shown in Figure 8.
  • the linker comprises
  • a cell associated with infection healing such as an immune cell or a wound healing cells such as a fibroblast
  • a composition comprising a targeting moiety linked, e.g., covalently linked, to a linker and a therapeutic moiety also linked, e.g., covalently linked to the linker, such as one of the prodrugs as described herein, and/or components of the prodrug, e.g., the targeting moiety linked to the linker, the targeting moiety alone (free targeting moiety), the therapeutic moiety alone (free therapeutic moiety), the therapeutic moiety linked to the linker, and/or the linker.
  • the infection healing cell can be one of the cells as described herein, for example, a neutrophil, or a fibroblast.
  • the targeting moiety- linker-therapeutic moiety and/or various components are located intracellularly, such as in cytosol and/or one or more organelles. In certain embodiments, at least some of the targeting moiety-linker-therapeutic moiety and/or various components are located in lysosomes of the cell.
  • the therapeutic moiety such as an antibiotic, e.g., an antibiotic comprising a tetracycline, beta-lactam, or fluoroquinolone, whether in a form where it is linked to the linker and/or released from the linker at the second attachment or at a site between the first and second attachments, may be present at a concentration greater than that at which it would accumulate in the cell under normal physiological conditions, e.g., at normal concentrations of administration of the therapeutic moiety, e.g., antibiotic alone, i.e., not as part of the prodrug.
  • an antibiotic e.g., an antibiotic comprising a tetracycline, beta-lactam, or fluoroquinolone
  • the therapeutic moiety e.g., antibiotic (free or attached, as described above)
  • extracellular concentration of therapeutic moiety e.g., antibiotic
  • extracellular concentration of therapeutic moiety e.g., antibiotic
  • Such a ratio may be determined by exposing a relevant infection healing cell, e.g., immune cell or fibroblast, to prodrug at a concentration equivalent to a concentration at which it would be present in the blood or tissue during normal administration (e.g., at normal concentrations of administration of the therapeutic moiety), and determining the intracellular concentration after a suitable period of exposure to the prodrug, or it may be determined from measurements of concentrations achieved intracellularly and extracellularly in vivo.
  • a relevant infection healing cell e.g., immune cell or fibroblast
  • the intracellular concentration of the therapeutic moiety is at least 0.001, 0.1, 1.0, 5, 10, 20, 50, 100, 200, 500, ng/ml or 1, 2, 3, 4, 5, 7, 10, 15, 20, 50, 100, or 500 ug/ml or 1, 2, 3, 4, 5, 7, 10, 15, 20, 50, 100, or 500 mg/ml; and/or not more than 0. 1, 1.0, 5, 10, 20, 50, 100, 200, 500, ng/ml or 1, 2, 3, 4, 5, 7, 10, 15, 20, 50, 100, 200, 500, ug/ml or 1, 2, 3, 4, 5, 7, 10, 15, 20, 50, 100, 500, or 1000 mg/ml.
  • the therapeutic moiety e.g., antibiotic is at least 0.001, 0.1, 1.0, 5, 10, 20, 50, 100, 200, 500, ng/ml or 1, 2, 3, 4, 5, 7, 10, 15, 20, 50, 100, or 500 ug/ml or 1, 2, 3, 4, 5, 7, 10, 15, 20, 50, 100, 500, or 1000 mg/ml.
  • the therapeutic moiety comprises an antibiotic that does not normally accumulate intracellularly or does not substantially accumulate in an infection healing cell, such as a beta-lactam, e.g., a cephalosporin.
  • the therapeutic moiety comprises an antibiotic that accumulates in the infection healing cell, but not at a concentration seen when it is contacted with the cell as part of a targeting moiety-linker-therapeutic moiety construct (prodrug), for example a tetracycline or fluoroquinolone.
  • prodrug for example a tetracycline or fluoroquinolone.
  • at least 50% of the therapeutic moiety, e.g., antibiotic is present in the cytosol.
  • the immune cell comprising the therapeutic moiety, e.g., antibiotic is capable of normal or substantially normal function.
  • the cell comprises an immune cell that is a phagocytic cell, for example, a neutrophil.
  • both the therapeutic moiety and the targeting moiety are present in the cell in free form, i. e.
  • the targeting moiety is itself a therapeutic moiety, e.g., an antibiotic; in certain embodiments both the targeting moiety and the therapeutic moiety are antibiotics, e.g., different antibiotics, such as a targeting moiety that comprises an antibiotic active against Gram positive bacteria and a therapeutic moiety that comprises an antibiotic that is active against Gram negative bacteria.
  • the free targeting moiety may be present in the cytosol of the cell and/or one or more organelles of the cell, as for the therapeutic moiety, and concentrations of the free targeting moiety.
  • the former can be expressed as the ratio of intracellular concentration of the targeting moiety, e.g., antibiotic to extracellular concentration of targeting moiety, e.g., antibiotic, e.g., a ratio of at least 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 27, 30, 25, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 300, 400, or 500 and/or not more than 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 27, 30, 25, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 300, 400, 500, or 1000.
  • Such a ratio may be determined by exposing a relevant infection healing cell, e.g., immune cell or fibroblast, to prodrug at a concentration equivalent to a concentration at which it would be present in the blood or tissue during normal administration, and determining the intracellular concentration after a suitable period of exposure to the prodrug, or it may be determined from measurements of concentrations achieved intracellularly and extracellularly in vivo.
  • a relevant infection healing cell e.g., immune cell or fibroblast
  • the intracellular concentration of the targeting moiety is at least 0.001, 0.1, 1.0, 5, 10, 20, 50, 100, 200, 500, ng/ml or 1, 2, 3, 4, 5, 7, 10, 15, 20, 50, 100, or 500 ug/ml or 1, 2, 3, 4, 5, 7, 10, 15, 20, 50, 100, or 500 mg/ml; and/or not more than 0.1, 1.0, 5, 10, 20, 50, 100, 200, 500, ng/ml or 1, 2, 3, 4, 5, 7, 10, 15, 20, 50, 100, 200, 500, ug/ml or 1, 2, 3, 4, 5, 7, 10, 15, 20, 50, 100, 500, or 1000 mg/ml.
  • the targeting moiety e.g., antibiotic is at least 0.001, 0.1, 1.0, 5, 10, 20, 50, 100, 200, 500, ng/ml or 1, 2, 3, 4, 5, 7, 10, 15, 20, 50, 100, or 500 ug/ml or 1, 2, 3, 4, 5, 7, 10, 15, 20, 50, 100, 500, or 1000 mg/ml.
  • the targeting moiety e.g., antibiotic
  • the targeting moiety comprises an antibiotic active against Gram positive bacteria and the therapeutic moiety comprises an antibiotic active against Gram negative bacteria.
  • a pharmaceutical composition comprising a composition comprising a targeting moiety linked to a linker and a therapeutic moiety also linked to the linker, such as one of the prodrugs as described herein, and a pharmaceutically acceptable excipient.
  • a pharmaceutically acceptable excipient may be any suitable excipient.
  • pharmaceutically acceptable refers to a carrier that is compatible with the other ingredients of a pharmaceutical composition and can be safely administered to a subject. The term is used synonymously with “physiologically acceptable” and “pharmacologically acceptable”. Pharmaceutical compositions and techniques for their preparation and use are known to those of skill in the art in light of the present disclosure.
  • a pharmaceutical composition will generally comprise agents for buffering and preservation in storage, and can include buffers and carriers for appropriate delivery, depending on the route of administration.
  • buffers and carriers include, without limitation, normal (0.9%) saline, phosphate-buffered saline (PBS) Hank’s balanced salt solution (HBSS) and multiple electrolyte solutions such as PlasmaLyte ATM (Baxter).
  • excipients include any that are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid, glutathione, cysteine, methionine and citric acid; preservatives (such as ethanol, benzyl alcohol, phenol, m-cresol, p-chlor-m-cresol, methyl or propyl parabens, benzalkonium chloride, or combinations thereof); amino acids such as arginine, glycine, ornithine, lysine, histidine, glutamic acid, aspartic acid, isoleucine, leucine, alanine, phenylalanine, tyrosine, tryptophan, methionine, serine, proline and combinations thereof; monosaccharides, disaccharides and other carbohydrates; low molecular weight (less than about 10 residues) polypeptides; proteins, such as gelatin or serum albumin;
  • a pharmaceutical composition comprising a composition comprising a targeting moiety covalently linked to a linker and a therapeutic moiety also covalently linked to the linker, such as one of the prodrugs as described herein, in a form suitable for inhalation therapy, which includes any suitable method for delivering the composition to the middle and lower airways and the lungs.
  • the composition is suitable for administration by an inhaler, by a ventilation apparatus, or by any other suitable means for introducing the composition into the airways and lungs of a subject.
  • a prodrug as described herein is produced as a pharmaceutical composition suitable for aerosol formation, acceptable taste, storage stability, and patient safety and tolerability.
  • a particular formulation of a prodrug as disclosed herein is combined with a particular aerosolizing device to provide an aerosol for inhalation that is optimized for suitable drug deposition at a site of infection and suitable tolerability.
  • Factors that can be optimized include solution or solid particle formulation, rate of delivery, and particle size and distribution produced by the aerosolizing device.
  • compositions include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., powders, liquids, suspensions, complexations, liposomes, particulates, or the like.
  • the composition is a solid composition suitable for dry powder aerosol formation and inhalation.
  • the composition is a liquid composition suitable for liquid aerosol formation and inhalation, e.g., a suspension or solution.
  • the composition is a liposomal composition.
  • a prodrug for inhalation can be administered either alone or in combination with a suitable pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium croscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like) and/or auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
  • a suitable pharmaceutical carrier e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium croscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like
  • auxiliary substances such as wetting agents
  • the formulation can lack a conventional pharmaceutical carrier, excipient or the like.
  • Certain embodiments include a formulation lacking lactose.
  • Certain embodiments comprise lactose at a concentration less than about 10%, 5%, 1%, or 0. 1%.
  • the pharmaceutical formulation will contain about 0.005% to 95%, such as about 0.5% to 50%, for example 5 to 40% by weight of a prodrug as described herein. [0103] Any suitable method may be used to prepare a composition of the invention.
  • compositions comprising a liposome comprising a first therapeutic agent.
  • the composition further comprises a second therapeutic agent different from the first.
  • the composition further comprises a third, fourth, fifth, sixth, seventh, eighth, ninth, and/or tenth therapeutic agent each of which is different from the others.
  • the therapeutic agents can be any suitable therapeutic agent, such as an antibiotic and/or a prodrug, or transporter inhibitor, as disclosed herein.
  • the first and/or second therapeutic agent can comprise a targeting moiety as disclosed herein, e.g., a targeting moiety linked by a linker to the therapeutic moiety.
  • the therapeutic agent comprises a chemotherapeutic agent.
  • the first therapeutic agent comprises a first antibiotic as disclosed herein, and the second therapeutic agent comprises a second antibiotic as disclosed herein different from the first.
  • the first therapeutic agent comprises a first antibiotic as disclosed herein, and the second therapeutic agent comprises a prodrug as disclosed herein.
  • the first therapeutic agent comprises a first antibiotic as disclosed herein, and the second therapeutic agent comprises a transporter inhibitor as disclosed herein.
  • the first therapeutic agent comprises a first antibiotic as disclosed herein, and the second therapeutic agent comprises a chemotherapeutic agent.
  • the first therapeutic agent comprises a first prodrug as disclosed herein, and the second therapeutic agent comprises a second prodrug as disclosed herein different from the first.
  • the first therapeutic agent comprises a first prodrug as disclosed herein, and the second therapeutic agent comprises a transporter inhibitor as disclosed herein.
  • the first therapeutic agent comprises a first prodrug as disclosed herein, and the second therapeutic agent comprises a chemotherapeutic agent.
  • the first therapeutic agent comprises a first transporter inhibitor as disclosed herein, and the second therapeutic agent comprises a second transporter inhibitor as disclosed herein different from the first.
  • the first therapeutic agent comprises a first transporter inhibitor as disclosed herein, and the second therapeutic agent comprises a chemotherapeutic agent.
  • the first therapeutic agent comprises a first chemotherapeutic agent and the second therapeutic agent comprises a second chemotherapeutic agent different from the first.
  • the therapeutic agent can be any suitable compound for the intended application.
  • the first and/or second therapeutic agent comprise an antimicrobial agent that is an antifungal, antiparasitic, antiviral, or antibacterial (antibiotic) agent.
  • the first and/or second therapeutic comprise an antimicrobial agent.
  • the first and/or second therapeutic agents comprises an antibiotic.
  • the antibiotic can comprise any suitable antibiotic.
  • the antibiotic comprises a fluoroquinolone, a beta-lactam, or a tetracycline.
  • the antibiotic comprises a fluoroquinolone.
  • the antibiotic comprises an antibiotic effective against a Gram-negative bacteria.
  • fluoroquinolone antibiotic can be used, such as acorafloxacin, amifloxacin, antofloxacin, avarofloxacin, balofloxacin, benofloxacin, besifloxacin, cadroflocacin, chinfloxacin, ciprofloxacin, clinafloxacin, danofloxacin, delafloxacin, ecenofloxacin, enoxacin, enrofloxacin, esafloxacin, fandofloxacin, finafloxacin, fleroxacin, gatifloxacin, gemifloxacin, grepafloxacin, irloxacin, lemefloxacin, levofloxacin, levonadifloxacin, lomefloxacin, marbofloxacin, merafloxacin, motifloxacin, nadifloxacin, nemonoxaci
  • the antibiotic comprises a macrolide antibiotic.
  • Any suitable macrolide antibiotic can be used, such as erythromycin, clarithromycin, fidaxomicin, spiramycin, telithromycin, carbonmycin A, josamycin, kitsamycin, midecamycin, oleandomycin, solithromycin, troleandomycin, tylosin, roxitromycin, azithromycin, or a combination thereof, preferably azithromycin, erythromycin, clarithromycin, or a combination thereof.
  • the macrolide antibiotic comprises azithromycin and/or erythromycin.
  • the antibiotic comprises azithromycin.
  • the antibiotic comprises erythromycin.
  • the antibiotic comprises clarithromycin.
  • the therapeutic moiety comprises an antibiotic effective for treating a non-tuberculosis mycobacterial (NTM) infection.
  • the antibiotic comprises an antibiotic effective for treating Mycobacterium avium complex (MAC)
  • the MAC comprises Mycobacterium avium and Mycobacterium intracellulare . Any suitable antibiotic can be used to target the NTM infection and/or MAC infection.
  • the antibiotic comprises a macrolide, such as azithromycin or clarithromycin, rifampin, ethambutol, aminoglycoside, inhaled amikacin, clfazimine, rifabutin, ciprofloxacin, moxifloxacin, or amikacin, or combinations thereof.
  • a targeting moiety comprises a macrolide, e.g., azithromycin, and a therapeutic moiety comprises a fluoroquinolone, such as ciprofloxacin or moxifloxacin; it will be appreciated that in such cases, the tarteting moiety also acts as a therapeutic moiety.
  • the antibiotic is an antibiotic that has been approved for use in humans (e.g., approved in the United States), as known in the art. In certain embodiments, the antibiotic is an antibiotic that has been approved for use in animals but not humans (e.g., in the United States), as known in the art.
  • the therapeutic moiety comprises a compound that inhibits one or more transporters (efflux pumps) involved in a drug resistance mechanism.
  • a composition comprising a targeting moiety and a transporter inhibitor linked by a linker, where the linker forms a first attachment with the targeting moiety and the linker forms a second attachment with the transporter inhibitor, and wherein the targeting moiety accumulates at a target that is present at and/or accumulates at and/or is activated at or near a target site, and the transporter inhibitor is active at the target site.
  • the transporter inhibitor can inhibit any suitable transporter.
  • the transporter inhibitor inhibits, or at least partially inhibits, one or more efflux pumps of the resistance-nodulation-division (RnD family, such as AcrAB-TolC (E. coli and S. typhimurium), which can export chloramphenicol, fluoroquinolone, tetracycline, novobiocin, rifampin, fusidic acid, anidixic acid, and beta-lactam antibiotics; MexAB-OprM, MexXY-OprM (P. aeruginosa), which can export fluoroquinolones, tetracycline, and chloramphenicol, AdeABC (A.
  • RnD family such as AcrAB-TolC (E. coli and S. typhimurium)
  • MexAB-OprM MexXY-OprM (P. aeruginosa)
  • AdeABC AdeABC
  • MFS multidrug and toxic compound extrusion
  • the tranporter inhibitor inhibits P -glycoprotein (P-gp), breast cancer resistance protein (BCRP), LmrA, ABC transporter, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, MATE-2K, OCT2, AdeABC, AmeABC, AmrAB, BpeAB, CmeABC, Bmr, Bit, AcrAB, AcrD, AcrEF, CusCFBA, EmrAB, EmrKY, MdtABC, MdtEF, FarAB, MtrCDE, MexAB, MexCD, MexEF, MexXY, ArpAB, SrpABC, TtgABC, TtgDEF, TtgGHI, AcrAB, AcrD, AcrEF, MacAB, MdsABC, MdtABC, MepA, QacA, SmeABC, SmeDEF, NorA, PmrA, OprM, or OqxAB or
  • the transport inhibitor inhibits a transporter involved in biofdm formation/maintenance, as known in the art. See, e.g., transporters and inhibitors described in Alav et al., J Antimicrob Chemother 2018 73: 2003-2020, for example one or more of the inhibitors CCCP, l-(l-napthylmethyl) piperazine (NMP), PABN, thioridazine, 4’,5’-O- dicaffeoylquinic acid, reserpine, chlorpromazine, or MP-601205, or a combination thereof.
  • a transporter involved in biofdm formation/maintenance as known in the art. See, e.g., transporters and inhibitors described in Alav et al., J Antimicrob Chemother 2018 73: 2003-2020, for example one or more of the inhibitors CCCP, l-(l-napthylmethyl) piperazine (NMP), PABN, thioridazine
  • the transporter inhibitor is MP-601205, for example, formulated in a composition suitable for inhalation, thus providing high local concentrations in the lungs and lower systemic exposure; thus such a composition can be used to treat bacterial infections of the lungs, e.g., in cystic fibrosis patients, generally in combination with one or more antibiotics or antibiotic conjugates, as described herein.
  • the transporter inhibitor inhibits, or at least partially inhibits, P-gp and/or BRCP, more preferably P-gp, even more preferably BRCP. In certain embodiments, the transporter inhibitor inhibits, or at least partially inhibits, a transporter comprising P- glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP). In certain embodiments, the transporter inhibitor inhibits, or at least partially inhibits, a transporter comprising P-glycoprotein (P-gp). In certain embodiments, the transporter inhibitor inhibits, or at least partially inhibits, a transporter comprising breast cancer resistance protein (BCRP).
  • PCRP breast cancer resistance protein
  • Any suitable transporter inhibitor can be used, such as benzylpenicillin, bromosulfopthalein, cimetidine, clofazimine, clonidine, cyclosporine, elacridar, estrone-3- sulfate, fumitremorgin C, ketoconazole, K0- 143, novobiocin, probenecid, pyrimethamine, quinidine, rifampicin, rifamycin SV, valspodar, verapamil, chloroquinolone, Ikoxyquinolone, alkylaminoquinolone, pyrridoquinolone, thioalkoxy quinolone, pheophorbide a, 3 -arylpiperidine, EA-371a ,EA-3718, Naphthylpiperazines, genistein, spinosan A, Tiliroside, phenylalanyl- arginyl-b-naphth
  • a composition as disclosed herein formulated as an emulsion such as a liposome, for example, a unilamellar liposome, a multilamellar liposome, a lipid nanoparticle, or a combination thereof.
  • the liposome is a unilamellar liposome.
  • the liposome is a multilamellar liposome.
  • the composition comprises a first population of liposomes comprising a first therapeutic agent as disclosed herein and a second population of liposomes comprising a second therapeutic agent as disclosed herein.
  • the first and second liposome populations are the same. Additionally or alternatively, the first and second therapeutic agents are the same.
  • the composition is formulated in such a way that the composition can be administered by inhalation.
  • the composition is formulated in such a way that the composition can be used in a delivery device for delivery to the lungs.
  • Any suitable delivery device can be used, such as an aerosolization device, for example a vibrating mesh nebulizer.
  • aerosols of the composition are provided herein.
  • the aerosol has a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to 2.5 microns.
  • the aerosol has a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to 2 microns. In certain embodiments the aerosol has a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to 1.8 microns.
  • the composition further comprises the delivery device, wherein the composition is operably loaded into the delivery device.
  • compositions comprising any one of the compositions as disclosed herein, or a salt, ester, prodrug, or conjugate thereof, or other pharmaceutically acceptable form thereof, in a form suitable for inhalation therapy, which includes any suitable method for delivering the composition to the middle and lower airways and the lungs.
  • the composition is suitable for administration by an inhaler, by a ventilation apparatus, or by any other suitable means for introducing the composition into the airways and lungs of a subject.
  • the composition as disclosed herein is produced as a pharmaceutical composition suitable for aerosol formation, acceptable taste, storage stability, and patient safety and tolerability.
  • a composition as disclosed herein is administered as an aerosol, e.g., to a site of infection in the respiratory tract.
  • aerosol delivery is used to treat an infection in the lungs.
  • An “aerosol,” as that term is used herein, includes a suspension of particles, which may comprise liquid, solid, liposomes, or a combination thereof, dispersed in air or gas.
  • Dry powder formulations generally require less time for drug administration, while liquid formulations generally have longer administration times.
  • a composition as disclosed herein is combined with a particular aerosolizing device to provide an aerosol for inhalation that is optimized for maximum drug deposition at a site of infection and maximal tolerability.
  • Factors that can be optimized include solution or solid particle formulation, rate of delivery, and particle size and distribution produced by the aerosolizing device.
  • Any form of a composition as disclosed herein that is suitable for administration by inhalation may be used.
  • Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., powders, liquids, suspensions, complexations, liposomes, particulates, or the like.
  • the composition is a solid composition suitable for dry powder aerosol formation and inhalation.
  • the composition is a liquid composition suitable for liquid aerosol formation and inhalation, e.g., a suspension or solution.
  • the composition is a liposomal composition.
  • a complex of a composition as disclosed herein with a suitable divalent or trivalent cation, e.g., magnesium can be used as is in a dry formulation, or in combination with additional agents, e.g., agents to provide ease of handling, such as bulking agents, as known in the art.
  • a composition as disclosed herein can be administered either alone, as a pre-formed complex with di- or trivalent metal ion, or in combination with a suitable pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium croscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like) and/or auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
  • a suitable pharmaceutical carrier e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium croscarmellose, glucose, gelatin, sucrose,
  • the formulation can lack a conventional pharmaceutical carrier, excipient or the like.
  • Certain embodiments include a formulation lacking lactose.
  • Certain embodiments comprise lactose at a concentration less than about 10%, 5%, 1%, or 0. 1%.
  • the pharmaceutical formulation will contain about 0.005% to 95%, such as about 0.5% to 50%, for example 5 to 40% by weight of a composition as disclosed herein or a salt, ester, or prodrug thereof.
  • the pharmaceutical formulation comprises a composition as disclosed herein and a divalent or trivalent metal ion, such as magnesium.
  • a pharmaceutical formulation includes a prodrug or conjugate as disclosed herein.
  • Some conjugates are also prodrugs.
  • Exemplary conjugates and prodrugs include phosphate derivatives, where a phosphate can be linked to a suitable group on the drug, e.g., at a carboxyl, an amine, or a hydroxyl; such phosphates are readily cleaved by a variety of phosphatases that are ubiquitous in bodily tissues.
  • a phosphate linked to the active carboxyl such a conjugate is a prodrug in that the phosphate must be released for the compound to exhibit maximum activity.
  • prodrugs or conjugates can be useful in increasing residence time of the compound in, e.g. , lung spaces to which it delivered, e.g. , decrease absorption into systemic circulation.
  • some conjugates/prodrugs such as phosphate conjugates/prodrugs, which are highly charged, are less likely to cross cell membranes.
  • release of active compound from a prodrug can allow for more prolonged maintenance of effective levels in the desired area of activity, e.g., lung spaces to which it is delivered.
  • Liquid compositions suitable for administration by inhalation can be prepared by dissolving, dispersing, etc. a composition as disclosed herein and optional pharmaceutical adjuvants in a liquid carrier, such as water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like, to form a solution or suspension.
  • Solutions to be aerosolized can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to aerosol production and inhalation.
  • the percentage of the composition as disclosed herein contained in such aerosol compositions can be, e.g., 0.01% to 90% in solution, or higher if the composition is a solid, which will be subsequently diluted to the above percentages.
  • the composition comprises 1.0%- 50.0% of the composition as disclosed herein in solution.
  • a liquid formulation e.g., aqueous formulation, suitable for administration by inhalation can have a concentration of a composition as disclosed herein of at least 5, 10, 12, 15, 17, 20, 22, 25, 30, 40, 50, 60, 70, 80, 90, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 300, 400, 500, or 600 mg/ml, and/or not more than 10, 12, 15, 17, 20, 22, 25, 30, 40, 50, 60, 70, 80, 90, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 300, 400, 500, 600 or 700 mg/ml.
  • the formulation has a concentration of the composition as disclosed herein of 10-200 mg/ml, or 10-100 mg/ml, or 20- 50 mg/ml, or 20-40 mg/ml, or 50-200 mg/ml, or 75-150 mg/ml, or 80-125 mg/ml, or 80-120 mg/ml, or 90-125 mg/ml, or 90-120 mg/ml, or 90-110 mg/ml preferably 10-200 mg/ml, more preferably 20-50 mg/ml , even more 50-200 mg/ml, still more preferably 75-150 mg/ml, yet more preferably 80-120 mg/ml.
  • the composition as disclosed herein is present at a concentration of 20-1000, 50-800, 50-750, 50-700, 50-675, 50-650, 50-600, 50-500, 50-400, 50-300, 50-200, 50-100, 75-800, 75-750, 75-700, 75-675, 75-650, 75-600, 75-500, 75- 400, 75-300, 75-200, 75-100, 100-800, 100-750, 100-700, 100-675, 100-650, 100-600, 100-500, 100-400, 100-300, or 100-200 mM, preferably 100-625 mM, more preferably 100-500 mM, even more preferably 100-300 mM.
  • a liquid formulation, e.g., aqueous formulation, suitable for administration by inhalation can have any suitable osmolarity, such as 200-1250, 300-500, 325-450, 350-425, or 350-400 mOsmol/kg.
  • the osmolality of the formulation is greater than about 300, 325, 350, 375, 400, 425, 450, 475, or 500 mOsmol/kg.
  • solution osmolality is 100-600 mOsmol/kg.
  • the solution osmolality is 200-1250 mOsmol/kg; in more preferred embodiments 250-1050 mOsmol/kg; in still more preferred embodiments 350-750 mOsmol/kg.
  • the osmolality of aqueous solutions of a composition as disclosed herein is adjusted by any suitable method, e.g., by providing excipients. Many patients have increased sensitivity to various chemical agents and have high incidence of bronchospastic, asthmatic or other coughing incidents. Their airways are particularly sensitive to hypotonic or hypertonic and acidic or alkaline conditions and to the presence of any permanent ion, such as chloride.
  • any imbalance in these conditions or a presence of chloride above certain value leads to bronchospastic or inflammatory events and/or cough which greatly impair treatment with inhalable formulations. Both these conditions prevent efficient delivery of aerosolized drugs into the endobronchial space.
  • a certain amount of chloride or another anion is needed for successful and efficacious delivery of aerosolized form of a composition as disclosed herein.
  • the chloride concentration is 30-300 mM, more preferably 50-150 mM.
  • Bromide or iodide anions may, in some cases, be substituted for chloride; in some cases, bicarbonate ion may be substituted for chloride.
  • permeant ion concentration is 25-400 mM, or 30-300 mM; or 40-200 mM; or 50-150 mM.
  • a pharmaceutical composition as disclosed herein that is suitable for administration by inhalation is formulated to have good taste, pH of 5.5-7, osmolarity of 200-1250 mOsmol/kg, and permeant ion concentration of 30-300 mM.
  • the solution or diluent used for preparation of an aerosol formulation has a pH high enough that it does not cause bronchospasm and low enough that it has tolerability in body tissues unable to buffer alkaline aerosols and also does not cause bronchospasm, e.g., a pH of at least 4, 4.2, 4.5, 4.7, 5, 5.2, 5.5, 5.7, 6, 6.2, 6.5, 6.7, 7.0, 7.2, 7.5, or 7.7, and/or not more than 4.2, 4.5, 4.7, 5, 5.2, 5.5, 5.7, 6, 6.2, 6.5, 6.7, 7, 7.2, 7.5, 7.7, or 8.
  • a pharmaceutical composition may include a buffer or a pH adjusting agent, such as a salt prepared from an organic acid or base.
  • exemplary buffers include organic acid salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, Tris, tromethamine, hydrochloride, or phosphate buffers.
  • a pharmaceutical composition suitable for administration by inhalation can include a divalent or trivalent cation, or a combination thereof.
  • the divalent or trivalent cation can be one or more of, magnesium, calcium, zinc, copper, aluminum, and/or iron, or a combination thereof.
  • the composition e.g., a solution, comprises magnesium chloride, magnesium sulfate, zinc chloride, or copper chloride.
  • the divalent or trivalent cation (or combination) concentration is from about 25- 400, or 50-400, or 100-300, preferably 100-250, more preferably 125-250, still more preferably 150-250, yet more preferably 175-225, or even more preferably 190-200 mM.
  • the magnesium chloride, magnesium sulfate, zinc chloride, or copper chloride has a concentration of 5-25%, 10-20%, or 15-20%.
  • the ratio of a composition as disclosed herein to divalent or trivalent cation (or combination) is 1: 1 to 2: 1 or 1: 1 to 1:2.
  • the ion is magnesium, for example, magnesium supplied by magnesium chloride.
  • aqueous formulations containing soluble or nanoparticulate particles of a composition as disclosed herein are provided.
  • a composition as disclosed herein may be present at a concentration of about 1 mg/mL up to about 700 mg/mL.
  • Such formulations provide effective delivery to appropriate areas of the lung, with the more concentrated aerosol formulations having the additional advantage of enabling large quantities of drug substance to be delivered to the lung in a very short period of time.
  • a formulation is optimized to provide a well-tolerated formulation, e.g., a formulation with acceptable safety profde and acceptable taste.
  • an aqueous pharmaceutical solution of a composition as disclosed herein formulated to have good taste, pH of 5.5-7, osmolarity of 200-1250 mOsmol/kg, permeant ion concentration of SO- SOO mM.
  • an aqueous pharmaceutical composition as described in this paragraph is contained in a single use sterile container, for example 5-500, 10-200, 20-500, 50- 450, or 100-400 mg of a composition as disclosed herein, such as at least or about 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 mg of a composition as disclosed herein, in some cases in a volume of preferably 0.5-10, more preferably 0.5-5, still more preferably 1-10, even more preferably 1-5 ml.
  • an aqueous pharmaceutical composition as described in this paragraph is contained in a nebulizer
  • an aqueous pharmaceutical solution comprising 5-80, 10-70, 20-60, 20-50, 20-40, 30-100, 40-100, preferably 50-120, more preferably 60-120, even more preferably 80-120, still more preferably 90-110, e.g., 100 mg/ml, of a composition as disclosed herein and preferably 160-240, more preferably 175-225, even more preferably 190- 210, e.g. 200 mM, of a cation.
  • the cation is magnesium, calcium, zinc, copper, aluminum, or iron, or a combination thereof.
  • the cation is magnesium, such as magnesium supplied by magnesium chloride or magnesium sulfate.
  • the osmolarity is 200-700, preferably 300-500, more preferably 350-400 mOsmol/kg.
  • the solution comprises a dose of a composition as disclosed herein of 10, 20, 30, 40, 50, 60, 70, 80, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 mg of the composition as disclosed herein.
  • an aqueous pharmaceutical composition as described in this paragraph is contained in a single use sterile container, for example 5-200, 10-100, 10-60, 20-500, 50-450, or 100-400 mg of a composition as disclosed herein, such as at least or about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 mg of a composition as disclosed herein, for example in 0.5- 10, 0.5-5, 1-10, or 1-5 ml.
  • an aqueous pharmaceutical composition as described in this paragraph is contained in a nebulizer
  • an aqueous pharmaceutical solution comprising 20-40, e.g., 30 mg/ml, or 40-60, e.g., 50 mg/ml, or 60-80, e.g., 70 mg/ml, or 80-100, e.g., 90 mg/ml, or 90-110, e.g., 100 mg/ml of a composition as disclosed herein and 190-210, e.g., 200 mM of a magnesium cation, for example supplied by magnesium chloride, or magnesium sulfate.
  • the osmolarity is 200-1250, 250-1050, 200-700, 300-500, 350-750, or 350-400 mOsmol/kg.
  • the solution comprises a dose of a composition as disclosed herein of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 mg of a composition as disclosed herein.
  • an aqueous pharmaceutical composition as described in this paragraph is contained in a single use sterile container, for example 20-500, 50-450, or 100-400 mg of a composition as disclosed herein, such as at least or about 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 mg of a composition as disclosed herein, for example in 0.5-10, 0.5-5, 1-10, or 1-5 ml.
  • an aqueous pharmaceutical composition as described in this paragraph is contained in a nebulizer
  • a pharmaceutical composition comprising an aqueous solution of a composition as disclosed herein and a divalent or trivalent cation, or a combination thereof, wherein the solution is suitable for inhalation into a lung.
  • the cation is a magnesium cation, for example supplied by magnesium chloride, or magnesium sulfate.
  • the concentration of chloride is 25-400, 100-250, or 125-250 mM.
  • the divalent or trivalent cation, or combination thereof is selected from one or more of calcium, aluminum, zinc, and iron, or a combination thereof.
  • the concentration of a composition as disclosed herein is at least 5, 10, 25, 35, 40, 50, 60, 70, 80, 90, or 100 mg/ml. In certain embodiments, the concentration of a composition as disclosed herein is 5-80, 10-70, 20-60, 20-50, 20-40, 80-120, 5-200, 10-100, 10- 60, 50-800, 75-700, 100-650, or 150-500 mM. In certain embodiments, the osmolarity is 200- 1250, 250-1050, 200-700, 300-500, 350-750, or 350-400 mOsmol/kg. In certain embodiments, the solution has a pH of 4.5-8, 4.5-7.5, 4.5-6, 5-6.5, or 5.5-6.5.
  • an aqueous pharmaceutical composition as described in this paragraph is contained in a single use sterile container, for example 20-500, 50-450, or 100-400 mg of a composition as disclosed herein, such as at least or about 10, 20, 30, 40, 50, 60, 70, 80, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 mg of a composition as disclosed herein, for example in 0.5-10, 0.5-5, 1-10, or 1-5 ml.
  • an aqueous pharmaceutical composition as described in this paragraph is contained in a nebulizer.
  • an aerosol of a solution comprising a composition as disclosed herein and a divalent or trivalent cation, or a combination thereof.
  • the cation is a magnesium cation, for example supplied by magnesium chloride, or magnesium sulfate.
  • the concentration of chloride is 25-400, 100-250, or 125-250 mM.
  • the divalent or trivalent cation is selected from one or more of calcium, aluminum, zinc, and iron, or a combination thereof.
  • the concentration of a composition as disclosed herein is at least 1, 5, 7, 10, 12, 15, 20, 25, 30 35, 40, 50, 60, 70, 80, 90, or 100 mg/ml.
  • the concentration of a composition as disclosed herein is 10-600, 50-800, 75-700, 100-650, or 150-500 mM.
  • the osmolarity is 200-1250, 250-1050, 200-700, 300-500, 350-750, or 350- 400 mOsmol/kg.
  • the solution has a pH of 4.5-8, 4.5-7.5, 4.5-6, 5-6.5, or 5.5-6.5.
  • the solution comprises greater than 20, 30, 40, or 50 mg/ml of a composition as disclosed herein and magnesium chloride, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.
  • the aerosol has a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to 2.5 microns.
  • the solution comprises a composition as disclosed herein at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 100 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.
  • the aerosol has a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to 2 microns.
  • the solution comprises a composition as disclosed herein at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 100 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.
  • the aerosol has a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to 1.8 microns.
  • the solution comprises a composition as disclosed herein at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 100 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg
  • an aerosol dose of a composition as disclosed herein and magnesium solution comprised of a concentration of the composition as disclosed herein greater than 20, 30, 40, or 50 mg/ml and a taste-masking concentration of magnesium wherein the aerosol is comprised of a mist having a mean particle size of between 2 and 5 microns or a particle size geometric standard deviation of less than or equal to 2 microns.
  • the magnesium concentration is 100-250 mM.
  • the pH of the aerosol is 4.5-8, 4.5-7.5, 4.5-6, 5-6.5, 5.5-7.5 or 5.5-6.5.
  • a quantity of the mist contains at least 0.1, 0.5, 0.7, 1, 1.5, 2, 5, 7, 10, 20, 50, 70, or 100 mg of a composition as disclosed herein.
  • the osmolarity is 200-1250, 250-1050, 200-700, 300-500, 350-750, or 350-400 mOsmol/kg.
  • the permeant ion concentration is 100-500, 100-450, 200-500, 200-450, 300-500, 300-450, or 350-450 mM.
  • a pharmaceutical aerosol for nasal, sinonasal or pulmonary administration comprising a dispersed liquid phase and a continuous gas phase, wherein the dispersed liquid phase comprises or consists essentially of aqueous droplets comprising a composition as disclosed herein, and at least one excipient, for example comprising a multivalent metal ion; has a mass median diameter from about 1 to about 5 pm; and has a droplet size distribution exhibiting a geometrical standard deviation less than or equal to about 3.0 pm.
  • the dispersed liquid phase has a mass median diameter from 2 to about 5 pm.
  • the dispersed liquid phase has a droplet size distribution exhibiting a geometrical standard deviation less than or equal to about 2 pm.
  • the aerosol comprises at least one further active compound optionally selected from non-quinolone antibiotics, antifungals, antivirals, lung surfactant, steroids, mucolytics, heparin, transporter inhibitors, chemotherapeutic agents, and anti-inflammatory drugs.
  • the aerosol comprises at least one further active compound optionally selected from non-quinolone antibiotics, antifungals, antivirals, lung surfactant, steroids, mucolytics, and heparin.
  • the aerosol is being emitted from an aerosol generator at a rate of at least about 0.
  • the liquid phase has a viscosity in the range from about 0.8 to about 3 mPa s, wherein a volume of not more than about 10 ml, or 1-5 ml, of the composition comprises an effective dose of the active compound.
  • the aerosol has a surface tension in the range from about 25 to 80 mN/m.
  • the liquid phase comprises at least one excipient capable of affecting the local bioavailability, the release, and/or the local residence time of the active compound at the site of aerosol deposition, such as one or more complexing agents, polymers, or amphiphilic compounds.
  • the liquid phase comprises at least one excipient capable of enhancing the AUC shape of the active compound.
  • the liquid phase comprises at least one taste -modifying excipient selected from the group consisting of flavors, sweeteners, complexing agents and taste masking agents, such as one or more of cyclodextrin, sugar, sugar alcohol, saccharin, aspartame, and arginine.
  • the one or more excipients can improve local tolerability and/or reduce local adverse events.
  • the liquid phase comprises at least one excipient selected from the group of divalent or trivalent metal ions
  • compositions for the preparation of an aerosol comprising an active compound comprising a composition as disclosed herein, and an excipient comprising a polymeric compound, wherein the polymeric compound is selected from the group consisting of derivatized cellulose, dextran, polymeric sugar, polyethylene glycols, pectin and cyclodextrins.
  • kits for the preparation and delivery of an aerosol comprising a composition as disclosed herein for nasal, sinonasal or pulmonary administration comprising a dispersed liquid phase and a continuous gas phase, wherein the dispersed liquid phase comprises or consists essentially of aqueous droplets comprising the composition as disclosed herein, and, in some cases, at least one excipient comprising a multivalent metal ion; has a mass median diameter from of 1-5, or 2-5 pm; and has a droplet size distribution exhibiting a geometrical standard deviation less than or equal to about 3.0 pm, wherein the kit comprises a nebulizer and an aqueous liquid composition, said composition comprising an effective dose of the composition as disclosed herein within a volume of not more than about 10 ml.
  • the dispersed liquid phase has a droplet size distribution exhibiting a geometrical standard deviation less than or equal to about 2 pm.
  • the composition comprises an effective dose of a composition as disclosed herein within a volume from about 1 to about 5 ml.
  • the nebulizer is selected from the group consisting of jet nebulizers, ultrasonic nebulizers, jet collision nebulizers, electrohydrodynamic nebulizers, capillary force nebulizers, perforated membrane nebulizers and perforated vibrating membrane nebulizers.
  • nebulizer is selected from the group consisting of jet nebulizers, ultrasonic nebulizers, and perforated vibrating membrane nebulizers.
  • the nebulizer is adapted to be capable of aerosolizing the liquid composition at a rate of at least about 0. 1 ml/min.
  • the nebulizer is adapted to be capable of aerosolizing a volume of the liquid composition comprising an effective dose of a composition as disclosed herein within not more than about 20 minutes.
  • the nebulizer is adapted to be capable of emitting at least about 50 wt.-% of the aqueous liquid composition as aerosol.
  • at least about 40 wt. -% of the loaded dose is comprised of droplets having a diameter of not more than about 5 um.
  • a method of preparing and delivering an aerosol to a person in need of nasal, sinonasal or pulmonary antibiotic treatment or prophylaxis comprising the steps of providing a liquid pharmaceutical composition comprising an effective dose of a composition as disclosed herein, and, in some cases, at least one excipient comprising a multivalent metal ion, in a volume of not more than about 10 ml; providing a nebulizer capable of aerosolizing said liquid pharmaceutical composition at a total output rate of at least 0.
  • the nebulizer further being adapted to emit an aerosol comprising a dispersed phase having a mass median diameter from about 1 to about 5 pm and a geometrical standard deviation less than or equal to about 3.0 pm; and operating the nebulizer to aerosolize the liquid composition.
  • the volume is from about 1 to about 5 ml.
  • the dispersed phase has a mass median diameter from 2 to about 5 pm.
  • the dispersed phase has a distribution exhibiting a geometrical standard deviation less than or equal to about 2.5 pm.
  • administration is conducted to last not more than about 20 minutes, or less than about 5 minutes.
  • kits comprising a sterile single use container comprising an aqueous solution of a composition as disclosed herein, in some cases also a divalent or trivalent cation, or a combination thereof, wherein the solution is suitable for inhalation into a lung; and a nebulizer adapted to receive solution from the container and to aerosolize the solution for delivery to the lung through oral inhalation.
  • the nebulizer operates by ultrasonic atomization.
  • the nebulizer operates by hydraulic atomization.
  • the nebulizer operates by a vibrating mesh.
  • the nebulizer is adapted to produce particles having a mass median aerodynamic diameter from about 2 microns to about 5. In certain embodiments the nebulizer is adapted to produce particles having a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to about 2 microns. In certain embodiments the nebulizer is adapted to produce particles having a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to about 1.8 microns.
  • the solution comprises a composition as disclosed herein at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 125 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.
  • a system comprising: a reservoir comprising an aqueous solution of a composition as disclosed herein and, in some cases, a divalent or trivalent cation, or a combination thereof, wherein the solution is suitable for inhalation into a lung; and a nebulizer configured to aerosolize the solution for delivery to the lung through oral inhalation.
  • the nebulizer operates by ultrasonic atomization.
  • the nebulizer operates by hydraulic atomization.
  • the nebulizer operates by a vibrating mesh.
  • the nebulizer is adapted to produce particles having a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to about 2.5 microns. In certain embodiments the nebulizer is adapted to produce particles having a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to about 2 microns. In certain embodiments the nebulizer is adapted to produce particles having a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to about 1.8 microns.
  • the solution comprises a composition as disclosed herein at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 125 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.
  • a pharmaceutical composition consisting essentially of an aqueous solution of greater than 20, 30, 40, or 50 mg/ml of a composition as disclosed herein and a divalent or trivalent cation, or a combination thereof, wherein the solution has a pH from about 5.5 to about 6.5 and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.
  • an aqueous pharmaceutical composition as described in this paragraph is contained in a nebulizer.
  • a dispersed liquid phase for nasal, sinonasal or pulmonary administration comprising a dispersed liquid phase and a continuous gas phase, wherein the dispersed liquid phase: consists essentially of aqueous droplets comprising an active compound comprising a composition as disclosed herein, and at least one excipient comprising a multivalent metal ion; has a mass median diameter from about 1 to about 5 m; and has a droplet size distribution exhibiting a geometrical standard deviation less than or equal to about 3.0 um.
  • an aqueous pharmaceutical solution comprising about 20, 30, 40, 50, 60, 70, 80, 90, or 100 mg/ml of a composition as disclosed herein and about 200 mM of magnesium chloride.
  • the solution can have a pH from 5-7.
  • the solution can have an osmolality from about 300 mOsmol/kg to about 500 mOsmol/kg.
  • the solution can comprise a dose of a composition as disclosed herein of 300 mg, or 280 mg, or 260 mg, or 240 mg, or 200 mg, or 180 mg, or 160 mg, or 140 mg, or 120 mg, or 100 mg, or 90 mg, or 80 mg, or 70 mg, or 60 mg, or 50 mg, or 40 mg, or 30 mg.
  • a pharmaceutical composition suitable for administration by inhalation can comprise a concentration of a composition as disclosed herein of 20-100, or 20-80, or 20-60, or 40-100, or 75-150 mg/ml, a magnesium chloride concentration of 150-250 mM, a pH of 5-7; an osmolality of 300-500 mOsmol/kg.
  • the composition lacks lactose.
  • a pharmaceutical composition comprising a composition as disclosed herein may comprise 7-700 mg, 14-300 mg, or 28-280 mg of the composition as disclosed herein per l-5ml of dilute saline (e.g., between 1/10 to 1/1 normal saline).
  • concentration of a solution of a composition as disclosed herein may be greater than about 15 mg/ml, 25 mg/ml, greater than about 35 mg/ml, greater than about 40 mg/ml, or greater than 50 mg/ml.
  • a pharmaceutical composition suitable for administration by inhalation comprises a concentration of a composition as disclosed herein of about 20, 30, 40, 50, 60, 70, 80, 90, or 100 mg/ml, a magnesium chloride concentration of about 200 mM, a pH about 6.2, an osmolality about 383 mOsmol/kg, and, optionally, lacks lactose.
  • a pharmaceutical composition suitable for administration by inhalation consists essentially of a concentration of a composition as disclosed herein of about 20, 30, 40, 50, 60, 70, 80, 90, or 100 mg/ml, a magnesium chloride concentration about of 200 mM, a pH of about 6.2 an osmolality of about 383 mOsmol/kg, and optionally, lacks lactose.
  • a pharmaceutical composition suitable for administration by inhalation consists of a concentration of a composition as disclosed herein of about 20, 30, 40, 50, 60, 70, 80, 90, or 100 mg/ml, a magnesium chloride concentration of about 200 mM, a pH of about 6.2 an osmolality of about 383 mOsmol/kg, and, optionally, lacks lactose.
  • a pharmaceutical composition suitable for administration by inhalation can include a composition as disclosed herein in combination with an additional active agent.
  • additional active agents can include one or more antibiotics, as described above.
  • additional active agents can include bronchodilators, anticholinergics, glucocorticoids, eicosanoid inhibitors, and combinations thereof.
  • bronchodilators include salbutamol, levosalbuterol, terbutaline, fenoterol, terbutlaine, pirbuterol, procaterol, bitolterol, rimiterol, carbuterol, tulobuterol, reproterol, salmeterol, formoterol, arformoterol, bambuterol, clenbuterol, indacterol, theophylline, roflumilast, cilomilast.
  • anticholinergics include pratropium, and tiotropium.
  • glucocorticoids examples include prednisone, fluticasone, budesonide, mometasone, ciclesonide, and beclomethasone.
  • eicosanoids examples include montelukast, pranlukast, zafirlukast, zileuton, ramatroban, and seratrodast.
  • More additional active agents can include puhnozyme, hypertonic saline, agents that restore chloride channel function in CF, inhaled beta-agonists, inhaled antimuscarinic agents, inhaled corticosteroids, and inhaled phosphodiesterase inhibitors.
  • the aerosol antibiotic therapy administered as a treatment or prophylaxis may be used in combination or alternating therapeutic sequence with an additional active agent.
  • the additional active agent may be administered as a treatment, alone, co-formulated, or administered with the aerosol antibiotic therapy.
  • the additional active agent can be mannitol.
  • a pharmaceutical composition suitable for administration by inhalation for example for use in cystic fibrosis, can include a composition as disclosed herein in combination with mannitol.
  • Compositions may further include flavoring agents, taste-masking agents, inorganic salts (e.g., sodium chloride), antimicrobial agents (e.g., benzalkonium chloride), sweeteners, antioxidants, antistatic agents, surfactants (e.g., polysorbates such as "TWEEN 20" and “TWEEN 80"), sorbitan esters, saccharin, cyclodextrins, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines), fatty acids and fatty esters, steroids (e.g., cholesterol), and chelating agents (e.g., EDTA, zinc and other such suitable cations).
  • compositions according to the invention are listed in “Remington: The Science & Practice of Pharmacy", 19.sup.th ed., Williams & Williams, (1995), and in the “Physician's Desk Reference", 52. sup. nd ed., Medical Economics, Montvale, N.J. (1998).
  • a pharmaceutical composition is formulated to improve and/or mask taste. Any suitable manner of improving and/or masking taste may be used.
  • Classes of taste-masking agents for formulation of a composition as disclosed herein include the addition of flavorings, sweeteners, and other various coating strategies.
  • Exemplary substances include sugars such as sucrose, dextrose, and lactose, carboxylic acids, salts such as magnesium and calcium (non-specific or chelation-based fluoroquinolone taste masking), menthol, amino acids or amino acid derivatives such as arginine, lysine, and monosodium glutamate, and synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits, etc.
  • cinnamon oils may include cinnamon oils, oil of wintergreen, peppermint oils, clover oil, bay oil, anise oil, eucalyptus, vanilla, citrus oil such as lemon oil, orange oil, grape and grapefruit oil, fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, apricot, etc.
  • Additional sweeteners include sucrose, dextrose, aspartame (NutrasweetTM ), acesulfame-K, sucralose and saccharin, organic acids (by nonlimiting example citric acid and aspartic acid).
  • Such flavors may be present at any suitable concentration, for example, 0.05-4%.
  • Another approach to improve or mask the taste of unpleasant inhaled drugs is to decrease the drugs solubility, e.g., drugs must dissolve to interact with taste receptors. Hence, to deliver solid forms of the drug may avoid the taste response and acquire the desired improved taste effect.
  • Taste-masking may be accomplished by creation of lipophilic vesicles.
  • Additional coating or capping agents include dextrates (by non-limiting example cyclodextrins may include, 2-hydroxypropyl-beta-cyclodextrin, 2-hydroxypropyl- gamma-cyclodextrin, randomly methylated beta-cyclodextrin, dimethyl-alpha-cyclodextrin, dimethyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin, glucosyl- 1 -alpha-cyclodextrin, glucosyl-2-alpha-cyclodextrin, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and sulfobutylether-beta-cyclodextrin), modified celluloses such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyl propyl methyl cellulose, polyalkylene glycols, polyal
  • non-dissolved forms of a composition as disclosed herein are to administer the drug alone or in simple, non-solubility affecting formulation as a crystalline micronized, dry powder, spray-dried, and nanosuspension formulation.
  • an alternative method is to include tastemodifying agents. These include a taste-masking substance that is mixed with, coated onto or otherwise combined with the active medicament of the composition as disclosed herein.
  • this addition may also serve to improve the taste of another chosen drug product addition, e.g., a mucolytic agent.
  • a mucolytic agent e.g., a mucolytic agent.
  • Such substances include acid phospholipids, lysophospholipid, tocopherol polyethylene glycol succinate, and embonic acid (pamoate). Many of these agents can be used alone or in combination with a composition as disclosed herein for aerosol administration.
  • a method of making a taste-masked pharmaceutical composition comprising forming a solution of a composition as disclosed herein and a divalent or trivalent cation, or a combination thereof, having a pH from about 5.5 to about 6.5 and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.
  • the solution comprises greater than 50 mg/ml of a composition as disclosed herein.
  • the divalent or trivalent cation is in magnesium chloride.
  • the pharmaceutical composition is provided in unit dosage form suitable for single administration of a precise dose.
  • the unit dosage form can also be assembled and packaged together to provide a patient with a prolonged supply, e.g, a weekly or monthly supply and can also incorporate other compounds such as saline, taste masking agents, pharmaceutical excipients, and/or other active ingredients or carriers.
  • solid drug nanoparticles are provided for use in generating dry aerosols or for generating nanoparticles in liquid suspension. Any suitable method may be used to produce the solid composition.
  • powder is made by spray-drying aqueous dispersions of a nanoparticulate drug and a surface modifier to form a dry powder which consists of aggregated drug nanoparticles.
  • the aggregates can have a size of 1-2 microns, which is suitable for deep lung delivery.
  • the aggregate particle size can be increased to target alternative delivery sites, such as the upper bronchial region or nasal mucosa by increasing the concentration of drug in the spray-dried dispersion or by increasing the droplet size generated by the spray dryer.
  • an aqueous dispersion of drug and surface modifier can contain a dissolved diluent such as lactose, mannitol, maltitol, erythritol, and/or allulose, which, when spray dried, forms respirable diluent particles, each of which contains at least one embedded drug nanoparticle and surface modifier.
  • a dissolved diluent such as lactose, mannitol, maltitol, erythritol, and/or allulose, which, when spray dried, forms respirable diluent particles, each of which contains at least one embedded drug nanoparticle and surface modifier.
  • the diluent particles with embedded drug can have a particle size of, e.g., 1-2 microns, suitable for deep lung delivery.
  • the diluent particle size can be increased to target alternate delivery sites, such as the upper bronchial region or nasal mucosa by increasing the concentration of dissolved diluent in the aqueous dispersion prior to spray drying, or by increasing the droplet size generated by the spray dryer.
  • Spray-dried powders can be used in DPIs or pMDIs, either alone or combined with freeze-dried nanoparticulate powder.
  • spray-dried powders containing drug nanoparticles can be reconstituted and used in either jet or ultrasonic nebulizers to generate aqueous dispersions having respirable droplet sizes, where each droplet contains at least one drug nanoparticle. Concentrated nanoparticulate dispersions may also be used in these aspects of the invention.
  • Nanoparticulate drug dispersions can also be freeze-dried to obtain powders suitable for nasal or pulmonary delivery.
  • Such powders may contain aggregated nanoparticulate drug particles having a surface modifier.
  • Such aggregates may have sizes within a respirable range, e.g., 2-5 microns MMAD.
  • Freeze dried powders of the appropriate particle size can also be obtained by freeze drying aqueous dispersions of drug and surface modifier, which additionally contain a dissolved diluent such as lactose or mannitol. In these instances, the freeze dried powders consist of respirable particles of diluent, each of which contains at least one embedded drug nanoparticle. [0160] Freeze-dried powders can be used in DPIs or pMDIs, either alone or combined with spray-dried nanoparticulate powder.
  • freeze-dried powders containing drug nanoparticles can be reconstituted and used in either jet or ultrasonic nebulizers to generate aqueous dispersions that have respirable droplet sizes, where each droplet contains at least one drug nanoparticle.
  • Certain embodiments are directed to a process and composition for propellant-based systems comprising nanoparticulate drug particles and a surface modifier.
  • Such formulations may be prepared by wet milling the coarse drug substance and surface modifier in liquid propellant, either at ambient pressure or under high pressure conditions.
  • dry powders containing drug nanoparticles may be prepared by spray-drying or freeze-drying aqueous dispersions of drug nanoparticles and the resultant powders dispersed into suitable propellants for use in conventional pMDIs.
  • Such nanoparticulate pMDI formulations can be used for either nasal or pulmonary delivery. For pulmonary administration, such formulations afford increased delivery to the deep lung regions because of the small (e.g., 1-2 microns MMAD) particle sizes available from these methods.
  • Concentrated aerosol formulations can also be employed in pMDIs.
  • Another embodiment is directed to dry powders which contain nanoparticulate compositions for pulmonary or nasal delivery.
  • the powders may consist of respirable aggregates of nanoparticulate drug particles, or of respirable particles of a diluent which contains at least one embedded drug nanoparticle.
  • Powders containing nanoparticulate drug particles can be prepared from aqueous dispersions of nanoparticles by removing the water via spray -drying or lyophilization (freeze drying).
  • Dry nanoparticulate compositions can be used in both dry powder inhaler devices (DPIs) and pressurized metered dose inhalers (pMDIs).
  • DPIs dry powder inhaler devices
  • pMDIs pressurized metered dose inhalers
  • dry includes a composition having less than about 5% water.
  • compositions are provided containing nanoparticles which have an effective average particle size of less than 1000 nm, or less than 400 nm, or less than 300 nm, or less than 250 nm, or less than 200 nm, as measured by, for example, light-scattering methods.
  • an effective average particle size of less than 1000 nm it is meant that at least 50% of the drug particles have a weight average particle size of less than 1000 nm when measured by, e.g., light scattering techniques.
  • At least 70% of the drug particles have an average particle size of less than 1000 nm, or at least 90% of the drug particles have an average particle size of less than 1000 nm, or at least 95% of the particles have a weight average particle size of less than 1000 nm.
  • the nanoparticulate agent may be present at a concentration of about 5.0 mg/mL up to about 700 mg/mL.
  • the nanoparticulate agent may be present at a concentration of about 5.0 mg/g up to about 1000 mg/g, depending on the desired drug dosage.
  • Concentrated nanoparticulate aerosols defined as containing a nanoparticulate drug at a concentration of 5.0-700 mg/mL for aqueous aerosol formulations, and 5.0-1000 mg/g for dry powder aerosol formulations, are specifically provided.
  • Such formulations provide effective delivery to appropriate areas of the lung or nasal cavities in short administration times, i.e., less than about 3-15 seconds per dose as compared to administration times of up to 4 to 20 minutes as found in conventional pulmonary nebulizer therapies.
  • Further characteristic suitable for dry powder formulations may be found in Muralidharan et al., Inhalable nanoparticulate powders for respiratory delivery, Nanomedicine: Nanotechnology, Biology, and Medicine 11(2015) 1189-1199.
  • Nanoparticulate drug compositions for aerosol administration can be made by, for example, (1) nebulizing a dispersion of a nanoparticulate drug, obtained by either grinding or precipitation; (2) aerosolizing a dry powder of aggregates of nanoparticulate drug and surface modifier (the aerosolized composition may additionally contain a diluent); or (3) aerosolizing a suspension of nanoparticulate drug or drug aggregates in a non-aqueous propellant.
  • the aggregates of nanoparticulate drug and surface modifier which may additionally contain a diluent, can be made in a non-pressurized or a pressurized non-aqueous system. Concentrated aerosol formulations may also be made via such methods.
  • Milling of aqueous drug to obtain nanoparticulate drug may be performed by dispersing drug particles in a liquid dispersion medium and applying mechanical means in the presence of grinding media to reduce the particle size of the drug to the desired effective average particle size.
  • the particles can be reduced in size in the presence of one or more surface modifiers.
  • the particles can be contacted with one or more surface modifiers after attrition.
  • Other compounds, such as a diluent, can be added to the drug/surface modifier composition during the size reduction process.
  • Dispersions can be manufactured continuously or in a batch mode.
  • Another method of forming nanoparticle dispersion is by microprecipitation.
  • This is a method of preparing stable dispersions of drugs in the presence of one or more surface modifiers and one or more colloid stability enhancing surface active agents free of any trace toxic solvents or solubilized heavy metal impurities.
  • Such a method comprises, for example, (1) dissolving the drug in a suitable solvent with mixing; (2) adding the formulation from step (1) with mixing to a solution comprising at least one surface modifier to form a clear solution; and (3) precipitating the formulation from step (2) with mixing using an appropriate nonsolvent.
  • the method can be followed by removal of any formed salt, if present, by dialysis or diafiltration and concentration of the dispersion by conventional means.
  • the resultant nanoparticulate drug dispersion can be utilized in liquid nebulizers or processed to form a dry powder for use in a DPI or pMDI.
  • a non-aqueous liquid having a vapor pressure of about 1 atm or less at room temperature and in which the drug substance is essentially insoluble may be used as a wet milling medium to make a nanoparticulate drug composition.
  • a slurry of drug and surface modifier may be milled in the nonaqueous medium to generate nanoparticulate drug particles.
  • suitable non-aqueous media include ethanol, trichloromonofluoromethane, (CFC-11), and dichlorotetrafluoroethane (CFC-114).
  • CFC-11 An advantage of using CFC-11 is that it can be handled at only marginally cool room temperatures, whereas CFC-114 requires more controlled conditions to avoid evaporation.
  • the liquid medium may be removed and recovered under vacuum or heating, resulting in a dry nanoparticulate composition.
  • the dry composition may then be filled into a suitable container and charged with a final propellant.
  • exemplary final product propellants which ideally do not contain chlorinated hydrocarbons, include HFA-134a (tetrafluoroethane) and HFA-227 (heptafluoropropane). While non-chlorinated propellants may be preferred for environmental reasons, chlorinated propellants may also be used in this aspect of the invention.
  • a non-aqueous liquid medium having a vapor pressure significantly greater than 1 atm at room temperature may be used in the milling process to make nanoparticulate drug compositions.
  • the milling medium is a suitable halogenated hydrocarbon propellant
  • the resultant dispersion may be filled directly into a suitable pMDI container.
  • the milling medium can be removed and recovered under vacuum or heating to yield a dry nanoparticulate composition. This composition can then be filled into an appropriate container and charged with a suitable propellant for use in a pMDI.
  • Spray drying is a process used to obtain a powder containing nanoparticulate drug particles following particle size reduction of the drug in a liquid medium.
  • spraydrying may be used when the liquid medium has a vapor pressure of less than about 1 atm at room temperature.
  • a spray-dryer is a device which allows for liquid evaporation and drug powder collection.
  • a liquid sample either a solution or suspension, is fed into a spray nozzle.
  • the nozzle generates droplets of the sample within a range of about 20 to about 100 pm in diameter which are then transported by a carrier gas into a drying chamber.
  • the carrier gas temperature is typically from 80-200 °C.
  • the droplets are subjected to rapid liquid evaporation, leaving behind dry particles which are collected in a special reservoir beneath a cyclone apparatus.
  • the collected product will consist of spherical aggregates of the nanoparticulate drug particles. If the liquid sample consists of an aqueous dispersion of nanoparticles in which an inert diluent material was dissolved (such as lactose or mannitol), the collected product will consist of diluent (e.g., lactose or mannitol) particles which contain embedded nanoparticulate drug particles.
  • an inert diluent material such as lactose or mannitol
  • the collected product will consist of diluent (e.g., lactose or mannitol) particles which contain embedded nanoparticulate drug particles.
  • the final size of the collected product can be controlled and depends on the concentration of nanoparticulate drug and/or diluent in the liquid sample, as well as the droplet size produced by the spray-dryer nozzle. Collected products may be used in conventional DPIs for pulmonary or nasal delivery, dispersed in propellants for
  • an inert carrier to the spray-dried material to improve the metering properties of the final product. This may especially be the case when the spray dried powder is very small (less than about 5 pm) or when the intended dose is extremely small, whereby dose metering becomes difficult.
  • carrier particles also known as bulking agents
  • Such carriers typically consist of sugars such as lactose, mannitol, or trehalose.
  • Other inert materials including polysaccharides and cellulosics, may also be useful as carriers.
  • Spray-dried powders containing nanoparticulate drug particles may be used in conventional DPIs, disperse in propellants for use in pMDIs, or reconstituted in a liquid medium for use with nebulizers.
  • compounds that are denatured or destabilized by heat such as compounds having a low melting point (i.e., 70-150 °C.), or for example, biologies, sublimation is preferred over evaporation to obtain a dry powder nanoparticulate drug composition. This is because sublimation avoids the high process temperatures associated with spray-drying.
  • sublimation also known as freeze-drying or lyophilization, can increase the shelf stability of drug compounds, particularly for biological products.
  • Freeze-dried particles can also be reconstituted and used in nebulizers. Aggregates of freeze-dried nanoparticulate drug particles can be blended with either dry powder intermediates or used alone in DPIs and pMDIs for either nasal or pulmonary delivery.
  • Sublimation involves freezing the product and subjecting the sample to strong vacuum conditions. This allows for the formed ice to be transformed directly from a solid state to a vapor state. Such a process is highly efficient and, therefore, provides greater yields than spraydrying.
  • the resultant freeze-dried product contains drug and modifier(s).
  • the drug is typically present in an aggregated state and can be used for inhalation alone (either pulmonary or nasal), in conjunction with diluent materials (lactose, mannitol, etc.), in DPIs or pMDIs, or reconstituted for use in a nebulizer.
  • a composition as disclosed herein is formulated into liposome particles, which can then be aerosolized for inhaled delivery.
  • Suitable lipids can be any of a variety of lipids including both neutral lipids and charged lipids. Carrier systems having desirable properties can be prepared using appropriate combinations of lipids, targeting groups and circulation enhancers.
  • the compositions provided herein can be in the form of liposomes or lipid particles, preferably lipid particles.
  • the term "lipid particle” includes a lipid bilayer carrier which "coats" a substance and has little or no aqueous interior.
  • the outer layer of the particle will typically comprise mixtures of lipids oriented in a tail-to-tail fashion (as in liposomes) with the hydrophobic tails of the interior layer.
  • the polar head groups present on the lipids of the outer layer will form the external surface of the particle.
  • Liposomal bioactive agents can be designed to have a sustained therapeutic effect or lower toxicity allowing less frequent administration and an enhanced therapeutic index.
  • Liposomes are composed of bilayers that entrap the desired pharmaceutical. These can be configured as multilamellar vesicles of concentric bilayers with the pharmaceutical trapped within either the lipid of the different layers or the aqueous space between the layers.
  • lipids used in the compositions may be synthetic, semisynthetic or naturally-occurring lipids, including phospholipids, tocopherols, steroids, fatty acids, glycoproteins such as albumin, negatively-charged lipids and cationic lipids.
  • Phospholipids include egg phosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), egg phosphatidylinositol (EPI), egg phosphatidylserine (EPS), phosphatidylethanolamine (EPE), and egg phosphatidic acid (EP A); the soya counterparts, soy phosphatidylcholine (SPC); SPG, SPS, SPI, SPE, and SPA; the hydrogenated egg and soya counterparts e.g., HEPC, HSPC), other phospholipids made up of ester linkages of fatty acids in the 2 and 3 of glycerol positions containing chains of 12 to 26 carbon atoms and different head groups in the 1 position of glycerol that include choline, glycerol, inositol, serine, ethanolamine, as well as the corresponding phosphatidic acids.
  • EPC egg phosphatidylcholine
  • compositions of the formulations can include dipalmitoyl phosphatidylcholine (DPPC), a major constituent of naturally-occurring lung surfactant as well as dioleoylphosphatidylcholine (DOPC) and dioleoylphosphatidylglycerol (DOPG).
  • DPPC dipalmitoyl phosphatidylcholine
  • DOPC dioleoylphosphatidylcholine
  • DOPG dioleoylphosphatidylglycerol
  • DMPC dimyristoylphosphatidycholine
  • DMPG dimyristoylphosphatidylglycerol
  • DPPC dipalmitoylphosphatidcholine
  • DPPG dipalmitoylphosphatidylglycerol
  • DSPC distearoylphosphatidylcholine
  • DSPG distearoylphosphatidylglycerol
  • DOPE dioleylphosphatidylethanolamine
  • PSPC palmitoylstearoylphosphatidylcholine
  • PSPG palmitoylstearoylphosphatidylglycerol
  • MOPE mono- oleoyl-phosphatidylethanolamine
  • PEG-modified lipids are incorporated into compositions as an aggregation-preventing agent.
  • the use of a PEG-ceramide has the additional advantages of stabilizing membrane bilayers and lengthening circulation lifetimes.
  • PEG- ceramides can be prepared with different lipid tail lengths to control the lifetime of the PEG- ceramide in the lipid bilayer. In this manner, "programmable" release can be accomplished which results in the control of lipid carrier fusion. For example, PEG-ceramides having C2o-acyl groups attached to the ceramide moiety will diffuse out of a lipid bilayer carrier with a half-life of 22 hours.
  • PEG-ceramides having C14- and Cs-acyl groups will diffuse out of the same carrier with half-lives of 10 minutes and less than 1 minute, respectively.
  • selection of lipid tail length provides a composition in which the bilayer becomes destabilized (and thus fusogenic) at a known rate.
  • other PEG-lipids or lipid-polyoxyethylene conjugates are useful in the present compositions.
  • suitable PEG-modified lipids include PEG- modified phosphatidylethanolamine and phosphatidic acid, PEG-modified diacylglycerols and dialkylglycerols, PEG-modified dialkylamines and PEG-modified l,2-diacyloxypropan-3- amines.
  • Liposomal compositions can be 50-400 nm in diameter.
  • PEG-ceramide conjugates e.g., PEG-Cer-Cs, PEG-Cer-Ci4 or PEG-Cer-C2o
  • Liposomal compositions can be 50-400 nm in diameter.
  • the size of the compositions can be larger or smaller depending upon the volume which is encapsulated. Thus, for larger volumes, the size distribution will typically be 80-300 nm.
  • a particular formulation of a composition as disclosed herein disclosed herein is combined with a particular aerosolizing device to provide an aerosol for inhalation that is optimized for acceptable drug deposition at a site of infection and acceptable tolerability.
  • Factors that can be optimized include solution or solid particle formulation, rate of delivery, and particle size and distribution produced by the aerosolizing device.
  • Pulmonary drug delivery may be accomplished by inhalation of an aerosol through the mouth and throat.
  • Particles having a mass median aerodynamic diameter (MMAD) of greater than about 5 microns generally do not reach the lung; instead, they tend to impact the back of the throat and are swallowed and possibly orally absorbed.
  • Particles having diameters of about 2 to about 5 microns are small enough to reach the upper- to mid-pulmonary region (conducting airways), but are too large to reach the alveoli. Smaller particles, i.e., about 0.5 to about 2 microns, are capable of reaching the alveolar region.
  • VMD volumetric mean diameter
  • MMD mass median diameter
  • MMAD mass median diameter
  • VMD, MMD and MMAD measurements are considered to be under standard conditions such that descriptions of VMD, MMD and MMAD will be comparable. Similarly, dry powder particle size determinations in MMD, and MMAD are also considered comparable.
  • the particle size of the aerosol is optimized to maximize deposition of a composition as disclosed herein at the site of infection and to maximize tolerability. Aerosol particle size may be expressed in terms of the mass median aerodynamic diameter (MMAD). Large particles (e.g., MMAD>5 um) may deposit in the upper airway because they are too large to navigate the curvature of the upper airway.
  • MMAD mass median aerodynamic diameter
  • Small particles may be poorly deposited in the lower airways and thus become exhaled, providing additional opportunity for upper airway deposition.
  • intolerability e.g., cough and bronchospasm
  • generation of a defined particle size with limited geometric standard deviation (GSD) may optimize deposition and tolerability.
  • Narrow GSD limits the number of particles outside the desired MMAD size range.
  • an aerosol containing a composition as disclosed herein having a MMAD from about 2 microns to about 5 microns with a GSD of less than or equal to about 2.5 microns.
  • an aerosol having an MMAD from about 2.8 microns to about 4.3 microns with a GSD less than or equal to 2 microns is provided.
  • an aerosol having an MMAD from about 2.5 microns to about 4.5 microns with a GSD less than or equal to 1.8 microns is provided.
  • a composition as disclosed herein intended for respiratory delivery can be administered as aqueous formulations, as suspensions or solutions in halogenated hydrocarbon propellants, or as dry powders.
  • Aqueous formulations may be aerosolized by liquid nebulizers employing either hydraulic or ultrasonic atomization.
  • Propellant-based systems may use suitable pressurized metered-dose inhalers (pMDIs).
  • Dry powders may use dry powder inhaler devices (DPIs), which are capable of dispersing the drug substance effectively.
  • DPIs dry powder inhaler devices
  • a nebulizer is selected on the basis of allowing the formation of an aerosol of a composition as disclosed herein having an MMAD predominantly between about 2 to about 5 microns.
  • the delivered amount of the composition as disclosed herein provides a therapeutic effect for respiratory infections.
  • nebulizers jet and ultrasonic, have been shown to be able to produce and deliver aerosol particles having sizes between 2 and 4 um. These particle sizes have been shown as being optimal for treatment of pulmonary bacterial infection cause by gramnegative bacteria such as Pseudomonas aeruginosa, Escherichia coli, Enterobacter species, Klebsiella pneumoniae, K.
  • a jet nebulizer utilizes air pressure breakage of an aqueous solution into aerosol droplets.
  • An ultrasonic nebulizer utilizes shearing of the aqueous solution by a piezoelectric crystal.
  • the jet nebulizers are only about 10% efficient under clinical conditions, while the ultrasonic nebulizer is only about 5% efficient.
  • the amount of pharmaceutical deposited and absorbed in the lungs is thus a fraction of the 10% in spite of the large amounts of the drug placed in the nebulizer.
  • a vibrating mesh nebulizer is used to deliver an aerosol of a composition as disclosed herein.
  • a vibrating mesh nebulizer consists of a liquid storage container in fluid contact with a diaphragm and inhalation and exhalation valves.
  • about 1 to about 5 ml of the composition as disclosed herein composition is placed in the storage container and the aerosol generator is engaged producing atomized aerosol of particle sizes selectively between about 1 and about 5 um.
  • a composition as disclosed herein is placed in a liquid nebulization inhaler and prepared in dosages to deliver from about 7 to about 700 mg from a dosing solution of about 1 to about 5 ml, preferably from about 14 to about 350 mg in about 1 to about 5 ml, and most preferably from about 28 to about 280 mg in about 1 to about 5 ml with MMAD particles sizes between about 2 to about 5 um being produced.
  • a nebulized form of a composition as disclosed herein may be administered in the described respirable delivered dose in less than about 20 min, preferably less than about 10 min, more preferably less than about 7 min, more preferably less than about 5 min, more preferably less than about 3 min, and in some cases most preferable if less than about 2 min.
  • a nebulized form of a composition as disclosed herein may achieve improved tolerability and/or exhibit an AUG shape-enhancing characteristic when administered over longer periods of time.
  • the described respirable delivered dose in more than about 2 min, preferably more than about 3 min, more preferably more than about 5 min, more preferably more than about 7 min, more preferably more than about 10 min, and in some cases most preferable from about 10 to about 20 min.
  • nebulizers including small volume nebulizers
  • Compressor- driven nebulizers incorporate jet technology and use compressed air to generate the liquid aerosol.
  • Such devices are commercially available from, for example, Healthdyne Technologies, Inc.; Invacare, Inc.; Mountain Medical Equipment, Inc.; Pari Respiratory, Inc.; Mada Medical, Inc.; Puritan-Bennet; Schuco, Inc., DeVilbiss Health Care, Inc.; and Hospitak, Inc.
  • Ultrasonic nebulizers rely on mechanical energy in the form of vibration of a piezoelectric crystal to generate respirable liquid droplets and are commercially available from, for example, Omron Healthcare, Inc. and DeVilbiss Health Care, Inc.
  • Vibrating mesh nebulizers rely upon either piezoelectric or mechanical pulses to respirable liquid droplets generate.
  • Other examples of nebulizers suitable for use with a composition as disclosed herein compositions described herein are described in U.S. Pat. Nos. 4,268,460; 4,253,468; 4,046,146; 3,826,255; 4,649,911;
  • nebulizers that can be used with a composition as disclosed herein include Respirgard IITM, AeronebTM, AeronebTM Pro, and AeronebTM. Go produced by Aerogen; AERxTM and AERx EssenceTM produced by Aradigm; Porta-NebTM, Freeway FreedomTM, Sidestream, Ventstream and I-neb produced by Respironics, Inc.; and PARI LC-PlusTM, PARI LC-StarTM, and e-Flow.sup.7m produced by PARI, GmbH.
  • Respirgard IITM AeronebTM, AeronebTM Pro, and AeronebTM. Go produced by Aerogen
  • AERxTM and AERx EssenceTM produced by Aradigm
  • Porta-NebTM Freeway FreedomTM, Sidestream, Ventstream and I-neb produced by Respironics, Inc.
  • PARI LC-PlusTM PARI LC-StarTM, and e-Flow.sup.7m produced by PAR
  • the drug solution is formed prior to use of the nebulizer by a patient.
  • the drug is stored in the nebulizer in solid form.
  • the solution is mixed upon activation of the nebulizer, such as described in U.S. Pat. No. 6,427,682 and PCT Publication No. WO 03/035030, both of which are hereby incorporated by reference in their entirety.
  • the solid drug optionally combined with excipients to form a solid composition, is stored in a separate compartment from a liquid solvent.
  • the liquid solvent is capable of dissolving the solid composition to form a liquid composition, which can be aerosolized and inhaled. Such capability is, among other factors, a function of the selected amount and, potentially, the composition of the liquid.
  • the sterile aqueous liquid may be able to dissolve the solid composition within a short period of time, possibly under gentle shaking.
  • the final liquid is ready to use after no longer than about 30 seconds.
  • the solid composition is dissolved within about 20 seconds, and advantageously, within about 10 seconds.
  • the terms “dissolve(d)", “dissolving”, and “dissolution” include the disintegration of the solid composition and the release, i.e., the dissolution, of the active compound.
  • a liquid composition is formed in which the active compound is contained in the dissolved state.
  • the active compound is in the dissolved state when at least about 90 wt.-% are dissolved, and more preferably when at least about 95 wt.-% are dissolved.
  • nebulizer design With regard to basic separated-compartment nebulizer design, it primarily depends on the specific application whether it is more useful to accommodate the aqueous liquid and the solid composition within separate chambers of the same container or primary package, or whether they should be provided in separate containers. If separate containers are used, these are provided as a set within the same secondary package. The use of separate containers is especially preferred for nebulizers containing two or more doses of the active compound. There is no limit to the total number of containers provided in a multi-dose kit. In one embodiment, the solid composition is provided as unit doses within multiple containers or within multiple chambers of a container, whereas the liquid solvent is provided within one chamber or container.
  • a favorable design provides the liquid in a metered-dose dispenser, which may consist of a glass or plastic bottle closed with a dispensing device, such as a mechanical pump for metering the liquid. For instance, one actuation of the pumping mechanism may dispense the exact amount of liquid for dissolving one dose unit of the solid composition.
  • both the solid composition and the liquid solvent are provided as matched unit doses within multiple containers or within multiple chambers of a container.
  • two-chambered containers can be used to hold one unit of the solid composition in one of the chambers and one unit of liquid in the other.
  • one unit is defined by the amount of drug present in the solid composition, which is one unit dose.
  • Such two-chambered containers may, however, also be used advantageously for nebulizers containing only one single drug dose.
  • a blister pack having two blisters is used, the blisters representing the chambers for containing the solid composition and the liquid solvent in matched quantities for preparing a dose unit of the final liquid composition.
  • a blister pack represents a thermoformed or pressure-formed primary packaging unit, most likely comprising a polymeric packaging material that optionally includes a metal foil, such as aluminum.
  • the blister pack may be shaped to allow easy dispensing of the contents. For instance, one side of the pack may be tapered or have a tapered portion or region through which the content is dispensable into another vessel upon opening the blister pack at the tapered end. The tapered end may represent a tip.
  • the two chambers of the blister pack are connected by a channel, the channel being adapted to direct fluid from the blister containing the liquid solvent to the blister containing the solid composition.
  • the channel is closed with a seal.
  • a seal is any structure that prevents the liquid solvent from contacting the solid composition.
  • the seal is preferably breakable or removable; breaking or removing the seal when the nebulizer is to be used will allow the liquid solvent to enter the other chamber and dissolve the solid composition.
  • the dissolution process may be improved by shaking the blister pack.
  • the final liquid composition for inhalation is obtained, the liquid being present in one or both of the chambers of the pack connected by the channel, depending on how the pack is held.
  • one of the chambers communicates with a second channel, the channel extending from the chamber to a distal position of the tapered portion.
  • this second channel does not communicate with the outside of the pack but is closed in an airtight fashion.
  • the distal end of the second channel is closed by a breakable or removable cap or closure, which may e g., be a twist-off cap, a break-off cap, or a cut-off cap.
  • a vial or container having two compartments is used, the compartment representing the chambers for containing the solid composition and the liquid solvent in matched quantities for preparing a dose unit of the final liquid composition.
  • the liquid composition and a second liquid solvent may be contained in matched quantities for preparing a dose unit of the final liquid composition (by non-limiting example in cases where two soluble excipients or the composition as disclosed herein and excipient are unstable for storage, yet desired in the same mixture for administration.
  • the two compartments are physically separated but in fluid communication so that when the vial or container are connected by a channel or breakable barrier, the channel or breakable barrier being adapted to direct fluid between the two compartments to enable mixing prior to administration.
  • the channel is closed with a seal or the breakable barrier intact.
  • a seal is any structure that prevents mixing of contents in the two compartments.
  • the seal is preferably breakable or removable; breaking or removing the seal when the nebulizer is to be used will allow the liquid solvent to enter the other chamber and dissolve the solid composition or in the case of two liquids permit mixing.
  • the dissolution or mixing process may be improved by shaking the container.
  • the final liquid composition for inhalation is obtained, the liquid being present in one or both of the chambers of the pack connected by the channel or breakable barrier, depending on how the pack is held.
  • the solid composition itself can be provided in various different types of dosage forms, depending on the physicochemical properties of the drug, the desired dissolution rate, cost considerations, and other criteria.
  • the solid composition is a single unit. This implies that one unit dose of the drug is comprised in a single, physically shaped solid form or article. In other words, the solid composition is coherent, which is in contrast to a multiple unit dosage form, in which the units are incoherent.
  • Examples of single units which may be used as dosage forms for the solid composition include tablets, such as compressed tablets, film-like units, foil-like units, wafers, lyophilized matrix units, and the like.
  • the solid composition is a highly porous lyophilized form.
  • Such lyophilizates, sometimes also called wafers or lyophilized tablets, are particularly useful for their rapid disintegration, which also enables the rapid dissolution of the active compound.
  • the solid composition may also be formed as a multiple unit dosage form as defined above.
  • multiple units are powders, granules, microparticles, pellets, beads, lyophilized powders, and the like.
  • the solid composition is a lyophilized powder.
  • Such a dispersed lyophilized system comprises a multitude of powder particles, and due to the lyophilization process used in the formation of the powder, each particle has an irregular, porous microstructure through which the powder is capable of absorbing water very rapidly, resulting in quick dissolution.
  • Another type of multiparticulate system which is also capable of achieving rapid drug dissolution is that of powders, granules, or pellets from water-soluble excipients which are coated with the drug, so that the drug is located at the outer surface of the individual particles.
  • the water-soluble low molecular weight excipient is useful for preparing the cores of such coated particles, which can be subsequently coated with a coating composition comprising the drug and, preferably, one or more additional excipients, such as a binder, a pore former, a saccharide, a sugar alcohol, a film-forming polymer, a plasticizer, or other excipients used in pharmaceutical coating compositions.
  • the solid composition resembles a coating layer that is coated on multiple units made of insoluble material.
  • insoluble units include beads made of glass, polymers, metals, and mineral salts.
  • the coating composition will, in addition to the drug and the water-soluble low molecular weight excipient, comprise one or more excipients, such as those mentioned above for coating soluble particles, or any other excipient known to be useful in pharmaceutical coating compositions.
  • one excipient may be selected for its drug carrier and diluent capability, while another excipient may be selected to adjust the pH. If the final liquid composition needs to be buffered, two excipients that together form a buffer system may be selected.
  • the liquid to be used in a separated-compartment nebulizer is an aqueous liquid, which is herein defined as a liquid whose major component is water.
  • the liquid does not necessarily consist of water only; however, in one embodiment it is purified water.
  • the liquid contains other components or substances, preferably other liquid components, but possibly also dissolved solids.
  • Liquid components other than water which may be useful include propylene glycol, glycerol, and polyethylene glycol.
  • a solid compound as a solute is that such a compound is desirable in the final liquid composition, but is incompatible with the solid composition or with a component thereof, such as the active ingredient.
  • the liquid solvent is sterile.
  • An aqueous liquid would be subject to the risk of considerable microbiological contamination and growth if no measures are taken to ensure sterility.
  • an effective amount of an acceptable antimicrobial agent or preservative can be incorporated or the liquid can be sterilized prior to providing it and to seal it with an air-tight seal.
  • the liquid is a sterilized liquid free of preservatives and provided in an appropriate air-tight container.
  • the liquid may be supplied in a multiple-dose container, such as a metered-dose dispenser, and may require a preservative to prevent microbial contamination after the first use.
  • MDI Meter Dose Inhaler
  • a propellant driven inhaler releases a metered dose of medicine upon each actuation.
  • the medicine is formulated as a suspension or solution of a drug substance in a suitable propellant such as a halogenated hydrocarbon.
  • pMDIs are described in, for example, Newman, S. P., Aerosols and the Lung, Clarke et al., eds., pp. 197-224 (Butterworths, London, England, 1984).
  • the particle size of the drug substance in an MDI may be optimally chosen.
  • the particles of active ingredient have diameters of less than about 50 microns. In some embodiments, the particles have diameters of less than about 10 microns. In some embodiments, the particles have diameters of from about 1 micron to about 5 microns. In some embodiments, the particles have diameters of less than about 1 micron. In one advantageous embodiment, the particles have diameters of from about 2 microns to about 5 microns.
  • the propellants for use with the MDIs may be any propellants known in the art.
  • propellants include chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluoromethane, and dichlorotetrafluoroethane; hydrofluoroalkanes (HFAs); and carbon dioxide.
  • CFCs chlorofluorocarbons
  • HFAs hydrofluoroalkanes
  • HFAs hydrofluoroalkanes
  • Examples of medicinal aerosol preparations containing HFAs are presented in U.S. Pat. Nos. 6,585,958; 2,868,691 and 3,014,844, all of which are hereby incorporated by reference in their entirety.
  • a co-solvent is mixed with the propellant to facilitate dissolution or suspension of the drug substance.
  • the propellant and active ingredient are contained in separate containers, such as described in U.S. Pat. No. 4,534,345, which is hereby incorporated by reference in its entirety.
  • the MDI used herein is activated by a patient pushing a lever, button, or other actuator.
  • the release of the aerosol is breath activated such that, after initially arming the unit, the active compound aerosol is released once the patient begins to inhale, such as described in U.S. Pat. Nos. 6,672,304; 5,404,871; 5,347,998; 5,284,133; 5,217,004; 5,119,806; 5,060,643; 4,664,107; 4,648,393; 3,789,843; 3,732,864; 3,636,949;
  • MDIs known in the art and suitable for use herein include U.S. Pat. Nos. 6,435,177; 6,585,958; 5,642,730; 6,223,746; 4,955,371; 5,404,871; 5,364,838; and 6,523,536, all of which are hereby incorporated by reference in their entirety.
  • DPI Dry Powder Inhaler
  • particle size of the aerosol formulation of a composition as disclosed herein may be optimized. If the particle size is larger than about 5 um MMAD then the particles are deposited in upper airways.
  • compositions comprising a composition as disclosed herein are prepared in dosages to deliver from about 7 to about 700 mg from a dosing solution of about 1 to about 5 ml, preferably from about 14 to about 350 mg in about 1 to about 5 ml, and most preferably from about 28 to about 280 mg in about 1 to about 5 ml with MMAD particles sizes between about 2 to about 5 um being produced.
  • a dry powder inhaler is used to dispense the composition as disclosed herein.
  • DPIs contain the drug substance in fine dry particle form.
  • inhalation by a patient causes the dry particles to form an aerosol cloud that is drawn into the patient's lungs.
  • the fine dry drug particles may be produced by any technique known in the art. Some well-known techniques include use of a jet mill or other comminution equipment, precipitation from saturated or super saturated solutions, spray drying, in situ micronization (Hovione), or supercritical fluid methods.
  • Typical powder formulations include production of spherical pellets or adhesive mixtures.
  • the drug particles are attached to larger carrier particles, such as lactose monohydrate of size about 50 to about 100 microns in diameter.
  • the larger carrier particles increase the aerodynamic forces on the carrier/drug agglomerates to improve aerosol formation. Turbulence and/or mechanical devices break the agglomerates into their constituent parts. The smaller drug particles are then drawn into the lungs while the larger carrier particles deposit in the mouth or throat.
  • DPIs There are three common types of DPIs, all of which may be used with the compositions comprising a composition as disclosed herein described herein.
  • a capsule containing one dose of dry drug substance/excipients is loaded into the inhaler. Upon activation, the capsule is breached, allowing the dry powder to be dispersed and inhaled using a dry powder inhaler. To dispense additional doses, the old capsule must be removed, and an additional capsule loaded. Examples of single-dose DPIs are described in U.S. Pat. Nos. 3,807,400; 3,906,950; 3,991,761; and 4,013,075, all of which are hereby incorporated by reference in their entirety.
  • a package containing multiple single dose compartments is provided.
  • the package may comprise a blister pack, where each blister compartment contains one dose.
  • Each dose can be dispensed upon breach of a blister compartment.
  • Any of several arrangements of compartments in the package can be used. For example, rotary or strip arrangements are common.
  • Examples of multiple unit dose DPIs are described in EPO Patent Application Publication Nos. 0211595A2, 0455463A1, and 0467172A1, all of which are hereby incorporated by reference in their entirety.
  • a multi-dose DPI a single reservoir of dry powder is used. Mechanisms are provided that measure out single dose amounts from the reservoir to be aerosolized and inhaled, such as described in U.S. Pat. Nos.
  • auxiliary energy in addition to or other than a patient's inhalation may be provided to facilitate operation of a DPI.
  • pressurized air may be provided to aid in powder de-agglomeration, such as described in U.S. Pat. Nos. 3,906,950; 5,113,855; 5,388,572; 6,029,662 and PCT Publication Nos. WO 93/12831, WO 90/07351, and WO 99/62495, all of which are hereby incorporated by reference in their entirety.
  • Electrically driven impellers may also be provided, such as described in U.S. Pat. Nos. 3,948,264; 3,971,377; 4,147,166; 6,006,747 and PCT Publication No.
  • WO 98/03217 all of which are hereby incorporated by reference in their entirety.
  • Another mechanism is an electrically poared tapping piston, such as described in PCT Publication No. WO 90/13327, which is hereby incorporated by reference in its entirety.
  • Other DPIs use a vibrator, such as described in U.S. Pat. Nos. 5,694,920 and 6,026,809, both of which are hereby incorporated by reference in their entirety.
  • a scraper system may be employed, such as described in PCT Publication No. WO 93/24165, which is hereby incorporated by reference in its entirety.
  • DPIs for use herein are described in U.S. Pat. Nos. 4,811,731; 5,113,855; 5,840,279; 3,507,277; 3,669,113; 3,635,219; 3,991,761; 4,353,365; 4,889,144, 4,907,538; 5,829,434; 6,681,768; 6,561,186; 5,918,594; 6,003,512; 5,775,320; 5,740,794; and 6,626,173, all of which are hereby incorporated by reference in their entirety.
  • a spacer or chamber may be used with any of the inhalers described herein to increase the amount of drug substance that gets absorbed by the patient, such as is described in U.S. Pat. Nos. 4,470,412; 4,790,305; 4,926,852; 5,012,803; 5,040,527; 5,024,467; 5,816,240; 5,027,806; and 6,026,807, all of which are hereby incorporated by reference in their entirety.
  • a spacer may delay the time from aerosol production to the time when the aerosol enters a patient's mouth. Such a delay may improve synchronization between the patient's inhalation and the aerosol production.
  • a mask may also be incorporated for infants or other patients that have difficulty using the traditional mouthpiece, such as is described in U.S. Pat. Nos. 4,809,692; 4,832,015; 5,012,804; 5,427,089; 5,645,049; and 5,988,160, all of which are hereby incorporated by reference in their entirety.
  • Dry powder inhalers which involve deaggregation and aerosolization of dry powders, normally rely upon a burst of inspired air that is drawn through the unit to deliver a drug dosage.
  • DPIs Dry powder inhalers
  • the linked moieties of the invention are used in the treatment of one or more conditions.
  • Any condition amenable to treatment by the linked moieties can be the subject of treatment, in particular a condition where the targeting moiety accumulates at the site of the condition and the therapeutic moiety has suitable activity at that site.
  • the condition is an infection.
  • An infection occurs when a microbial agent invades an organism’s body tissues, multiplying therein and causing damage to host tissues by the infectious agent and/or toxins they produce.
  • a microbial infection can be caused by bacteria, viruses, fungi, or parasites, and the appropriate active agent, e.g., antibacterial (antibiotic), antiviral, antifungal, or antiparasitic can be targeted to one or more infection sites using the methods and compositions described herein.
  • any suitable bacterial infection may be targeted with a suitable agent, including Gram-positive and Gram-negative bacteria.
  • Drug resistance is a growing global public health threat. According to the CDC report, more than 2.8 million antibiotic-resistant infections occur in the U.S. each year, resulting in about 35,000 deaths annually. Since 2004, only a handful of new antibiotics has been approved for the treatment of resistant Gram-negative bacteria. In 2014, a task force was established in the US to tackle this issue. Resistant bacteria have far reaching implications that may affect many advanced surgical procedures such as joint replacement as it results in a significant risk increase. US drug spending on antibiotics ranges between $8.4 to $10.6 billion annually. Globally, about 700,000 people die of drug-resistant infections every year with 13.5 billion dollars in annual financial losses due to hospital infections in the US and Europe alone. Drug resistance may push 28.3 million people into extreme poverty by 2050.
  • a drug-resistant infection is treated using methods and compositions provided herein.
  • a drug-resistant bacterial infection is treated by targeting one or more antibiotics to the site of infection, for example, by linking the one or more antibiotics to a target ligand that associates with one or more types of immune cells that are drawn to the site of infection, so that the local concentration of the antibiotic or antibiotics is increased to a point that it overcomes the resistance of the bacteria causing the infection.
  • Such local concentrations typically are high enough that, were they to be achieved by normal systemic administration of antibiotics, undesirable toxicity would result.
  • an important aspect of certain embodiments provided herein is that very high local concentrations of the desired active agent can be achieved with little or no systemic toxicity. Thus, the therapeutic index is improved.
  • Gram-negative highly resistant bacteria are targeted, such as, P. aeruginosa, Acinetobacter baumannii, Enterobacteriaceae, Neisseria gonorrhoeae, Campylobacter spp., Salmonellae spp., Shigella spp.
  • P. aeruginosa Acinetobacter baumannii
  • Enterobacteriaceae Neisseria gonorrhoeae
  • Campylobacter spp. Salmonellae spp.
  • Salmonellae spp. Shigella spp.
  • MO A mechanism of action
  • an antibiotic is used that is a broad-spectrum antibiotic, such as fluoroquinolones and beta-lactams (e.g., cephalosporins, monobactams and carbapenem).
  • a broad-spectrum antibiotic such as fluoroquinolones and beta-lactams (e.g., cephalosporins, monobactams and carbapenem).
  • prodrugs of commercially available antibiotics with known safety and efficacy that target specific infection healing cells such as immune cells or fibroblasts to increase intracellular concentrations of antibiotics can be used.
  • Antibiotic travels with the carrier cells and is present at the site of infection in active form. This approach improves efficacy against both intracellular and extracellular pathogens. It can reduce systemic concentrations which may improve the overall safety profile of the therapeutic moiety. Higher concentrations at the site of action eliminates highly resistant strains of bacteria and restore susceptibility of the bacteria to the antibiotic.
  • one of two classes of commercially available antibiotics that demonstrated broad spectrum activity for both Gram-positive and Gram-negative and are considered the last resort to treat infections of highly resistant Gram-negative bacteria may be used.
  • These include beta-lactams, in particular, carbapenem, and fluoroquinolones.
  • the therapeutic moiety is an antibiotic effective against Gram negative bacteria.
  • P. aeruginosa infections are increasingly resistant to many antibiotics, and the organism may acquire resistance during therapy.
  • Those most at risk of infection with P. aeruginosa include patients in hospitals, especially those on breathing machines (ventilators), with devices such as catheters and with wounds from surgery or bums. The latter is especially important for wounded service members/warfighters.
  • P. aeruginosa is the primary pathogen responsible for the chronic pulmonary infections, the primary cause of morbidity and mortality, in subjects with cystic fibrosis (CF).
  • P. aeruginosa infections are generally treated with antibiotics such as fluoroquinolones, beta-lactams, and aminoglycosides with known antipseudomonal activity.
  • antibiotics such as fluoroquinolones, beta-lactams, and aminoglycosides with known antipseudomonal activity.
  • P. aeruginosa infections are becoming more difficult to treat because of increasing antibiotic resistance.
  • Some types of MDR P. aeruginosa are resistant to nearly all antibiotics.
  • Treatment of P. aeruginosa infections requires two agents from different classes when the risk of antibiotic resistance is high. Treatment can include antipseudomonal quinolones, beta-lactam (e.g., penicillin or cephalosporin), aminoglycoside, and carbapenems (e.g., imipenem, meropenem).
  • beta-lactam e.g., penicillin or cephalosporin
  • aeruginosa caused an estimated 32,600 infections among hospitalized patients and 2,700 estimated deaths and $757,000,000 estimated attributable healthcare costs in the US.
  • a 2017 surveillance summary of / ⁇ aeruginosa infections in military treatment facilities reported 47.9% of / ⁇ aeruginosa infections were healthcare-associated cases and that none of the strains tested displayed 100% susceptibility to any antibiotic tested. As such there is a huge unmet medical need to develop more effective therapy for pseudomonas infections.
  • compositions and method of the invention are used to treat an infection that comprises Gram negative bacteria, such as P. aeruginosa.
  • the Gram-negative bacteria such as P. aeruginosa
  • the infection is a pulmonary infection.
  • methods include treatment of cystic fibrosis, e.g., an infection associated with cystic fibrosis, such as an antibiotic-resistant infection, for example an antibiotic resistant P. aeruginosa infection.
  • an infection associated with cystic fibrosis such as an antibiotic-resistant infection, for example an antibiotic resistant P. aeruginosa infection.
  • Cystic fibrosis (CF) lung disease is a progressive genetic disease characterized by airway obstruction, chronic bacterial infection, and a vigorous host inflammatory response.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • Lung damage secondary to chronic infection is the main determinant of morbidity and mortality in individuals with CF. Accumulation of thick mucus in the lungs of CF patients creates an optimal environment for bacterial growth, leading to infections.
  • Most common bacteria in CF include: P. aeruginosa, Staphylococcus aureus, Hemophilus influenzae, Stenotrophomonas maltophilia, Achromohacter xylosoxidans , and Burkholderia species.
  • P. aeruginosa is a Gram-negative, opportunistic human pathogen and is considered to be one of the main pathogens associated with nosocomial infections.
  • aeruginosa is the key agent responsible for CF lung infections, and infectious lesions caused by this bacterium can result in blood-borne transmission, bacteremia, and sepsis.
  • P. aeruginosa infection is related to a three-fold increase in mortality risk and a seven-fold increase in hospitalization risk.
  • Antibiotics have been successfully used for the treatment of CF based on microbiological outcome (bacterial eradication) and lung function improvement (FEV1). Fluoroquinolones have a broad spectrum of antimicrobial activity and are often used in the treatment of lung infection in P. aeruginosa eradication regimens, the treatment of mild exacerbations in those chronically infected with P.
  • aeruginosa and for the treatment of infections with other bacteria, including P. aeruginosa, Burkholderia cepacia complex, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Staphylococcus aureus.
  • Fluoroquinolone antibiotics namely ciprofloxacin and levofloxacin, play an important role in treating infection in CF and ciprofloxacin remains the last widely used and orally available antipseudomonal agent.
  • ciprofloxacin namely ciprofloxacin and levofloxacin
  • This antibiotic is a novel dual-targeting anionic fluoroquinolone and differs from previous agents in its class, as it lacks a protonatable substituent.
  • In vitro susceptibilities on 52 non-mucoid P. aeruginosa and P. aeruginosa ATCCTM 27853 reference strain, showed statistical superiority to delafloxacin (p 0.0005) than ciprofloxacin.
  • ciprofloxacin may play an important role in CF therapy.
  • Fluoroquinolone’s therapy provides several additional advantages in CF patients. Pulmonary infection in CF may involve organisms growing in an anaerobic niche (e.g., within mucus plugs) and it is advantageous for an antibiotic to be active against obligate anaerobes or organisms such as P. aeruginosa, which can be facultative anaerobes. Some quinolones, such as levofloxacin, are equally active in an aerobic or anaerobic environment.
  • P. aeruginosa produces a biofilm minimizing contact with antibiotics. Fluoroquinolones have greater antimicrobial activity than tobramycin and aztreonam in biofilms produced by P. aeruginosa. Unlike tobramycin, fluoroquinolones’ activity is not reduced in CF sputum.
  • Fluoroquinolones have favorable pharmacokinetic/pharmacodynamic properties. They can be administered intravenously or orally. In addition, fluoroquinolones show that bacterial killing and clinical efficacy is linked to the plasma area under the concentration-time curve (AUC)ZMIC ratio or maximum plasma concentration (C max )/MIC ratio and that high peak concentrations relative to the MIC may reduce the selection of drug-resistant bacteria in vitro and in vivo.
  • AUC concentration-time curve
  • C max maximum plasma concentration
  • a 400 mg dose of ciprofloxacin twice or three times daily may be inadequate to treat an exacerbation as the area under the curve (AUC)Zminimum inhibitory concentration (MIC) was suggested to be suboptimal in 70-90% of simulated patients.
  • AUC area under the curve
  • MIC minimum inhibitory concentration
  • Aerosol administration of levofloxacin produces C ma x/MIC and AUC/MIC ratios in the airways that are substantially greater than those that can be obtained with parenteral or oral administration.
  • High concentrations delivered to the lung may be active against even highly resistant organisms and may also reduce the selection of resistant bacteria.
  • Inhalation Therapy Aerosol delivery of an antibiotic directly to the lung increases the local concentration of the drug at the site of infection, thereby enhancing bacterial killing and reducing the selection of resistance compared to the outcomes of systemic administration.
  • TOBI Novartis Pharmaceuticals, East Hanover, NJ
  • aztreonam lysine for inhalation (Cayston; Gilead Pharmaceuticals, Seattle, WA) are the two aerosol antibiotics approved in the United States for the management of CF patients with P. aeruginosa.
  • inhaled levofloxacin in a mouse model of pulmonary infection achieved a 9-fold higher area under the curve (AUC) and 30-fold higher maximum concentration (C ma x) in lung tissue when compared with the dose-normalized intraperitoneal administration of levofloxacin.
  • AUC area under the curve
  • C ma x maximum concentration
  • in human inhaled levofloxacin resulted in rapid but minimal absorption of levofloxacin from the lungs.
  • the inhaled levofloxacin 24-hour serum AUC values were 12-19% of the value obtained from a 750 mg oral dose of levofloxacin, which suggests that inhaled administration has the potential to offer improved efficacy an improved safety and tolerability profile.
  • a novel approach of targeted delivery of marketed antibiotics to the site of infection utilizing the immune cells may provide an alternative way to improve clinical outcome and tackle resistance to P. aeruginosa infection.
  • This approach combines the power of the immune system and the PK and PD of fluoroquinolone to further increase exposure of fluoroquinolones at the site of infection while minimizing systemic exposure. This balanced approach will improve efficacy and reduce unwarranted systemic toxicity including younger patients.
  • a method of accumulating a therapeutic moiety in a cell and/or a cell’s local environment comprising (i) contacting the cell extracellularly with a composition comprising a targeting moiety and the therapeutic moiety linked by a linker, where the linker forms a first attachment with the targeting moiety and the linker forms a second attachment with the therapeutic moiety; (ii) allowing the composition to be transported into the cell and/or an organelle of the cell and/or the environment of the cell, where the therapeutic moiety is active, e.g., where one or both attachments of the linker, or the linker between the two attachments, is cleaved, or, in some cases, no cleavage, if the therapeutic moiety retains sufficient activity for its intended purpose, so that the therapeutic moiety accumulates in the cell and/or its environment.
  • the targeting moiety has desirable properties, such as its own therapeutic action
  • the targeting moiety is active, e.g., where one or both attachments of the linker, or the linker between the two attachments, is cleaved, or, in some cases, no cleavage, if the targeting moiety retains sufficient activity for its intended purpose, in the cell and/or organelle of the cell and/or local environment of the cell.
  • the therapeutic moiety comprises an antibiotic, such as one of the antibiotics described herein, for example, a tetracycline, beta-lactam, or fluoroquinolone antibiotic, such as ciprofloxacin, moxifloxacin, gemifloxacin, levofloxacin, levonadifloxacin or delafloxacin.
  • an antibiotic such as one of the antibiotics described herein, for example, a tetracycline, beta-lactam, or fluoroquinolone antibiotic, such as ciprofloxacin, moxifloxacin, gemifloxacin, levofloxacin, levonadifloxacin or delafloxacin.
  • the therapeutic moiety such as antibiotic, retains its normal activity or a substantial portion of its normal activity, such as at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99, or 100% of normal activity.
  • the method comprises releasing the therapeutic moiety, e.g, antibiotic into the extracellular environment, e.g., by lysing the cell or allowing the cell to be lysed.
  • the therapeutic moiety such as an antibiotic
  • the therapeutic moiety may become part of a structure of the cell that is used to contact other cells to destroy them, such as part of a phagosome used by phagocytic cells to destroy invading organisms or abnormal cells.
  • the intracellular concentration of the therapeutic moiety, e.g., antibiotic, in the cell increases so that it is at least 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 27, 30, 25, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 300, 400, or 500 and/or not more than 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 27, 30, 25, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 300, 400, 500 or 1000-fold the extracellular concentration of the therapeutic moiety, e.g., antibiotic.
  • the therapeutic moiety e.g., antibiotic
  • the concentration of the therapeutic moiety, e.g., antibiotic, in the cell is increased to at least 1 pg, 10 pg, 100 pg, 1 ng, 10 ng, 100 ng, 1 ug, 10 ug, 100 ug, 1 mg, 10 mg, 100 mg or 500 mg and/or not more than 10 pg, 100 pg, 1 ng, 10 ng, 100 ng, 1 ug, 10 ug, 100 ug, 1 mg, 10 mg, lOOmg, 500 mg, or 1000 mg per milliliter.
  • the intracellular concentration of the targeting moiety increases so that it is at least 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 27, 30, 25, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 300, 400, or 500 and/or not more than 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 27, 30, 25, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 300, 400, or 500-fold the extracellular concentration of the targeting moiety, e.g., another antibiotic.
  • the concentration of the targeting moiety, e.g. , another antibiotic, in the cell is at least 1 pg, 10 pg, 100 pg, 1 ng, 10 ng, 100 ng, 1 ug, 10 ug, 100 ug, 1 mg, 10 mg, 100 mg, or 500 mg; and/or not more than 10 pg, 100 pg, 1 ng, 10 ng, 100 ng, 1 ug, 10 ug, 100 ug, 1 mg, 10 mg, 100 mg, 500 mg, or 1000 mg per milliliter.
  • a method of delivering a therapeutic moiety comprising an antimicrobial agent, e.g., antibiotic, to a site of an infection in an individual, where the infection is mediated by one or more microbial agents comprising (i) administering to the individual a composition comprising a targeting moiety and the therapeutic moiety comprising the antimicrobial agent, e.g., antibiotic, linked by a linker, where the linker forms a first attachment with the targeting moiety and the linker form a second attachment with the therapeutic moiety comprising the antimicrobial, e.g., antibiotic where the targeting moiety interacts with an infection healing cell such as an immune cell or wound healing cell such as a fibroblast, to concentrate the antimicrobial agent in and/or in the local environment of the infection healing cell, wherein the infection healing cell is a cell that is present at the site of infection and/or that preferentially travels to the site of infection, by movement of the composition into the infection healing cell.
  • an infection healing cell such as an immune cell or wound healing cell such as
  • the composition may further undergo cleavage at the first and/or second attachments or in the linker between the first and second attachments, and release the therapeutic moiety in active or substantially active form; in certain embodiments, the therapeutic agent is active or substantially active as part of the composition without cleavage.
  • the therapeutic agent in active form (by cleavage or not, depending on the composition) may be present in the cell, e.g. , in an organelle of the cell such as a lysosome and/or in the local environment of the cell, e.g., when released as part of an oxidative burst.
  • the presence of the active antimicrobial agent allows it to interact with the one or more microbial agents at the site of infection.
  • the concentration of the antimicrobial agent, e.g., antibiotic, at the infection site increases so that the concentration is at least 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 27, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 200, or 500-fold the concentration of the antimicrobial agent in the general circulation of the individual, and/or no more than 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 27, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 500, or 1000-fold the concentration of the antimicrobial agent in the general circulation of the individual.
  • the concentration of the antimicrobial agent e.g., antibiotic
  • the method produces a concentration of the antimicrobial agent at the infection site is at least 1 pg, 10 pg, 100 pg, 1 ng, 10 ng, 100 ng, 1 ug, 10 ug, 100 ug, 500 ug, 1 mg, 10 mg, 100 mg, or 500 mg and/or not more than 10 pg, 100 pg, 1 ng, 10 ng, 100 ng, 1 ug, 10 ug, 100 ug, 500 ug, 1 mg, 10 mg, 100 mg, 500 mg, or 1000 mg, per milliliter.
  • the targeting moiety also has a therapeutic function, and the targeting moiety is concentrated in and/or around the infection healing cell, by presence of therapeutically active form of targeting moiety in the cell (e.g., by cleavage of one or both attachments or between attachments, or no cleavage, depending on the composition), so that the targeting moiety provides a further therapeutic effect at the site of the infection.
  • the targeting moiety is another antibiotic, such as a macrolide antibiotic, and the therapeutic function of the targeting may include its antibiotic function and/or other therapeutic functions, such as an anti-inflammatory, antiviral, or other function at the site of the infection.
  • the concentration of the targeting moiety e.g., a moiety comprising another antibiotic such as a macrolide
  • the concentration of the targeting moiety increases so that the concentration is at least 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 27, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 200, or 500-fold the concentration of the targeting moiety in the general circulation of the individual, and/or no more than 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 25, 27, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 500, or 1000-fold the concentration of the targeting moiety in the general circulation of the individual.
  • the method produces a concentration of the targeting moiety at the infection site is at least 1 pg, 10 pg, 100 pg, 1 ng, 10 ng, 100 ng, 1 ug, 10 ug, 100 ug, 500 ug, 1 mg, 10 mg, 100 mg, or 500 mg and/or not more than 10 pg, 100 pg, 1 ng, 10 ng, 100 ng, 1 ug, 10 ug, 100 ug, 500 ug, 1 mg, 10 mg, 100 mg, 500 mg, or 1000 mg, per milliliter.
  • a method of treating an infection caused by one or more microbial agents in an individual suffering from the infection comprising administering to the individual an effective amount of a composition comprising a targeting moiety and a therapeutic moiety comprising an antimicrobial agent, e.g., antibiotic, linked by a linker, where the linker forms a first attachment with the targeting moiety and the linker form a second attachment with the therapeutic moiety comprising the antimicrobial, e.g., antibiotic, where the targeting moiety interacts with an infection healing cell such as an immune cell or fibroblast to concentrate the antimicrobial agent in and/or in the local environment of the infection healing cell, wherein the infection healing cell is a cell that is present at the site of infection and/or that preferentially travels to the site of infection, by movement of the composition into the infection healing cell.
  • an infection healing cell such as an immune cell or fibroblast
  • the composition may further undergo cleavage at the first or second attachments or between the first and second attachments, and release the therapeutic moiety in active or substantially active form; in certain embodiments, the therapeutic agent is active or substantially active as part of the composition without cleavage.
  • the therapeutic agent in active form (by cleavage or not, depending on the composition) may occur in the cell, e.g. , in an organelle of the cell such as a lysosome and/or in the environment of the cell, e.g., when released as part of an oxidative burst.
  • the infection may be a bacterial infection, a viral infection, a fungal infection, or a parasitic infection. In certain embodiments the infection comprises a bacterial infection and the antimicrobial agent comprises an antibiotic.
  • the individual may be an animal; in certain embodiments, the individual is mammal, such as a human.
  • individuals include mammals, such as humans and non-human primates, such as monkeys, as well as dogs, cats, horses, bovines, rabbits, rats, mice, goats, pigs, and other mammalian species.
  • Subjects can also include avians.
  • a patient can be an individual that is seeking treatment, monitoring, adjustment or modification of an existing therapeutic regimen, etc.
  • the terms “effective amount,” “effective dose,” and “therapeutically effective amount,” include an amount of an agent, such as a composition as described herein, that is sufficient to generate a desired response, such as reduce or eliminate a sign or symptom of a condition or ameliorate a disorder.
  • an “effective amount” is one that treats (including prophylaxis) one or more symptoms and/or underlying causes of any of a disorder or disease and/or prevents progression of a disease.
  • a therapeutically effective amount will show an increase or decrease of therapeutic effect at least any of 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%.
  • Therapeutic efficacy can also be expressed as “-fold” increase or decrease.
  • a therapeutically effective amount can have at least any of a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control.
  • dose and “dosage” are used interchangeably herein.
  • a dose refers to the amount of active ingredient given to an individual at each administration.
  • the dose will vary depending on a number of factors, including frequency of administration; size and tolerance of the individual; severity of the condition; risk of adverse effects; the route of administration.
  • the term “dosage form” refers to the particular format of the pharmaceutical, and depends on the route of administration.
  • a dosage form can be in a liquid, e.g., a saline solution for injection.
  • Dosage forms can be prepared for mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, intramuscular, or intraarterial injection, either bolus or infusion), oral, inhalation, or transdermal administration to a patient.
  • mucosal e.g., nasal, sublingual, vaginal, buccal, or rectal
  • parenteral e.g., subcutaneous, intravenous, intramuscular, or intraarterial injection, either bolus or infusion
  • oral, inhalation e.g., transdermal administration to a patient.
  • dosage forms include, but are not limited to: dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water- in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
  • suspensions e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water- in-
  • the composition is given orally.
  • the dose of composition to be administered is chosen in order to provide effective therapy for the patient and is in the range of less than 0. 1 mg/kg body weight to about 25 mg/kg body weight or in the range 1 mg- 2 g per patient. In some cases, the dose is in the range 1- 100 mg/kg, or approximately 50 mg- 8000 mg / patient.
  • the dose may be repeated at an appropriate frequency which may be in the range once per day to once every three months, depending on the pharmacokinetics of the composition (e.g., half-life of the composition in the circulation) and the pharmacodynamic response (e.g., the duration of the therapeutic effect of the composition).
  • the in vivo half-life of between about 0.5 and about 25 days and composition dosing is repeated between once per every four hours and once every 3 months.
  • Administration or use can be periodic.
  • the dose can be administered, e.g., once every 0.25, 0.33, 0.5, 1, 2, 3, 4, 5, 6, 7, 10, 14, 21, or 28 days or longer (e.g., once every 2, 3, 4, or 6 months).
  • administration is more frequent, e.g., 2 or 3 times per day.
  • the patient can be monitored to adjust the dosage and frequency of administration depending on therapeutic progress and any adverse side effects, as will be recognized by one of skill in the art.
  • additional administration is dependent on patient progress, e.g., the patient is monitored between administrations.
  • the patient can be monitored for indications of infection, or general disease-related symptoms such as weakness, pain, nausea, etc.
  • a set course of administration is used regardless of clinical picture, except in the case of adverse effects.
  • a composition e.g., including a therapeutic and/or diagnostic agent
  • 1 mg/kg to about 200 mg/kg, or about 1 mg/kg to about 100 mg/kg, or about 10 mg/kg to about 50 mg/kg, can be used.
  • the dosage is varied depending upon the requirements of the patient, the severity of the condition being treated, and the targeted composition being employed.
  • the dose administered to a patient, in the context of the present invention, should be sufficient to affect a beneficial therapeutic response in the patient over time.
  • the size of the dose will also be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a particular targeted composition in a particular patient, as will be recognized by the skilled practitioner.
  • the dosage of therapeutic agent, e.g., antibiotic, contained in the composition to be administered is a suitable dosage; in some cases, the dosage is higher than the normal toxic dose for the therapeutic agent, e.g., antibiotic, such as at least 1, 1.2, 1.5, 1.7, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, or 10- fold the normal toxic dose.
  • the therapeutic agent e.g., antibiotic
  • when bound in the composition is not active or only partially active, and becomes completely active only when released at the site of the infection; thus, the systemic dose of active therapeutic agent, e.g., antibiotic, is below toxic levels even the dosage in the composition as administered is above toxic levels.
  • the concentration of active therapeutic agent, e.g., antibiotic achieved at the site of infection is at least 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 12, 15, 20, 30, 40, 50, 70, 100, 200, 300, 400, or 500 times the concentration of active therapeutic agent, e.g., antibiotic, in the blood and/or not more than 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 12, 15, 20, 30, 40, 50, 70, 100, 200, 300, 400, 500, or 1000 times the concentration of active therapeutic agent, e.g., antibiotic, in the blood.
  • the infection is a bacterial infection. Any suitable bacterial infection may be treated using methods and compositions provided herein.
  • Exemplary bacterial infections include gonorrhea, pulmonary infections, and food-borne diseases.
  • the infection comprises an intracellular infection.
  • the infection comprises an extracellular infection.
  • the bacterial infection is caused, at least in part, by one or more drug-resistant bacteria.
  • One or more compositions as described herein that comprise at least one antibiotic moiety are administered to the individual at an effective dose, frequency, and duration. The composition may be administered after conventional antibiotic treatment has been tried, or may be administered without a conventional antibiotic treatment trial. The composition administered may be any suitable composition, such as the antibiotic compositions described herein.
  • the composition administered comprises a fluoroquinolone antibiotic linked to a macrolide that interacts with one or more infection healing cells, e.g., immune cells and/or fibroblasts, to cause the composition to be concentrated inside the cells; in some cases it further releases the antibiotic inside and/or in the environment of the cell.
  • the composition administered comprises a beta lactam antibiotic linked to a macrolide that interacts with one or more infection healing cells, e.g., immune cells and/or fibroblasts, to cause the composition to be concentrated inside the; in some cases it further releases the antibiotic inside and/or in the environment of the cell.
  • the composition administered comprises a tetracycline antibiotic linked to a macrolide that interacts with one or more infection healing cells, e.g., immune cells and/or fibroblasts, to cause the composition to be concentrated inside the cell; in some cases it further releases the antibiotic inside and/or in the environment of the cell.
  • infection is a pulmonary infection and the composition is administered by inhalation. Forms of compositions suitable for inhalation are described herein.
  • Gram negative bacteria such as Gram-negative highly resistant bacteria are targeted, such as, P. aeruginosa, Acinetobacter baumannii, Enterobacteriaceae, Neisseria gonorrhoeae, Campylobacter spp., Salmonellae spp., Shigella spp.
  • P. aeruginosa is targeted.
  • These can be targeted using any suitable antibiotic, e.g., using commercially available antibiotics with known mechanism of action (MO A). Targeted delivery of commercially available antibiotics results in higher efficacy, lower toxicity and an improved probability of success for development and registration.
  • MO A mechanism of action
  • an antibiotic is used that is a broad-spectrum antibiotic, such as fluoroquinolones and beta-lactams (e.g., cephalosporins, monobactams and carbapenem).
  • a broad-spectrum antibiotic such as fluoroquinolones and beta-lactams (e.g., cephalosporins, monobactams and carbapenem).
  • the antibiotic comprises a fluoroquinolone comprising comprises acorafloxacin, amifloxacin, antofloxacin, avarofloxacin, balofloxacin, benofloxacin, besifloxacin, cadroflocacin, chinfloxacin, ciprofloxacin, clinafloxacin, danofloxacin, delafloxacin, ecenofloxacin, enoxacin, enrofloxacin, esafloxacin, fandofloxacin, finafloxacin, fleroxacin, gatifloxacin, gemifloxacin, grepafloxacin, irloxacin, lemefloxacin, levofloxacin, levonadifloxacin, lomefloxacin, marbofloxacin, merafloxacin, motifloxacin, nadifloxacin,
  • the antibiotic comprises a fluoroquinolone comprising ciprofloxacin, moxifloxacin, gemifloxacin, levofloxacin, levonadifloxacin or delafloxacin, or a combination thereof.
  • the targeting moiety comprises another antibiotic, such as a macrolide antibiotic, for example erythromycin, clarithromycin, fidaxomicin, spiramycin, telithromycin, carbonmycin A, josamycin, kitsamycin, midecamycin, oleandomycin, solithromycin, troleandomycin, tylosin, roxitromycin or azithromycin.
  • the targeting moiety is azithromycin, erythromycin, or clarithromycin.
  • an antibiotic such as a macrolide antibiotic
  • the targeting antibiotic may also be present in active form, e.g., in some cases may also be released from the composition intracellularly and/or in the environment of the cell, and itself have a therapeutic effect, which can include an antibacterial effect (Gram positive bacteria, in the case of macrolides) and/or an anti-inflammatory and/or antiviral effect.
  • Antibiotic is associated with the carrier cells and is present at the site of infection in active form; in some cases, the antibiotic is inactive or only partially active when linked to a targeting moiety and is released at the site of infection in its active form due to cleavage of the antibiotic-linker bond in the environment of the infection healing cells.
  • This approach improves efficacy against both intracellular and extracellular pathogens. It can reduce systemic concentrations which may improve the overall safety profde of the therapeutic agent. Higher concentrations at the site of action eliminates highly resistant strains of bacteria and restore susceptibility of the bacteria to the antibiotic.
  • fibroblasts carrier cells
  • Developing oral antibiotics for resistant bacteria, especially for Gram-negative infections, is globally recognized as an urgent unmet medical need.
  • the technology can be applied to other infectious diseases including anti-viral and anti-fungal therapies.
  • Targeted delivery combining the power of infection healing cells armed with commercially available antibiotics to deliver higher concentrations at the site of action can result in: improved efficacy for both intracellular and extracellular bacteria; improved efficacy in low perfusion tissues due to improved distribution and increased half-life; improved efficacy in certain diseases such as cystic fibrosis and diabetes; reversal of resistance by restoring the susceptibility of the bacteria; improved safety profile by reducing systemic exposure; increased likelihood of success as entities with known efficacy and safety are being used; shorter clinical development times; fast track status (QIDP designation); and/or additional 5-year of exclusivity (GAIN act)
  • a candidate can meet the following criteria: prodrug has sufficient stability in plasma; prodrug accumulates at desired immune cells; prodrug does not interfere or substantially interfere with immune cell migration; antibiotic is active (e.g., released) at the site of infection.
  • a battery of in vitro and in situ studies can be identified and/or developed. These screening studies ensure that the prodrug meets certain criteria. For example, stability studies in blood/plasma can be used to screen stability. Accumulation in the immune cells can be achieved using in situ assay in, e.g., freshly isolated cells. In vivo PK/PD studies in animals can be used to confirm the hypothesis that the antibiotic is accumulating in the cells and is active, e.g., released to site of infection, and comparative studies in animal model of infectious disease can identify a safe and effective dose. Clinical Phase 1 PK/PD study can be utilized to confirm hypothesis in human and Phase 3 trial(s) can be used to provide the ultimate evidence of safety and efficacy in hard-to-treat infections.
  • Suitable targeted drug compositions e.g., prodrug compositions.
  • a large library of novel prodrugs that utilizes the immune cells as a carrier in combination with multiple classes of suitable antibiotics, e.g., marketed antibiotics may be synthesized. Once synthetized these prodrugs are screened, based on preset criteria, and the lead candidate(s) can be selected for ADMET (absorption, distribution, metabolism, elimination, and toxicity) and in vivo animal studies. These studies can mainly be the proof-of- concept studies to start preclinical development. Once the proof-of-concept studies have been completed, the lead candidate can rapidly move into preclinical development.
  • ADMET absorption, distribution, metabolism, elimination, and toxicity
  • Available data can include MIC (if applicable), mode of action, resistance frequency, evidence of activity against resistant strains, in vitro ADMET, animal data, PK, tox data.
  • antibiotics if commercially used antibiotics are used, they can be selected for their broad-spectrum activity, known potency against hard-to-treat infections, e.g., caused primarily by Gram-negative bacteria, such as P. aeruginosa, with proven wide therapeutic range. Ciprofloxacin and meropenem have been used as a last resort for hard-to-treat bacteria. However, the incidence of resistance against these antibiotics is rising and threatens to limit the gains that have been made. The approach described herein combines the power of immune system and the commercially available antibiotics to increase potency by elevating the concentrations of the antibiotics at the site of action.
  • kits for treating an infection include delivering the agent to an individual suffering from an infection.
  • Any suitable method of delivering an agent as provided herein may be used.
  • the individual is an individual with CF ; in certain of these embodiments the infection is a bacterial antibiotic-resistant infection, such as an antibiotic-resistant P. aeruginosa infection.
  • intravenous (IV) and/or oral delivery is used. The IV can be used in ICU setting while the oral allows treatment continuation at home. This is merely exemplary and any suitable mode of delivery or combination of modes may be used.
  • the infection is a pulmonary infection and the route of administration includes administration by inhalation.
  • the route of delivery of any one of the compositions as disclosed herein is topical.
  • a method of treating an infection caused by one or more microbial agents in an individual suffering from the infection comprising administering to the individual an effective amount of a composition comprises any one of the compositions as disclosed herein.
  • the infection comprises a Gram negative bacteria.
  • the infection comprises an antibiotic resistant Gram negative bacteria.
  • the bacteria comprise P. aeruginosa.
  • the infection comprises a nontuberculous mycobacterial (NTM) infection.
  • the NTM infection comprises Mycobacterium avium complex (MAC).
  • the MAC comprises Mycobacterium avium and Mycobacterium intracellulare .
  • the effective amount of the composition is delivered to the individual by an aerosolizing device.
  • the composition is inhaled by the individual.
  • the individual is suffering from cystic fibrosis. In addition to the infection.
  • prodrugs target specific endogenous infection healing cells, e.g., immune and/or fibroblast carrier cells to increase intracellular concentrations of antibiotics.
  • specific endogenous infection healing cells e.g., immune and/or fibroblast carrier cells
  • the antibiotics associate with them and are active, e.g., released at the site of infection in their active form.
  • This approach improves efficacy against both intracellular and extracellular pathogens.
  • Due to the targeted delivery the prodrug is removed from the blood stream resulting in lower drug exposure in the systemic circulation which in turn will improve upon side-effect profile of the therapeutic agent.
  • Use of existing drugs with proven safety and efficacy shortens the development phase and increase the probability of success.
  • Example 1 Preparation of azithromycin conjugate without protection of azithromycin
  • the following schemes exemplify methodologies useful for preparation of prodrugs of azithromycin and fluoroquinolones.
  • Alternative protecting groups for the amino functionality of a fluoroquinolone can be used such as hydrogenolitically removable 4-nitrocarbobenzyloxy or UV sensitive 3,4- dimethoxy-6-nitrocarbobenzyloxy (Alvarez, Karine, et al. “Photocleavable protecting groups as nucleobase protections allowed the solid-phase synthesis of base-sensitive SATE- prooligonucleotides . ”) .
  • Example 2 Preparation of azithromycin conjugate without protection of fluoroquinolone
  • Fluoroquinolones without a primary or secondary amine functionality can be used for conjugation without protection.
  • levofloxacin intermediate can be prepared using https://pubchem.Bcbi.nbB.nih.gov/compoun /560859 benzyl 2-chloropropanoate as shown in Figure 15.
  • Example 3 Preparation of azithromycin conjugates at multiple positions on azithromycin [0281] Linking the conjugated fluoroquinolone to other positions of azithromycin requires protection of selected hydroxy groups of the macrolide. Position 2’ can be protected with easily hydrolysable acetate group, with protecting groups removable by hydrogenolysis (carbobenzyloxy, 4-nitrocarbobenzyloxy), or by UV irradiation (3,4-dimethoxy-6- nitrocarbobenzyloxy; Alvarez, Karine, et al. “Photocleavable protecting groups as nucleobase protections allowed the solid-phase synthesis of base-sensitive SATE-prooligonucleotides.” The Journal of Organic Chemistry 64. 17 (1999): 6319-6328.) or by reduction with zinc (nitrate ester functionality US 2020/0262857 Al).
  • FIG. 17 Exemplary protection strategies for azithromycin are shown in Figure 17.
  • Corresponding 2’ protected azithromycin intermediates can be conjugated at 11 position hydroxy group with appropriately activated form of fluoroquinolone intermediate and followed by hydrogenolytic deprotection in an example using CBz protected ciprofloxacin intermediate as show in Figure 18 or followed by hydrolysis of labile 2’ protecting acetate group in an example using levofloxacin intermediate as shown in Figures 19 and 20.
  • This example shows multiple strategies for linking fluoroquinolone to multiple positions of azithromycin.
  • embodiment 1 provided is a composition comprising(i) a targeting moiety; (ii) a therapeutic moiety; and(iii) a linker, wherein the linker forms a first attachment with the targeting moiety and the linker forms a second attachment with the therapeutic moiety, and wherein the targeting moiety accumulates at a target that is present at and/or accumulates at and/or is activated at a target site, and the therapeutic moiety is active at the target site.
  • embodiment 2 provided is the composition of embodiment 1 wherein the second attachment is cleavable at the target of the targeting moiety.
  • embodiment 3 provided is the composition of embodiment 1 or 2 wherein the first attachment is cleavable at the target of the targeting moiety.
  • composition of embodiment 1 wherein the first and second attachments are cleavable at the target of the targeting moiety.
  • embodiment 5 provided is the composition of any one of the preceding embodiments further comprising a cell or cells.
  • embodiment 6 provided is the composition of embodiment 5 wherein the target of the targeting moiety is the cell or cells.
  • embodiment 7 provided is the composition of embodiment 6 wherein the cell or cells are associated with a response to a pathological condition.
  • embodiment 8 provided is the composition of embodiment 6 or 7 wherein the cell or cells is not causative of the pathological condition.
  • embodiment 9 provided is the composition of any one of the preceding embodiments wherein the first and second attachments are covalent bonds.
  • embodiment 11 provided is the composition of any one of embodiments5 through 9 wherein the targeting moiety preferentially accumulates in the cell to a level that is at least 50- fold its level in plasma.
  • embodiment 12 provided is the composition of any one of embodiments 5 or 11 wherein the cell or cells is a cell that participates in infection healing.
  • embodiment 13 provided is the composition of embodiment 12 wherein the cell or cells comprise immune cells.
  • embodiment 14 provided is the composition of embodiment 13 wherein the cell or cells comprise phagocytic cells.
  • composition of embodiment 14 wherein the phagocytic cells comprise neutrophils, monocytes, macrophages, mast cells, or dendritic cells.
  • the phagocytic cells comprise neutrophils.
  • embodiment 17 provided is the composition of any one of embodiments 12 through 16 wherein the cell or cells comprise fibroblasts.
  • the fibroblasts comprise differentiated fibroblasts.
  • embodiment 19 provided is the composition of any one of embodiments 5 through 18 wherein the therapeutic moiety further accumulates in lysosomes of the target cell or cells.
  • the therapeutic moiety comprises an antimicrobial agent that is an antifungal, antiparasitic, antiviral, or antibacterial (antibiotic) agent.
  • the therapeutic moiety comprises an antimicrobial agent.
  • the antimicrobial agent comprises an antibiotic.
  • the antibiotic comprises a fluoroquinolone, a beta-lactam, or a tetracycline.
  • the antibiotic comprises an antibiotic effective against Gram negative bacteria.
  • the antibiotic comprises a fluoroquinolone antibiotic comprising acorafloxacin, amifloxacin, antofloxacin, avarofloxacin, balofloxacin, benofloxacin, besifloxacin, cadroflocacin, chinfloxacin, ciprofloxacin, clinafloxacin, danofloxacin, delafloxacin, ecenofloxacin, enoxacin, enrofloxacin, esafloxacin, fandofloxacin, finafloxacin, fleroxacin, gatifloxacin, gemifloxacin, grepafloxacin, irloxacin, lemefloxacin, levofloxacin, levonadifloxacin,
  • the antibiotic comprises a carboxy group and the second attachment between the linker and the antibiotic is at the carboxy group.
  • the antibiotic comprises an amino group and the second attachment between the linker and the antibiotic is at the amino group.
  • the antibiotic comprises an antibiotic effective for treating a non-tuberculosis mycobacterial (NTM) infection.
  • NTM non-tuberculosis mycobacterial
  • MAC Mycobacterium avium complex
  • embodiment 33 is the composition of embodiment 31 or 32 wherein the antibiotic comprises a macrolide, such as azithromycin or clarithromycin, rifampin, ethambutol, aminoglycoside, inhaled amikacin, clfazimine, rifabutin, ciprofloxacin, moxifloxacin, or amikacin, or combinations thereof.
  • a macrolide such as azithromycin or clarithromycin, rifampin, ethambutol, aminoglycoside, inhaled amikacin, clfazimine, rifabutin, ciprofloxacin, moxifloxacin, or amikacin, or combinations thereof.
  • the targeting moiety comprises an antibiotic.
  • the antibiotic comprises a macrolide antibiotic.
  • composition of embodiment 35 wherein the macrolide antibiotic comprises a hydroxy group and the first attachment between the linker and the macrolide antibiotic is at the hydroxy group.
  • the macrolide antibiotic comprises erythromycin, clarithromycin, fidaxomicin, spiramycin, telithromycin, carbonmycin A, josamycin, kitsamycin, midecamycin, oleandomycin, solithromycin, troleandomycin, tylosin, roxitromycin, azithromycin, or a combination thereof.
  • embodiment 38 provided is the composition of any one of embodiments 35 through 37 wherein the macrolide antibiotic comprises azithromycin, erythromycin, clarithromycin, or a combination thereof.
  • the macrolide antibiotic comprises azithromycin or erythromycin.
  • the macrolide antibiotic comprises clarithromycinin embodiment 41 provided is the composition of embodiment 39 or 40 wherein the first attachment is at a 4” oxygen, a 2’ oxygen, a l l oxygen, or a 12 oxygen atom.
  • embodiment 42 provided is the composition of embodiment 38 or 39 wherein the macrolide antibiotic comprises azithromycin.
  • embodiment 43 provided is the composition of embodiment 38 or 39 wherein the macrolide antibiotic comprises erythromycin.
  • composition 44 provided is the composition of any one of the preceding embodiments wherein the second attachment and, optionally, the first attachment, are hydrolytically cleavable.
  • embodiment 45 provided is the composition of embodiment 44 wherein the hydrolysis of the second attachment and, optionally, the first attachment, is/are assisted enzymatically, assisted by an acidic local environment, or occurring due to limited stability in aqueous medium.
  • embodiment 47 provided is the composition of embodiment 46 wherein the linker comprises one of the structures of Figure 6.
  • embodiment 48 provided is the composition of any one of embodiments 1 through 45 1 through 45 wherein the linker comprises-C(O)O- C(R1)(R2)-, wherein R1 and R2 are independently selected from H, Me, Et, i-Pr, CH2NH2, CH2NHMe, CH2NHC(O)Me, CH2NMeC(O)Me, CH2NHMe, CH2NMe2, OMe.
  • embodiment 49 provided is the composition of embodiment 48 wherein the linker comprises one of the structures of Figure 7.
  • embodiment 50 provided is the composition of any one of embodiments 1 through 45 wherein the linker comprises-CH2OC(O)O-C(Rl)(R2)- wherein R1 and R2 are independently selected from H, Me, Et, i-Pr, CH2NH2, CH2NHMe, CH2NHC(O)Me, CH2NMeC(O)Me, CH2NHMe, CH2NMe2.
  • the linker comprises one of the structures of Figure 8.
  • any one of embodiments 1 through 45 wherein the linker comprises-C(O)O-(C(Rl)(R2))n-, wherein n 2-5 and wherein R1 and R2 are independently selected from H, Me, Et, i-Pr, CH2NH2, CH2NHMe, CH2NHC(O)Me, CH2NMeC(O)Me, CH2NHMe, CH2NMe2, OH, OMe, OCH2CH2OH, and wherein R1 and R2 together may also represent carbonyl -C(O)-.
  • the linker comprises one of the structures of Figure 9.
  • embodiment 55 is the composition of embodiment 54 wherein the linker comprises one of the structures of Figure 10.
  • embodiment 57 provided is the composition of embodiment 56 wherein the linker comprises one of the structures of Figure 11.
  • embodiment 58 is a composition comprising(i) a targeting moiety;(ii) a transporter inhibitor; and(iii) a linker, wherein the linker forms a first attachment with the targeting moiety and the linker forms a second attachment with the transporter inhibitor, and wherein the targeting moiety accumulates at a target that is present at and/or accumulates at and/or is activated at a target site, and the transporter inhibitor is active at the target site.
  • the second attachment is cleavable at the target of the targeting moiety.
  • embodiment 60 is the composition of embodiment 58 or 59 wherein the first attachment is cleavable at the target of the targeting moiety.
  • embodiment 61 is the composition of embodiment 58 wherein the first and second attachments are cleavable at the target of the targeting moiety.
  • embodiment 62 provided is the composition of any one of embodiments 58 through 61 further comprising a cell or cells.
  • embodiment 63 is the composition of embodiment 62 wherein the target of the targeting moiety is the cell or cells.
  • embodiment 64 provided is the composition of embodiment 63 wherein the cell or cells are associated with a response to a pathological condition.
  • embodiment 65 is the composition of embodiment 63 or 64 wherein the cell or cells is not causative of the pathological condition.
  • embodiment 66 provided is the composition of any one of embodiments 58 through 65 wherein the first and second attachments are covalent bonds.
  • any one of embodiments 62 through 66 wherein the targeting moiety preferentially accumulates in the cell to a level that is at least 5-fold its level in plasma.
  • embodiment 68 provided is the composition of any one of embodiments 62 through 66 wherein the targeting moiety preferentially accumulates in the cell to a level that is at least 50-fold its level in plasma.
  • embodiment 69 provided is the composition of any one of embodiments 62 or 68 wherein the cell or cells is a cell that participates in infection healingin embodiment 70 provided is the composition of embodiment 69 wherein the cell or cells comprise immune cells.
  • embodiment 71 provided is the composition of embodiment 70 wherein the cell or cells comprise phagocytic cells.
  • embodiment 72 provided is the composition of embodiment 71 wherein the phagocytic cells comprise neutrophils, monocytes, macrophages, mast cells, or dendritic cells.
  • embodiment 73 provided is the composition of embodiment 72 wherein the phagocytic cells comprise neutrophils.
  • embodiment 74 provided is the composition of any one of embodiments 69 through 73 wherein the cell or cells comprise fibroblasts.
  • embodiment 75 provided is the composition of embodiment 74 wherein the fibroblasts comprise differentiated fibroblasts.
  • the transporter inhibitor comprises benzylpenicillin, bromosulfopthalein, cimetidine, clofazimine, clonidine, cyclosporine, elacridar, estrone-3-sulfate, fumitremorgin C, ketoconazole, KO- 143, novobiocin, probenecid, pyrimethamine, quinidine, rifampicin, rifamycin SV, valspodar, verapamil, chloroquinolone, Ikoxyquinolone, alkylaminoquinolone, pyrridoquinolone, thioalkoxy quinolone, pheophorbide a, 3 -arylpiperidine, EA-371a ,EA-3718, Naphthylpiperazines, genistein, spinosan A, Tiliroside, phenylalanyl-arginy
  • the transporter inhibitor comprises clofazimine.
  • the targeting moiety comprises an antibiotic.
  • the antibiotic comprises a macrolide antibiotic.
  • the macrolide antibiotic comprises a hydroxy group and the first attachment between the linker and the macrolide antibiotic is at the hydroxy group.
  • embodiment 85 provided is the composition of embodiment 83 or 84 wherein the macrolide antibiotic comprises erythromycin, clarithromycin, fidaxomicin, spiramycin, telithromycin, carbonmycin A, josamycin, kitsamycin, midecamycin, oleandomycin, solithromycin, troleandomycin, tylosin, roxitromycin, azithromycin, or a combination thereof.
  • the macrolide antibiotic comprises azithromycin, erythromycin, clarithromycin, or a combination thereof.
  • the macrolide antibiotic comprises azithromycin or erythromycin.
  • embodiment 88 provided is the composition of embodiment 86 wherein the macrolide antibiotic comprises clarithromycinin
  • embodiment 89 provided is the composition of embodiment 87 or 88 wherein the first attachment is at a 4” oxygen, a 2’ oxygen, a l l oxygen, or a 12 oxygen atom.
  • embodiment 90 provided is the composition of embodiment 86 or 87 wherein the macrolide antibiotic comprises azithromycin.
  • embodiment 91 provided is the composition of embodiment 86 or 87 wherein the macrolide antibiotic comprises erythromycin.
  • embodiment 92 provided is the composition of any one of the embodiments 58 through 91 wherein the second attachment and, optionally, the first attachment, are hydrolytically cleavable.
  • embodiment 93 provided is the composition of embodiment 92 wherein the hydrolysis of the second attachment and, optionally, the first attachment, is/are assisted enzymatically, assisted by an acidic local environment, or occurring due to limited stability in aqueous medium.
  • embodiment 95 is the composition of embodiment 94 wherein the linker comprises one of the structures of Figure 6.
  • embodiment 96 provided is the composition of any one of the embodiments 58 through 93 wherein the linker comprises-C(O)O-C(Rl)(R2)-, wherein R1 and R2 are independently selected from H, Me, Et, i-Pr, CH2NH2, CH2NHMe, CH2NHC(O)Me, CH2NMeC(O)Me, CH2NHMe, CH2NMe2, OMe.
  • embodiment 97 provided is the composition of embodiment 96 wherein the linker comprises one of the structures of Figure 7.
  • embodiment 98 provided is the composition of any one of embodiments 58 through 93 wherein the linker comprises-CH2OC(O)O-C(Rl)(R2)-, wherein R1 and R2 are independently selected from H, Me, Et, i-Pr, CH2NH2, CH2NHMe, CH2NHC(O)Me,CH2NMeC(O)Me, CH2NHMe, CH2NMe2.
  • the linker comprises one of the structures of Figure 8.
  • the linker comprises one of the structures of Figure 9.
  • embodiment 103 provided is the composition of embodiment 102 wherein the linker comprises one of the structures of Figure 10.
  • embodiment 105 provided is the composition of embodiment 104 wherein the linker comprises one of the structures of Figure 11.
  • embodiment 106 provided is a composition comprising a first composition of any one of embodiments 1 through 57 and a second composition of any one of embodiments 58 through 105.
  • embodiment 107 is a composition comprising (i) a first antibiotic, (ii) a second antibiotic; and (iii) a linker that is attached to the first antibiotic at a first attachment and to the second antibiotic at a second attachmentin
  • embodiment 108 provided is the composition of embodiment 107 wherein the first and second antibiotics are different antibiotics.
  • embodiment 109 provided is the composition of embodiment 107 or 108 wherein the first and second attachments comprise covalent bonds.
  • embodiment 110 provided is the composition of any one of embodiments 107 through 109 wherein the first antibiotic comprises a macrolide antibiotic.
  • composition of embodiment 110 wherein the macrolide antibiotic comprises a hydroxy group and the first attachment between the linker and the macrolide antibiotic is at the hydroxy group.
  • the macrolide antibiotic comprises erythromycin, clarithromycin, fidaxomicin, spiramycin, telithromycin, carbonmycin A, josamycin, kitsamycin, midecamycin, oleandomycin, solithromycin, troleandomycin, tylosin, roxitromycin, azithromycin, or a combination thereof.
  • embodiment 113 is the composition of any one of embodiments 110 through 112 wherein the macrolide antibiotic comprises azithromycin, erythromycin, clarithromycin, or a combination thereof.
  • the macrolide antibiotic comprises azithromycin or erythromycin, and the first attachment is at a 4” oxygen, a 2’ oxygen, a 6 oxygen, a l l oxygen, or a 12 oxygen atom.
  • the macrolide antibiotic comprises clarithromycin, and the first attachment is at a 4” oxygen, a 2’ oxygen, a l l oxygen, or a 12 oxygen atom.
  • embodiment 116 is the composition of embodiment 113 wherein the macrolide antibiotic comprises azithromycin, and the first attachment is at a 4” oxygen, a 2’ oxygen, a 6 oxygen, a l l oxygen, or a 12 oxygen atom.
  • the second antibiotic comprises a fluoroquinolone, a beta-lactam, or a tetracycline.
  • the second antibiotic comprises a fluoroquinolone.
  • the second antibiotic comprises an antibiotic effective against Gram negative bacteria.
  • the second antibiotic comprises a fluoroquinolone antibiotic comprising acorafloxacin, amifloxacin, antofloxacin, avarofloxacin, balofloxacin, benofloxacin, besifloxacin, cadroflocacin, chinfloxacin, ciprofloxacin, clinafloxacin, danofloxacin, delafloxacin, ecenofloxacin, enoxacin, enrofloxacin, esafloxacin, fandofloxacin, finafloxacin, fleroxacin, gatifloxacin, gemifloxacin, grepafloxacin, irloxacin, lemefloxacin, levofloxacin, levonadifloxacin, lomefloxacin, marbofloxacin, merafloxacin
  • any one of embodiments 117 through 120 wherein the fluoroquinolone comprises ciprofloxacin, moxifloxacin, gemifloxacin, levofloxacin, levonadifloxacin or delafloxacin, or a combination thereof.
  • the second antibiotic comprises a carboxy group and the second attachment between the linker and the antibiotic is at the carboxy group.
  • the second antibiotic comprises an amino group and the second attachment between the linker and the antibiotic is at the amino group.
  • composition 124 provided is the composition of any one of embodiments 107 through 121 wherein the second antibiotic comprises a hydroxy group and the second attachment between the linker and the antibiotic is at the hydroxy group.
  • embodiment 125 provided is the composition of any one of embodiments 107 through 124 wherein the first and/or second attachments are cleavable by hydrolysis, and hydrolysis of the second attachment and, optionally, the first attachment, is/are assisted enzymatically, assisted by an acidic local environment, or occurring due to limited stability in aqueous medium.
  • the linker comprises one of the structures of Figure 6.
  • embodiment 128 provided is the composition of any one of embodiments 107 through 125 wherein the linker comprises -C(O)O-C(R1)(R2)-, wherein R1 and R2 are independently selected from H, Me, Et, i-Pr, CH2NH2, CH2NHMe, CH2NHC(O)Me, CH2NMeC(O)Me, CH2NHMe, CH2NMe2, OMe.
  • the linker comprises one of the structures of Figure 7.
  • embodiment 130 is the composition of any one of embodiments 107 through 125 wherein the linker comprises - CH2OC(O)O-C(R1)(R2)-, wherein R1 and R2 are independently selected from H, Me, Et, i-Pr, CH2NH2, CH2NHMe, CH2NHC(O)Me, CH2NMeC(O)Me, CH2NHMe, CH2NMe2.
  • the linker comprises one of the structures of Figure 8.
  • the linker comprises one of the structures of Figure 9.
  • embodiment 135 is the composition of embodiment 134 wherein the linker comprises one of the structures of Figure 10.
  • embodiment 137 provided is the composition of embodiment 136 wherein the linker comprises one of the structures of Figure 11.
  • a cell associated with infection healing comprising a composition comprising a targeting moiety linked to a linker and a therapeutic moiety also linked to the linker, and/or a component or components of the composition.
  • the component or components of the composition comprise the targeting moiety linked to the linker, the targeting moiety alone (free targeting moiety), the therapeutic moiety alone (free therapeutic moiety), the therapeutic moiety linked to the linker, and/or the linker.
  • the linkages comprise covalent bonds.
  • embodiment 141 provided is the cell of any one of embodiments 138 through 140 wherein the cell comprises an immune cell or a wound healing cell.
  • embodiment 142 is the cell of any one of embodiments 138 through 141 wherein the cell comprises a cell associated with a response to a pathological condition, and not a cell that is causative of the pathological condition.
  • embodiment 143 is the cell of embodiment 141 or 142 wherein the cell comprises an immune cell.
  • embodiment 144 provided is the cell of embodiment 143 wherein the cell comprises a phagocytic cell.
  • embodiment 145 provided is the cell of embodiment 144 wherein the phagocytic cell comprises a neutrophil, monocyte, macrophage, mast cell, or dendritic cell.
  • embodiment 146 provided is the cell of embodiment 145 wherein the phagocytic cell comprises a neutrophil.
  • embodiment 147 provided is the cell of embodiment 141 or 142 wherein the cell comprises a fibroblast.
  • embodiment 148 provided is the cell of any one of embodiments 138 through 147 wherein the targeting moiety-linker-therapeutic moiety and/or various components are located intracellularly, such as in cytosol and/or one or more organelles.
  • embodiment 149 provided is the cell of embodiment 138 through 148 wherein the therapeutic moiety is present in lysosomes of the target cell or cells.
  • embodiment 150 provided is the cell of embodiment 149 wherein the ratio of concentration of the therapeutic moiety in the lysosomes to its concentration in cytosol is at least 1: 1.
  • embodiment 151 provided is the cell of embodiment 148 through 150 wherein the therapeutic moiety in active form, whether in a form where it is linked to the linker and/or released from the linker at the second attachment or at a site between the first and second attachments, is present at a concentration greater than that at which it would accumulate in the cell under normal physiological conditions, e. g. , at normal concentrations of administration of the antibiotic alone, i. e. , not as part of the prodrug.
  • a ratio of intracellular concentration of the therapeutic moiety, e. g. , antibiotic to extracellular concentration of therapeutic moiety is at least 5.
  • a ratio of intracellular concentration of the therapeutic moiety, e. g. , antibiotic to extracellular concentration of therapeutic moiety is at least 50.
  • the cell of embodiment 138 through 153 wherein the active therapeutic moiety is present intracellularly at a concentration of at least 10 ng/ml.
  • the targeting moiety is located intracellularly, such as in cytosol and/or one or more organelles.
  • the targeting moiety is present in lysosomes of the target cell or cells.
  • embodiment 157 provided is the cell of embodiment 156 wherein the ratio of concentration of the targeting moiety in the lysosomes to its concentration in cytosol is at least 1: 1.
  • embodiment 158 provided is the cell of any one of embodiments 151 through 157 wherein a ratio of intracellular concentration of the targeting moiety to extracellular concentration of targeting moiety is at least 5.
  • embodiment 159 provided is the cell of any one of embodiments 151 through 157 wherein a ratio of intracellular concentration of the targeting moiety to extracellular concentration of targeting moiety is at least 25.
  • embodiment 160 provided is the cell of any one of embodiments 151 through 157 wherein a ratio of intracellular concentration of the targeting moiety to extracellular concentration of free targeting moiety is at least 50.
  • embodiment 161 provided is the cell of embodiment 138 through 160 wherein the targeting moiety is present intracellularly at a concentration of at least 10 ng/ml.
  • embodiment 162 provided is the cell of embodiment 138 wherein the targeting moiety comprises an antibiotic active against Gram positive bacteria and the therapeutic moiety comprises an antibiotic active against Gram negative bacteria.
  • embodiment 163 is provided a pharmaceutical composition comprising any of the compositions of embodiments 1 through 137 and a pharmaceutically acceptable excipient.
  • embodiment 164 is a composition comprising a liposome comprising a first therapeutic agent.
  • embodiment 165 is the composition of embodiment 164 further comprising a second therapeutic agent different from the first.
  • the first and/or second therapeutic agent comprise an antimicrobial agent that is an antifungal, antiparasitic, antiviral, or antibacterial (antibiotic) agent.
  • the first and/or second therapeutic agent comprise an antimicrobial agent.
  • the antimicrobial agent comprises an antibiotic.
  • embodiment 169 provided is the composition of embodiment 168 wherein the antibiotic comprises a fluoroquinolone, a beta-lactam, or a tetracycline.
  • embodiment 170 provided is the composition of embodiment 169 wherein the antibiotic comprises a fluoroquinolone.
  • embodiment 171 provided is the composition of any one of embodiments 168 through 170 wherein the antibiotic comprises an antibiotic effective against Gram negative bacteria.
  • the antibiotic comprises a fluoroquinolone antibiotic comprising acorafloxacin, amifloxacin, antofloxacin, avarofloxacin, balofloxacin, benofloxacin, besifloxacin, cadroflocacin, chinfloxacin, ciprofloxacin, clinafloxacin, danofloxacin, delafloxacin, ecenofloxacin, enoxacin, enrofloxacin, esafloxacin, fandofloxacin, finafloxacin, fleroxacin, gatifloxacin, gemifloxacin, grepafloxacin, irloxacin, lemefloxacin, levofloxacin, levonadifloxacin, lomefloxacin, marbofloxacin, merafloxacin
  • composition 173 provided is the composition of any one of embodiments 169 through 172 wherein the antibiotic comprises a fluoroquinolone antibiotic comprising ciprofloxacin, moxifloxacin, gemifloxacin, levofloxacin, levonadifloxacin or delafloxacin, or a combination thereof.
  • the antibiotic comprises a macrolide antibiotic.
  • embodiment 175 provided is the composition of embodiment 174 wherein the macrolide antibiotic comprises erythromycin, clarithromycin, fidaxomicin, spiramycin, telithromycin, carbonmycin A, josamycin, kitsamycin, midecamycin, oleandomycin, solithromycin, troleandomycin, tylosin, roxitromycin, azithromycin, or a combination thereof.
  • the antibiotic comprises azithromycin, erythromycin, clarithromycin, or a combination thereof.
  • the macrolide antibiotic comprises azithromycin or erythromycin.
  • the macrolide antibiotic comprises azithromycin. In embodiment 179 provided is the composition of embodiment 176 wherein the macrolide antibiotic comprises erythromycin. In embodiment 180 provided is the composition of embodiment 176 wherein the macrolide antibiotic comprises clarithromycin. In embodiment 181 provided is the composition of embodiment 168 wherein the antibiotic comprises an antibiotic effective for treating a non-tuberculosis mycobacterial (NTM) infection. In embodiment 182 provided is the composition of embodiment 181 wherein the antibiotic comprises an antibiotic effective for treating Mycobacterium avium complex (MAC).
  • NTM non-tuberculosis mycobacterial
  • MAC Mycobacterium avium complex
  • the first and/or second therapeutic agent comprise a transporter inhibitor.
  • embodiment 185 provided is the composition of embodiment 184 wherein the transporter inhibitor inhibits, or at least partially inhibits, P -glycoprotein (P-gp), breast cancer resistance protein (BCRP), LmrA, ABC transporter, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, MATE-2K, OCT2, AdeABC, AmeABC, AmrAB, BpeAB, CmeABC, Bmr, Bit, AcrAB, AcrD, AcrEF, CusCFBA, EmrAB, EmrKY, MdtABC, MdtEF, FarAB, MtrCDE, MexAB, MexCD, MexEF, MexXY, ArpAB, SrpABC, TtgABC, TtgDEF, TtgGHI, AcrAB, AcrD, AcrEF, MacAB, MdsABC, MdtABC, MepA, QacA, SmeABC, SmeDEF, NorA, P
  • the transporter inhibitor comprises benzylpenicillin, bromosulfopthalein, cimetidine, clofazimine, clonidine, cyclosporine, elacridar, estrone-3-sulfate, fumitremorgin C, ketoconazole, KO- 143, novobiocin, probenecid, pyrimethamine, quinidine, rifampicin, rifamycin SV, valspodar, verapamil, chloroquinolone, Ikoxyquinolone, alkylaminoquinolone, pyrridoquinolone, thioalkoxyquinolone, pheophorbide a, 3 -arylpiperidine, EA-371a ,EA-3718, Naphthylpiperazines, genistein, spinosan A, Tiliroside, phenylalanyl-arginy
  • embodiment 190 provided is the composition of embodiment 184 through 189 wherein the transporter inhibitor comprises clofazimine.
  • embodiment 191 provided is the composition of any one of embodiments 164 through 190 wherein the first and/or second therapeutic agent comprise a composition of any one of embodiments 1 through 137.
  • embodiment 192 provided is the composition of any one of embodiments 164 through 191 wherein the first and/or second therapeutic agent comprises a chemotherapeutic agent.
  • embodiment 193 provided is the composition of any one of embodiments 164 through 192 wherein the liposome is unilamellar or multilamellar.
  • embodiment 194 provided is the composition of embodiment 193 wherein the liposome is unilamellar.
  • embodiment 195 is the composition of embodiment 193 wherein the liposome is multilamellar.
  • embodiment 196 provided is the composition of any one of embodiments 164 through 195 wherein the composition is formulated in such a way that the composition can be administered by inhalation.
  • embodiment 197 provided is the composition of any one of embodiments 164 through 196 wherein the composition is formulated in such a way that the composition can be used in a delivery device for delivery to the lungs.
  • embodiment 198 provided is the composition of embodiment 197 wherein the delivery device is an aerosolization device.
  • embodiment 199 provided is the compositon of embodiment 198 wherein the aerosolization device comprises a vibrating mesh nebulizer.
  • composition of any one of embodiments 196 through 199 wherein the composition has a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to about 2. 5 microns.
  • composition of any one of embodiments 196 through 199 wherein the aerosol has a mass median aerodynamic diameter from about 2. 8 microns to about 4. 3 microns with a geometric standard deviation less than or equal to about 2 microns.
  • embodiment 202 provided is the composition of any one of embodiments 196 through 199 wherein the aerosol has a mass median aerodynamic diameter from about 2. 5 microns to about 4. 5 microns with a geometric standard deviation less than or equal to about 1. 8 microns.
  • composition 2 provided is the composition of any one of embodiments 197 through 202 further comprising the delivery device.
  • 204 provided is a composition comprising a first liposome comprising a first therapeutic agent and a second liposome comprising a second therapeutic agent.
  • 205 provided is the composition of embodiment 204 wherein the first and second liposomes are the same.
  • 206 provided is the composition of embodiment 204 or 205 wherein the first and second therapeutic agents are different.
  • the first and/or second therapeutic agent comprise an antimicrobial agent that is an antifungal, antiparasitic, antiviral, or antibacterial (antibiotic) agent.
  • composition 208 is the composition of embodiment 207 wherein the first and/or second therapeutic agent comprise an antimicrobial agent.
  • the antimicrobial agent comprises an antibiotic.
  • the antibiotic comprises a fluoroquinolone, a beta-lactam, or a tetracycline.
  • the antibiotic comprises a fluoroquinolone.
  • the antibiotic comprises an antibiotic effective against Gram negative bacteria.
  • the antibiotic comprises a fluoroquinolone antibiotic comprising acorafloxacin, amifloxacin, antofloxacin, avarofloxacin, balofloxacin, benofloxacin, besifloxacin, cadroflocacin, chinfloxacin, ciprofloxacin, clinafloxacin, danofloxacin, delafloxacin, ecenofloxacin, enoxacin, enrofloxacin, esafloxacin, fandofloxacin, finafloxacin, fleroxacin, gatifloxacin, gemifloxacin, grepafloxacin, irloxacin, lemefloxacin, levofloxacin, levonadifloxacin, lomefloxacin, marbofloxacin, merafloxacin
  • composition 214 provided is the composition of any one of embodiments 209 through 213 wherein the antibiotic comprises a fluoroquinolone antibiotic comprising ciprofloxacin, moxifloxacin, gemifloxacin, levofloxacin, levonadifloxacin or delafloxacin, or a combination thereof.
  • the antibiotic comprises a macrolide antibiotic.
  • embodiment 216 is the composition of embodiment 215 wherein the macrolide antibiotic comprises erythromycin, clarithromycin, fidaxomicin, spiramycin, telithromycin, carbonmycin A, josamycin, kitsamycin, midecamycin, oleandomycin, solithromycin, troleandomycin, tylosin, roxitromycin, azithromycin, or a combination thereof.
  • the antibiotic comprises azithromycin, erythromycin, clarithromycin, or a combination thereof.
  • the macrolide antibiotic comprises azithromycin or erythromycin.
  • the macrolide antibiotic comprises azithromycin.
  • the macrolide antibiotic comprises erythromycin.
  • the macrolide antibiotic comprises clarithromycin.
  • the antibiotic comprises an antibiotic effective for treating a non-tuberculosis mycobacterial (NTM) infection.
  • the antibiotic comprises an antibiotic effective for treating Mycobacterium avium complex (MAC).
  • embodiment 224 provided is the composition of embodiment 222 or 223 wherein the antibiotic comprises a macrolide, such as azithromycin or clarithromycin, rifampin, ethambutol, aminoglycoside, inhaled amikacin, clfazimine, rifabutin, ciprofloxacin, moxifloxacin, or amikacin, or combinations thereof.
  • the first and/or second therapeutic agent comprise a transporter inhibitor.
  • embodiment 226 provided is the composition of embodiment 225 wherein the transporter inhibitor inhibits, or at least partially inhibits, P -glycoprotein (P-gp), breast cancer resistance protein (BCRP), LmrA, ABC transporter, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, MATE-2K, OCT2, AdeABC, AmeABC, AmrAB, BpeAB, CmeABC, Bmr, Bit, AcrAB, AcrD, AcrEF, CusCFBA, EmrAB, EmrKY, MdtABC, MdtEF, FarAB, MtrCDE, MexAB, MexCD, MexEF, MexXY, ArpAB, SrpABC, TtgABC, TtgDEF, TtgGHI, AcrAB, AcrD, AcrEF, MacAB, MdsABC, MdtABC, MepA, QacA, SmeABC, SmeDEF, NorA, P
  • the transporter inhibitor comprises benzylpenicillin, bromosulfopthalein, cimetidine, clofazimine, clonidine, cyclosporine, elacridar, estrone-3-sulfate, fumitremorgin C, ketoconazole, K0- 143, novobiocin, probenecid, pyrimethamine, quinidine, rifampicin, rifamycin SV, valspodar, verapamil, chloroquinolone, Ikoxyquinolone, alkylaminoquinolone, pyrridoquinolone, thioalkoxyquinolone, pheophorbide a, 3 -arylpiperidine, EA-371a ,EA-3718, Naphthylpiperazines, genistein, spinosan A, Tiliroside, phenylalanyl-arginyl
  • embodiment 231 provided is the composition of embodiment 225 through 230 wherein the transporter inhibitor comprises clofazimine.
  • the first and/or second therapeutic agent comprise a composition of any one of embodiments 1 through 137.
  • the first and/or second therapeutic agent comprises a chemotherapeutic agent.
  • embodiment 234 provided is the composition of any one of embodiments 204 through 233 wherein the liposome is unilamellar or multilamellar.
  • embodiment 235 provided is the composition of embodiment 234 wherein the liposome is unilamellar.
  • composition of embodiment 234 wherein the liposome is multilamellar is provided.
  • embodiment 238 provided is the composition of any one of embodiments 204 through 237 wherein the composition is formulated in such a way that the composition can be used in a delivery device for delivery to the lungs.
  • the delivery device is an aerosolization device.
  • the aerosolization device comprises a vibrating mesh nebulizer.
  • compositions of any one of embodiments 237 through 240 wherein the composition has a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to about 2. 5 microns.
  • aerosol has a mass median aerodynamic diameter from about 2. 8 microns to about 4. 3 microns with a geometric standard deviation less than or equal to about 2 microns.
  • aerosol has a mass median aerodynamic diameter from about 2. 5 microns to about 4. 5 microns with a geometric standard deviation less than or equal to about 1. 8 microns.
  • composition of any one of embodiments 197 through 243 further comprising the delivery device.
  • embodiment 245 provided is a pharmaceutical composition comprising any of the compositions of embodiments 1 through 137 or 164 through 244 and in a form suitable for administration by inhalation.
  • a pharmaceutical composition comprising any of the compositions of embodiments 1 through 137 and in a form suitable for oral administration.
  • a pharmaceutical composition comprising any of the compositions of embodiments 1 through 137 and in a form suitable for topical administration.
  • a pharmaceutical composition comprising any of the compositions of embodiments 1 through 137 and in a form suitable for administration by subcutaneous, intramuscular, or intravenous injection.
  • embodiment 249 provided is a composition comprising the pharmaceutical composition of embodiment 245 that is operably disposed in aerosolizing device.
  • a method of accumulating a therapeutic moiety in a cell and/or a cell’s local environment comprising (i) contacting the cell extracellularly with a composition comprising a targeting moiety and the therapeutic moiety linked by a linker, where the linker forms a first attachment with the targeting moiety and the linker forms a second attachment with the therapeutic moiety; (ii) allowing the composition to be transported into the cell and/or an organelle of the cell and/or local environment of the cell, where the therapeutic moiety is active, so that the therapeutic moiety accumulates in the cell and/or its environment.
  • embodiment 251 provided is the method of embodiment 250 wherein one or both attachments of the linker, or the linker between the two attachments, is cleaved, or there is no cleavage, so that the therapeutic moiety retains sufficient activity for its intended purpose.
  • embodiment 252 provided is the method of embodiment 250 wherein the targeting moiety is active in the cell and/or organelle of the cell and/or local environment of the cell.
  • embodiment 253 provided is the method of embodiment 252 wherein one or both attachments of the linker, or the linker between the two attachments, is cleaved, or there is no cleavage, so that the targeting moiety retains sufficient activity for its intended purpose.
  • the targeting moiety also has a therapeutic function.
  • the intracellular concentration of the targeting moiety is at least 5-fold greater than the extracellular concentration of the targeting moiety.
  • the intracellular concentration of the targeting moiety is at least 50-fold greater than the extracellular concentration of the targeting moiety.
  • the intracellular concentration of the targeting moiety is at least 10 ng/mL.
  • the composition comprising a targeting moiety and the therapeutic moiety linked by a linker is any one of the compositions of embodiments 1-79.
  • the therapeutic moiety comprises an antibiotic.
  • the antibiotic comprises a fluoroquinolone, a beta lactam, or a tetracycline.
  • the intracellular concentration of the therapeutic moiety is at least 5 -fold greater than the extracellular concentration of the therapeutic moiety.
  • the intracellular concentration of the therapeutic moiety is at least 50-fold greater than the extracellular concentration of the therapeutic moiety.
  • the intracellular concentration of the therapeutic moiety is at least 10 ng/mL.
  • the targeting moiety comprises an antibiotic.
  • the targeting moiety comprises a macrolide antibiotic.
  • a method of delivering a therapeutic moiety comprising an antimicrobial agent to a site of an infection in an individual, where the infection is mediated by one or more microbial agents comprising (i) administering to the individual a composition comprising a targeting moiety and the therapeutic moiety comprising the antimicrobial agent linked by a linker, where the linker forms a first attachment with the targeting moiety and the linker forms a second attachment with the therapeutic moiety comprising the antimicrobial, wherein the targeting moiety interacts with an infection healing cell to concentrate the antimicrobial agent in the infection healing cell and/or in the local environment of the infection healing cell, wherein the infection healing cell is a cell that is present at the site of infection and/or that preferentially travels to the site of infection, by movement of the composition into the infection healing cell.
  • the therapeutic moiety comprises an antibiotic.
  • the infection healing cell is an immune cell or a wound healing cell.
  • the composition is cleaved at the first and/or second attachments or in the linker between the first and second attachments and releases the antimicrobial in active or substantially active form in the cell, in an organelle of the cell, and/or in the local environment of the cell.
  • the composition is not cleaved and the antimicrobial is active or substantially active in the cell, in an organelle of the cell, and/or in the local environment of the cell.
  • embodiment 271 provided is the method of embodiment 266 wherein the concentration of the antimicrobial agent increases so that the concentration is at least 5-fold greater than the concentration of the antimicrobial agent, e. g. , antibiotic in the general circulation of the individual.
  • embodiment 272 provided is the method of embodiment 266 wherein the concentration of the antimicrobial agent increases so that the concentration is at least 50-fold greater than the concentration of the antimicrobial agent, e. g. , antibiotic in the general circulation of the individual.
  • embodiment 273 provided is the method of embodiment 266 wherein the concentration of the antimicrobial agent at the site of the infection is at least 10 ng/ml.
  • the targeting moiety also has a therapeutic function, and the targeting moiety is concentrated in the infection healing cell and/or in the local environment of the infection healing cell in active or substantially active form.
  • the targeting moiety is in active or substantially active form as part of the composition, or is converted to active or substantially active form by cleavage of the first and/or second attachments or by cleavage of the linker between the first and second attachments.
  • the antibiotic comprises a fluoroquinolone, beta lactam, or tetracycline.
  • the targeting moiety comprises an antibiotic.
  • the antibiotic comprises a macrolide antibiotic.
  • the concentration of the targeting moiety increases so that the concentration is at least 5- fold greater than the concentration of the targeting moiety in the systemic circulation of the individual.
  • the concentration of the targeting moiety increases so that the concentration is at least 50-fold greater than the concentration of the targeting moiety in the systemic circulation of the individual.
  • the concentration of the targeting moiety at the site of the infection is at least 10 ng/ml.
  • embodiment 283 provided is a method of treating an infection caused by one or more microbial agents in an individual suffering from the infection comprising administering to the individual an effective amount of a composition comprising a targeting moiety and a therapeutic moiety comprising an antimicrobial agent linked by a linker, where the linker forms a first attachment with the targeting moiety and the linker forms a second attachment with the therapeutic moiety comprising the antimicrobial, e. g.
  • antibiotic and wherein the targeting moiety interacts with an infection healing cell to concentrate the antimicrobial agent in the infection healing cell and/or in the local environment of the infection healing cell, wherein the infection healing cell is a cell that is present at the site of infection and/or that preferentially travels to the site of infection, by movement of the composition into the infection healing cell and release of the therapeutic moiety from the linker inside the infection healing cell.
  • the infection healing cell comprises an immune cell or a wound healing cell.
  • the infection comprises a bacterial infection and the antimicrobial agent comprises an antibiotic.
  • embodiment 286 provided is the method of embodiment 285 wherein the bacterial infection comprise a pulmonary infection and the composition is administered by inhalation.
  • embodiment 287 provided is the method of any one of embodiments 283 through 286 wherein the composition comprises a macrolide linked to another antibiotic.
  • embodiment 288 provided is the method of embodiment 287 wherein the other antibiotic comprises a fluoroquinolone, beta lactam, or tetracycline.
  • embodiment 289 provided is the method of embodiment 287 or 288 wherein the other antibiotic comprises a fluoroquinolone.
  • embodiment 290 provided is the method of any one of embodiments 283 through 289 wherein the infection comprises Gram negative bacteria.
  • embodiment 291 provided is the method of embodiment 290 wherein the bacteria comprise antibiotic resistant Gram-negative bacteria.
  • embodiment 292 provided is the method of embodiment 290 or 291 wherein the bacteria comprise P. aeruginosa.
  • the infection comprises a nontuberculous mycobacterial (NTM) infection.
  • NTM infection comprises Mycobacterium avium complex (MAC).
  • MAC Mycobacterium avium complex
  • MAC comprises Mycobacterium avium and Mycobacterium intracellulare.
  • embodiment 296 provided is a method of treating an infection caused by one or more microbial agents in an individual suffering from the infection comprising administering to the individual an effective amount of a composition comprising any one of embodiments 164 through 244.
  • the infection comprises Gram negative bacteria.
  • the bacteria comprise antibiotic resistant Gram-negative bacteria.
  • the bacteria comprise P. aeruginosa.
  • embodiment 300 provided is the method of any one of embodiments
  • the infection comprises a nontuberculous mycobacterial (NTM) infection.
  • NTM infection comprises Mycobacterium avium complex (MAC).
  • MAC Mycobacterium avium complex
  • embodiment 303 provided is the method of any one of embodiments 296 through 302 wherein the composition is delivered to the individual by an aerosolizing device.
  • embodiment 304 provided is the method of embodiment 303 wherein the composition is inhaled by the individual.
  • embodiment 305 provided is the method of any one of embodiments 296 through 304 wherein the individual is suffering from cystic fibrosis.

Abstract

L'invention concerne des procédés et des compositions utilisant une fraction de ciblage liée à un lieur au niveau d'une première fixation et une fraction thérapeutique liée au lieur au niveau d'une seconde fixation. En outre, la présente invention concerne des méthodes de traitement d'une infection chez un individu avec une composition comprenant une fraction de ciblage liée à un lieur au niveau d'une première fixation et une fraction thérapeutique liée au lieur au niveau d'une seconde fixation.
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