Patent Application
20060084910
The present invention relates to a device for aerosol delivery of therapeutic agents.
Therapeutic agents are often delivered directly to target sites of diseased tissue in various contemporary medical procedures. This direct delivery has proven to be an advantageous approach when treating numerous medical conditions. Advantages of this procedure are that only the target site may be exposed to the therapeutic and a controlled dose of therapeutic may be directly delivered to the target tissue.
In the case of conventional anti-cancer therapeutics, many such therapeutics are inherently toxic, exposing both the patient and the healthcare provider to risks. Drug delivery systems can be used to improve the solubility and stability of drug solutions to eliminate mixing and to minimize exposure risks. Currently, drug delivery systems have been limited to inhalers and transdermal applications. The disadvantage of such systems are that they are limited to the specific drug used. Medical practice requires greater flexibility to use multiple drugs and dosing during the treatment regiment. Accordingly, there is a need for a delivery system to allow for such flexibility.
In an embodiment, the present invention provides a drug delivery sheath having an annular wall defining a cannula. The sheath comprises a channel located within and extending partially through the annular wall and first and second lateral recesses defined by the annular wall and configured to respectively seat first and second cassettes containing therapeutic agents. The first and second lateral recesses also each have at least one first and second inlet port, respectively. The sheath further comprises a first manifold and a second manifold. The first manifold is in fluid communication with the channel and in fluid communication with the at least one first inlet port, and the second manifold is in fluid communication with the channel and in fluid communication with the at least one second inlet port.
In an embodiment, the present invention provides a drug delivery sheath having an annular wall defining a cannula. The sheath comprises a first channel and a second channel located within and extending partially through the annular wall. The sheath further comprises first and second lateral recesses defined by the annular wall and configured to respectively seat first and second cassettes containing therapeutic agents. The first and second lateral recesses also each have at least one first and second inlet port, respectively. The sheath further comprises a first and second manifold. The first manifold is in fluid communication with the first channel and in fluid communication with the at least one first inlet port, and the second manifold is in fluid communication with the second channel and in fluid communication with the at least one second inlet port.
The present invention further provides drug delivery systems including a drug delivery sheath according to the present invention and an endoscope disposed within the cannula of the drug delivery sheath. The drug delivery systems may further comprise a pressurized gas source in fluid communication with the channel or channels of the drug delivery sheath.
The present invention also provides kits including a drug delivery sheath of the present invention and first and second cassettes that are configured to be inserted and seated into the first and second lateral recesses of the drug delivery sheath. Such cassettes may optionally be pre-filled with therapeutic agents.
The present invention will become more fully understood from the detailed description given hereinbelow and the accompanying drawings which are given by way of illustration only and wherein:
Referring to
As indicated by the bold arrows in
Manifolds 100 and 110, according to the present invention, may have any configuration so long as pressurized gas can access first and second cassettes 70 and 80. For example, referring to
Sheath 10 may have any number of lateral recesses in any location in annular wall 20 in addition to first lateral recess 30 and second lateral recess 40 to seat additional cassettes carrying therapeutic agents. For example, referring to
Sheath 10 may also have any number of channels 90 located within and extending partially through any side of annular wall 20 that are in communication with any number of manifolds. For example, referring to
In another embodiment that also provides for selective release of therapeutic agents from their respective cassettes, manifolds of any of the embodiments of the present invention comprise valves which can be opened and closed to provide or prevent access of the pressurized gas through the manifolds. For example, referring back to
Because sheath 10 has an annular wall 20 defining a cannula 25 and because channel 90 is located within annular wall 20 so that cannula 25 is unobstructed, sheath 10 of the present invention allows any instrument to be disposed within cannula 25. For example, referring to
The present invention also provides for drug delivery systems that include a pressurized gas source that is in fluid communication with channel 90 of sheath 10. For example, referring to
The present invention also provides kits comprising sheath 10 and cassettes 70 and 80 for placement in lateral recesses 30 and 40, respectively, of annular wall 20. Such kits may include as many cassettes as there are recesses defined in annular wall 20. For example, in embodiments where annular wall 20 additionally defines third and fourth lateral recesses 200 and 210, kits of the present invention include cassettes 180 and 190 for respective placement in recesses 200 and 210. The cassettes may be pre-filled with therapeutic agents 230 or may be empty and include a sealable port through which therapeutic agents 230 may be introduced. All cassettes may contain the same or different therapeutic agents 230 and any cassette may contain a combination of different therapeutic agents.
The therapeutic agents 230 of the present invention contained within the cassettes of the present invention may be any pharmaceutically acceptable agents such as non-genetic therapeutic agents, biomolecules, small molecules, or cells. Any of the therapeutic agents may be combined to the extent such combination is biologically compatible.
Exemplary non-genetic therapeutic agents include anti-thrombogenic agents such heparin, heparin derivatives, prostaglandin (including micellar prostaglandin E1), urokinase, and PPack (dextrophenylalanine proline arginine chloromethylketone); anti-proliferative agents such as enoxaprin, angiopeptin, sirolimus (rapamycin), tacrolimus, everolimus, monoclonal antibodies capable of blocking smooth muscle cell proliferation, hirudin, and acetylsalicylic acid; anti-inflammatory agents such as dexamethasone, rosiglitazone, prednisolone, corticosterone, budesonide, estrogen, estrodiol, sulfasalazine, acetylsalicylic acid, mycophenolic acid, and mesalamine; anti-neoplastic/anti-proliferative/anti-mitotic agents such as paclitaxel, cladribine, 5-fluorouracil, methotrexate, doxorubicin, daunorubicin, cyclosporine, cisplatin, vinblastine, vincristine, epothilones, endostatin, trapidil, and angiostatin; anti-cancer agents such as antisense inhibitors of c-myc oncogene; anti-microbial agents such as triclosan, cephalosporins, aminoglycosides, nitrofurantoin, silver ions, compounds, or salts; biofilm synthesis inhibitors such as non-steroidal anti-inflammatory agents and chelating agents such as ethylenediaminetetraacetic acid, O,O′-bis (2-aminoethyl)ethyleneglycol-N,N,N′,N′-tetraacetic acid and mixtures thereof; antibiotics such as gentamycin, rifampin, minocyclin, and ciprofolxacin; antibodies including chimeric antibodies and antibody fragments; anesthetic agents such as lidocaine, bupivacaine, and ropivacaine; nitric oxide; nitric oxide (NO) donors such as lisidomine, molsidomine, L-arginine, NO-carbohydrate adducts, polymeric or oligomeric NO adducts; anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing compound, heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin antibodies, anti-platelet receptor antibodies, enoxaparin, hirudin, Warafin sodium, Dicumarol, aspirin, prostaglandin inhibitors, platelet inhibitors and tick antiplatelet factors; vascular cell growth promotors such as growth factors, transcriptional activators, and translational promotors; vascular cell growth inhibitors such as growth factor inhibitors, growth factor receptor antagonists, transcriptional repressors, translational repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules consisting of a growth factor and a cytotoxin, bifunctional molecules consisting of an antibody and a cytotoxin; cholesterol-lowering agents; vasodilating agents; agents which interfere with endogeneus vascoactive mechanisms; and any combinations and prodrugs of the above.
Exemplary biomolecules include peptides, polypeptides and proteins; oligonucleotides; nucleic acids such as double or single stranded DNA (including naked and cDNA), RNA, antisense nucleic acids such as antisense DNA and RNA, small interfering RNA (siRNA), and ribozymes; genes; carbohydrates; angiogenic factors including growth factors; cell cycle inhibitors; and anti-restenosis agents. Nucleic acids may be incorporated into delivery systems such as, for example, vectors (including viral vectors), plasmids or liposomes.
Non-limiting examples of proteins include monocyte chemoattractant proteins (“MCP-1) and bone morphogenic proteins (“BMP's”), such as, for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15. Preferred BMPS are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7. These BMPs can be provided as homdimers, heterodimers, or combinations thereof, alone or together with other molecules. Alternatively, or in addition, molecules capable of inducing an upstream or downstream effect of a BMP can be provided. Such molecules include any of the “hedghog” proteins, or the DNA's encoding them. Non-limiting examples of genes include survival genes that protect against cell death, such as anti-apoptotic Bcl-2 family factors and Akt kinase and combinations thereof. Non-limiting examples of angiogenic factors include acidic and basic fibroblast growth factors, vascular endothelial growth factor, epidermal growth factor, transforming growth factor α and β, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor α, hepatocyte growth factor, and insulin like growth factor. A non-limiting example of a cell cycle inhibitor is a cathespin D (CD) inhibitor. Non-limiting examples of anti-restenosis agents include p15, p16, p18, p19, p21, p27, p53, p57, Rb, nFkB and E2F decoys, thymidine kinase (“TK”) and combinations thereof and other agents useful for interfering with cell proliferation.
Exemplary small molecules include hormones, nucleotides, amino acids, sugars, and lipids and compounds have a molecular weight of less than 100 kD.
Exemplary cells include stem cells, progenitor cells, endothelial cells, adult cardiomyocytes, and smooth muscle cells. Cells can be of human origin (autologous or allogenic) or from an animal source (xenogenic), or genetically engineered.
With respect to delivery of genetically engineered cells, the present invention provides a less invasive method of delivering genetically engineered cells to a target site compared to the conventional delivery of engineered cells using matrices or scaffold sheets of engineered tissue. Furthermore, the present invention provides for direct contact of the engineered cells with the cells at the target site. The cassettes may contain the engineered cells in addition to other agents to aid in the healing process such as antibiotics, anesthetic agents, and growth enhancing agents.
The therapeutic agents of the present invention may be micronized or microencapsulated to provide for sustained release. Specifically, the therapeutic agents may be micronized by destructive or constructive methods, where non-limiting examples of destructive methods include crushing and grinding, granulation, and spray formation and non-limiting examples of constructive methods include evaporation/condensation, physico-chemical methods, crystallization, and vapor condensation. The therapeutic agents of the present invention may also be microencapsulated in a polymer shell. Such microencapsulation may be performed by phase separation processes such as simple coacervation in an aqueous medium, complex coacervation in an aqueous medium, coacervation in a non-aqueous medium; interface polycondensation processes such as pan coating, fluid bed coating, and air-suspension coating; and matrix solidification processes such as spray drying, spray congealing, solvent evaporation, and spray polycondensation. The therapeutic agents may also be adsorbed onto small carrier particles.
The polymer or polymers used in the present invention to encapsulate the therapeutic agent are preferably capable of absorbing a substantial amount of drug solution and may be hydrophilic or hydrophobic, and may be selected from the group consisting of polycarboxylic acids, cellulosic polymers, including cellulose acetate and cellulose nitrate, gelatin, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyanhydrides including maleic anhydride polymers, polyamides, polyvinyl alcohols, copolymers of vinyl monomers such as EVA, polyvinyl ethers, polyvinyl aromatics, polyethylene oxides, glycosaminoglycans, polysaccharides, polyesters including polyethylene terephthalate, polyacrylamides, polyethers, polyether sulfone, polycarbonate, polyalkylenes including polypropylene, polyethylene and high molecular weight polyethylene, halogenated polyalkylenes including polytetrafluoroethylene, polyurethanes, polyorthoesters, proteins, polypeptides, silicones, siloxane polymers, polylactic acid, polyglycolic acid, polycaprolactone, polyhydroxybutyrate valerate and blends and copolymers thereof as well as other biodegradable, bioabsorbable and biostable polymers and copolymers. Encapsulation from polymer dispersions such as polyurethane dispersions (BAYHDROL®, etc.) and acrylic latex dispersions are also within the scope of the present invention. The polymer may be a protein polymer, fibrin, collage and derivatives thereof, polysaccharides such as celluloses, starches, dextrans, alginates and derivatives of these polysaccharides, an extracellular matrix component, hyaluronic acid, or another biologic agent or a suitable mixture of any of these, for example. In one embodiment of the invention, the preferred polymer is polyacrylic acid, available as HYDROPLUS® (Boston Scientific Corporation, Natick, Mass.), and described in U.S. Pat. No. 5,091,205, the disclosure of which is hereby incorporated herein by reference.
The therapeutic agents contained within the cassettes can be delivered to any target site in the body, particularly any endoluminal target sites such as the gastrointestinal, vascular, or air exchange lumens. Other target sites include the, esophagus, trachea, colon, biliary tract, urinary tract, prostate, brain, lung, liver, heart, skeletal muscle, kidney, bladder, intestines, stomach, pancreas, ovary, cartilage, eye, bone, and the like.
The therapeutic agents can be used, for example, in any application for treating, preventing, or otherwise affecting the course of a disease or tissue or organ dysfunction. For example, the sheath of the present invention can by used to induce or inhibit angiogenesis, as desired, to present or treat restenosis, to treat a cardiomyopathy or other dysfunction of the heart, for treating Parkinson's disease or a stroke or other dysfunction of the brain, for treating cystic fibrosis or other dysfunction of the lung, for treating or inhibiting malignant cell proliferation, for treating any malignancy, and for inducing nerve, blood vessel or tissue regeneration in a particular tissue or organ.
The foregoing description and example have been set forth merely to illustrate the invention and are not intended as being limiting. Each of the disclosed aspects and embodiments of the present invention may be considered individually or in combination with other aspects, embodiments, and variations of the invention. In addition, unless otherwise specified, none of the steps of the methods of the present invention are confined to any particular order of performance. Modifications of the disclosed embodiments incorporating the spirit and substance of the invention are within the scope of the present invention.
