Field of the Invention

The present invention is an inflatable balloon which, is enclosed by an expandable cover which becomes increasingly porous/permeable during expansion. The balloon is coated or enclosed, with a matrix which coxrtaim a pharmaceutically active agent. During expansion of the balloon, the pharmaceutically active agent is released or extruded through the expandable cover (e.g., a membrane) into a body cavity such as an artery or vein. The present invention also provides for a method of delivering the inflatable balloon as well as the pharmaceutically active agent to a body cavity.

Background

Atherosclerosis nvolves a thickening of the arterial wall. Pathologically,

atherosclerosis results from invasion and accumulation of white blood cells (also referred to as foam cells) and proliferation of intimal smooth muscle ceil which forms a fibrofatt plaque in the arterial wall Potentially, atherosclerosis can affect any arterial blood vessel, either centrally, or peripherally, causing a narrowing or even complete- obstruction, of any artery. Angioplasty is a therapeutic technique involving mechanical widening of the obstructed artery.

Percutaneous coronary intervention (PCI), also known as coronary angioplasty, is a therapeutic procedure used to treat the narrowed or stenotic section of the coronary artery of the heart due to coronar lesions or obstructions, A guide catheter ma be used in PCI to provide support and easier passage for another catheter or device (microeatheter, stents, balloons, etc.) to access the target site. For example, a guide catheter can be inserted through the aorta and into the ostium of the coronary arter . The guide catheter is men inserted into the opening or ostium of the artery to be treated and a guidewire or other instrument passed through the lumen of the guide catheter and inserted into the artery beyond the occlusion or stenosis. Peripherally, percutaneous transluminal intervention or PTA is used to treat narrowing or stenosis of arteries such as the iliac, femoral, popliteal, renal or carotid arteries. Neurovascular angioplasty is also growing in importance as a means for treating stroke.

In certain circumstances, a stent may be insetted into the blood vessel, during

angioplasty in order to maintain patency of the lumen. However, a known complication of stealing is restenosis, where the blood vessel narrows as a result of the invasion of smooth

I muscle ceils and accumulation, of the extracellular matrix in response to injury from

angioplasty,, In order to prevent restenosis, stents may be coated with a variety of different, antiproliferative pharmacological agents such as siro!iraus (drag ehiting stents). Although drag eiuting stents have proved very effective at treating occluded coronary arteries, there remains a small but neasureable incidence of severe complications after stent implantation resulting from stent thrombosis. Loscher et ai. Circulation 1 15:1051 (2007). Stem

thrombosis has a very mortality and morbidity. Id.

Drag elutmg balloons (DEB) offer an alternative to POBA (Plain Old Angioplasty ^' Balloon), or bare or drug elating stents, importantly, DEB can provide several distinct advantages when compared with these other modes of intervention . Waksmao et ai.

Circulation: Cardiovascular interventions 2:352 (2009). For example, dmg eiuting stents do not work welt with long tortuous vessels, small vessels (i.e., less then 2.5mm in diameter) or in long, diffuse calcified lesions, id. First generation DEB have bee limited to the delivery of paclitaxel given the method and mechanics of drug transfer from th balloon surface to the vessel wail Moreover, sustained release of paclitaxel is not required for a long lasting antiproliferative effect. A drug eiuting balloon allows for rapid delivery of a comparatively large quantity of drug over a short period of time. Other advan tages of a drug eiuting balloon include, (a) homogenous drug transfer to the entire vessel wall; (b) rapid release of high concentrations of the drug over periods no longer than a week; (c) absence of foreign body, i.e., stent, could decrease chronic inflammation and the trigger for late thrombosis; (d) absence of a stent allows the artery's original anatomy to remai intact, such as in cases of bimrcation or small vessels; and (e) with local drag delivery, dependence on antiplatelet therapy could be decreased. Id.

T hus, there is an on-going need to develo drag eiuting _. balloons, which: can deliver drugs effectively to the vascular space or to any other body cavity over a sustained period of time.

Summary of the invention

The present invention is an inflatable balloon which is enclosed by an expandable cover which becomes increasingly porous or permeable during expansion. The balloon may comprise a coating. The coating may father comprise at least one pharmaceutical agent. The coating may be a biocompatible matrix. During expansion of the balloon, the

pharmaceutically active agent is released through the expandable cover (e.g., a membrane) into a body cavity such as an artery or vein. The present invention also provides for a method of treating a condition or disease by delivering (or inserting) the inflatable balloon to a body caviiy with subsequent delivery of a pharmaceutically active agent to the body cavity.

T he inflatable balloon can be an angioplasty balloon which is positioned on a catheter or other flexible shaft device. The balloon is coaied with at least one pharmaceutically active agent. The coating may be in the form of any biocompatible matrix. For example, the biocompatible matrix may be a semisolid such as a gel, a tape, a tube, spiral-cut tube or otter form of wrapping. The pharmaceutically active agent may be suspended, embedded or dissolved in a biocompatible matrix. The pharmaceutically active agent may be miscible or immiscible with the biocompatible matrix. In certain embodiments, the pharmaceutically acti ve agent may be encapsulated in one or more particles such as one or more, microspheres, liposomes, nanoparticles (e.g., nanogels) or other particles such as, cyelodextran. The gel may be a bydroget which can be dried arid then re-hydrated prior to the expansion of the balloon in vivo or in vitro.

In certain embodiments, the balloon and the biocompatible matrix are enclosed by an expandable cover which conforms to the balloon. The expandable cover may be semipermeable or porous when the balloon is in an unexpanded state. In other embodiments, the expandable cover is substantially impermeable or non-porous when the balloon is in an unexpanded state.

When the balloon expands, permeability or porosity of the expandable cover to the external environment (e.g., plasma, blood, body fluid, etc.) increases. For example, during inflation of the balloon, the expansion of the balloon stretches or radial l expands the expandable co ver. As the balloon expands, pores or channels may form or may increase in size and qr number in the expandable cover. In certain, embodiments, when the coated balloon is initially exposed to an aqueous environment, e.g., plasma or phosphate buffered saline, for a defined period of time, fluid is able to penetrate the expandable cover and begin to solubilize the biocompatible matrix. This initial solubilization of the biocompatible facilitates expansion of the coating (fluid i/.es) as the expandable balloon is inflated. As the balloon expands, plasma or other aqueous fluids, can continue to diffuse into the annular space or lumen between the expandable cover and the balloon. Upon inflation, the coating continues to dissolve, releasing the pharniaceatically active agent through he expandable cover into the body cavity, such as as the artery or vein, in one embodiment, the coating is initially dehydrated. Once in contact with the plasma or oilier aqueous fluid, the coating is rehydrated and then di ssolved. The rate of release of the harmaceuti call active agen t is variable and is dependent on a msmber of different factors, including the rehydration process and nature of the biocompatible matrix, the rate of extent of expansion of the balloon and the degree of porosity /permeability of the expandable cover.

T he expandable cover may comprise a plurality of pores.

The permeability and/or porosity of the expandable cover in an expanded state is greater than the permeability and or porosi ty of the expandable cover when it i s in an unexpanded state. The permeability and/or porosity of the expandable cover in the expanded state may be at least 20% greater, at least 30% greater, at least 40% greater, at least 50% greater, at least 60% greater, at least 70% greater, at least 80% greater, at least 90% greater, at least 1.00% greater, at least 120% greater, at least 150% greater, at least 200% greater, at least 250% greater, at least 300% greater, or range from about 20% to about 400% greater, from about 50% to about 300% greater, or from about 100% to about 200% greater, as compared with the permeability and/or porosity of the expandable cover in an unexpanded state.

in one embodiment, the coating is or comprises a biocompatible matrix such as a hydrogef

The pharmaceutical agent can be encapsulated in a plurality of microspheres, nanoparticles (e.g., nanogels), liposomes, or cyclodextran particles in the biocompatible matrix, in certain embodiments, the nanopartiele is formed from a nanogel which may be formed from N~isopropy lacry lamide, N-vinyl pyrrolidone and pegyiated maieic acid and combinations thereof

in another embodiment, the coating is a th n film which can be formed from hydroxyptopyS methylcellulose (HPMC), carboxymethy! cellulose (CMC), hydroxypropyl cellulose (HFC), poly (vinyl pyrrolidone) (PV.P), poly (viny l alcohol) (PVA), poly (ethylene oxide) (FEO), pullulan, chitosaii, sodium alginate, carrageenan or gelatin. The coating may be in the form of a tape which can be wrapped around the balloon, e.g., in a spiral configuration.

in one embodiment, the expandable cover is formed from a polymer such as ex an ed poiy(teu"ailuorGeihy! ene) (ePTFE) or ultrahigh molecular weight polyethylene.

In certain embodiments, the total surface load of the pharmaceutically active agent in the coating on the balloon ranges from about I pg rara* to about 50 pgtmm .

When the balloon is in an unexpanded state, less than about 10% (w/w) of the pharmaceutically acti ve agent is released from the inflatable balloon in an unexpended state, when the inflatable balloon is incubated for about one boot: at 3TC in an aqueous solution. In certain embodiments, when the balloon is expanded, greater than, about 50% (w/w), greater than about 60% (w/w), greater than about 70% (w/w), greater than about 80% (w/w), greater than about 90% (w/w), or greater than about 95% (w/w), of the pharmaceutically active agent is released from the inflatable balloon in an expanded state, when die inflatable balloon is incubated for one bout ^" in an aqueous solution at 3?°C. in certain embodiments, about 100% (w/w) of the pharmaceutically active agent is released from the inilaiable balloon in an.

expanded state when the inflatable balioon is incubated for one hour in an aqueous solution at 3?°C.

When the balloon is expanded, the diameters o f the pores range from about 1 um to about 1 0 tira or about 20 μηι to about SO μ.π¾.

The pharmaceutically active agent may be an anti-proliferativs agent such as paelitaxel, everoUmos, tacrolimus, siroiimus, zotarolinius, bioJimus and rapamycin or mixtures thereof.

In one embodiment, the expandable cover is tabular in shape.

The inflatable balloon may be used to treat a disease or a condition. The method may involve inserting the inflatable balloon into a body cav ty. The bod cavity can be an artery such ^' as a coronary, inframgidnai, aortoiliac, subclavian, mesenteric, basilar and renal artery. Alternatively, the body cavity can be a urethra, bladder, ureters, esophagus, stomach, colon, trachea, bronchi or alveoli.

In certain embodiments, the present disclosure provides for an inilaiable balloon comprisin - _. at least on inflatable body portion and at least one pharmaceutically: active agent. The inflatable body portion of the inflatable balloon is covered b a cover that is permeable to said pharmaceutically active agent at least when said inflatable body portion is in an expanded state, wherein said pharmaceutically active agent resides in between said body portion and said cover. During use of the inilaiable balloon, said pharmaceutically active agen is released from, said inflatable body portion. in certain embodiments, said cover is an expandable cover, and wherein, when said cover is hi expanded state, a permeability of said cover is greater than the permeability of said cover when said cover is in a non-expanded state.

The device is an inflatable balloon which may be positioned on a catheter or other flexible shaft device, in an embodiment, the balloon segment of the catheter is encapsulated, coated or otherwise provided with at least one therapeutic or pharmaceutically active agent such as everolimus, tacrolimus, sirol nus, zoiarolimus, bioirraiis, rapamycui or an equivalent active praraaeeutical ingredient, which is encapsulated or suspended in a biocompatible matrix.

In certain embodiments, the pharmaceutically active agent can be embedded, layered, suspended or dissolved in a matrix such as gel. The gei or matrix may be a hydrogel which can be dried and re«hydrated prior to the expansion of the balloon in vivo. In one embodiment, the gel matrix comprises a .hydratable suspension. In one embodiment, the gel matrix may be dehydrated.

hi certain embodiments, the balloon and the matrix are encapsulated by an expandable cover.

The expandable cover may be a polymer membrane (or an expandable membrane), having a plurality pores (having an average size). In, certam embodiments, the average size of said pores is greater in an expanded state of said membrane than in a non-expanded state of said membrane. In certam embodiments, the membrane is non-permeable or semi-permeable in an unexpended state. When the balloon expands, the permeability of the cover may increase. For example, during inflation of the balloon catheter, the expansion of the balloon body stretches the membrane, and pores or channels may form i or throughout the cover which increase in diameter as the balloon expands. The diameter of the pores or material porosity may range from about l μιη to about 1 0 μοι, or from about 20 μπι to about 80 μτη or abou 1 urn to 50 μηι, whe the membrane is expanded. The membrane may be hydrophobic and non-permeable when non-expanded while the matrix is being extruded through the membrane once the balloon is being inflated and exerts pressure on the matrix , in certain embodiments, the inflatable balloon comprises a longitudinal axis and a plurality of pleats folded along the longitudinal axis of the baiioon.

The balloon may be coated with at least one pharmaceutically active agent.

The cover may he formed as an expandable tubular sleeve that encloses the balloon, while being substantially compliant with said balloon in its non-inflated state. In certain embodiments, the cover comprises a tubular sleeve tha is provided over at least said- inflatable body portion of said balloon, and in that said cover lies -substantially compliant with said body portion of the balloon in the non-inflated state of said balloon.

In certain embodiments, the cover may be formed from a braid.

The cover may compose a porous iayer (e.g., an elastomeric porous layer) having a porosity. In one embodiment, the porosity of said iayer is greater in an expanded sta te of said layer than hi a non-expanded state of said layer.

When expanded, the porosity of the expandable cover may be greater than trie porosity of the expandable cover when it is in an unexpanded state. The expandable cover may have a plurality of pores. After expansion, the porosity of the expandable cover in the expanded state ranges from about 20% to about 400% greater, from about 50% to about 300% greater, or from about 100% to about 200% greater, as compared with the unexpanded state.

The ^■ pharmaceutically active agent Is suspended in a matrix. The matrix can be a gel such as a hydrogel. During expansion of the balloon, die therapeutic agent is released to a body cavity such as a blood vessel or other bodily lumen.

The cover can be formed from a polymer such as ePTTB or ultra-high molecular weight polyethylene.

In certain embodiments, the pharmaceutically active agent may b suspended or encapsulated in a plurality of biodegradable nano-sized and/or micron-sized bodies, such as beads, spheres or cells that are several nanometers to a few micrometers in size. These biodegradable bodies may be suspended and distributed (e.g., homogeneously) in a (further) matrix. In one embodiment, the inflatable body portion of the balloon is coated with said matrix, containing said bodies, in one embodiment, the cover is coated with said, matrix, containing said bodies. In one embodiment, said bodies are suspended in a soluble film, which may be wrapped around at least the inflatable body portion of said balloon. The said film may comprise a water degradabSe matrix that contains said bodies. In one embodiment, said film is a solvent cast or extruded thin film formulation containing said bodies. In one embodiment, said f lm comprises a polysaccharide polymer consisting of maitotriose units, inter ali known, as pullolan. In one embodiment, said .film, contains between.5% and 30% (w/w) of the pharmaceutically active agent. In one embodiment said film comprises one or more auxiliary agents from a group comprising stabilizers, thickening agents, and permeability enhancers . Particularly said ^' (further) matrix may be formed into a tube, spiral cut tubular construction, · tape- or film thai may he wrapped, around said inflatable portion of said balloon. The film may be a waier-sweSlable dehydrated film that degrades and dissolves one (in. vivo) in contact with water. The naao/micro bodies are then vented or pressed through the cover and into surrounding tissue of a body lumen, particularly an artery or vein, while the balloon is inflated in vivo and will then based on composition of drug release said pharmaceutically active agent over a prolonged period of time. Typically said prolonged period of time ma be over 25 days, particularly over 30 days. The bodies may incorporate- as much as between 5% w w to 30 % w/w of the active pharmaceutical ingredient

The film ma comprise a polysaccharide polymer consisting of rnaltotriose units, inter alia known as pul!u!an. Puiiulan is a polysaccharide polymer consisting of maitotriose units, also known as a*l,4« ;a«l ,6-glucan. Three glucose units in maitotriose are connected by an a- 1,4 glvcosidic bond, whereas consecutive maitotriose units are connected to each other by an a- 1 ,6 glvcosidic bond. Puiiulan is produced from starch by the fungus Aureobasidium pullulans. Puiiulan is mainly used by the cell to resist desiccation and predation. The presence of this polysaccharide also facilitates diffusion of molecules both into and out of the cell.

The film may comprise one or more auxiliary agents from a group comprising stabilizers, thickening agents and permeability enhancers.

in some embodiments, less than about 10% (w/w) of the pharmaceutically active agent is released from the balloon at body temperature in about one hour in a aqueous environment, when the balloon is non-inflated, in certain embodiments, greater titan about 50% (w/w), 60% (w/w), 70% (w/w) or 80% (w/w) of the pharmaceutically active agent is released from the balloon at bod temperature in abou t one hour in an aqueous environment (such as PBS), when the balloon is inflated.

In certain embodiments, the pharmaceutically active agent comprises an antiproliferative agent such as everolimus, tacrolimus, sirolimos, zoiarolimus, hiolimus, rapamycin, an M-tor inhibitor active agent, or a pharmaceutically equivalent agent.,

hi certain embodiments, between 5% and 30% w/w of said pharmace-utically active agent is present in the matrix.

The present disclosure also provides for a catheter comprising the inflatable balloon as described herein. Brief Description f the Drawings

Figure I shows the giiidewire and the balloon in. an. nnexpanded state. Figure 2 shows the balloon in an expanded state.

Figure 3 shows a cross sectional view of the balloon in an unexpended state with pleats and an expandable cover. Figure 4 shows the balloon in an expanded state with extrusion of the matrix.

Figure 5 shows a close-up view of Figure 4.

Figure 6 shows a cross sectional view of the balloon i an expanded state with extrusion of the matrix/gel.

Figure ? shows the gel matrix forming a ^' thin film wrapping around the balloon in a spiral configuration. Figure 8 shows a cross sectional view of the balloon, in. an. unexpended slate enclosed by an expandable cover aod a gel matrix formed m a wrap.

Figure 9 shows the matrix formed as spiral wrap, enclosed with an. expandable cover, and a close-up view of the balloon with extrusion of the gel through the pores/slits.

Detailed Description

The present disclosure provides for an inflatable balloon which is enclosed by an expandable cover which becomes increasingly porous permeable daring expansion. The ^' balloon is coated or enclosed with a matrix that contains a pharmaceutically acti ve agent During expansion of the balloon, the pharmaceutically active agent is released through the expandable membrane into a body cavity such as an artery or vein. The present invention also provides for a method of treating a disease or condi tion by delivering th inflatable balloon to the artery, vein or body cavity.

The inflatable balloon can be an angioplasty balloon which is positioned on a catheter or other flexible shaft device. The balloon is coated with at least one pharmaceutically active agent. The coating may be in the form of any biocompa tible matrix (as used herein, coating refers to coating, covering, enclosing or disposing (disposed) between the balloon and the expandable cover). For example, the biocompatible matrix may be a semisolid such as a gel. The coating incorporating the pharmaceutically active agent may also be wrapped around the balloon using a tape which may be in the form of a spiral, spiral-cut tube or spiral-cut wrapping enclosing the balloon. The balloon may be wrapped 1, 2, 3, 4, 5, 6, 7, 8, 9. 10 ... n times with the biocompatible matrix. The pharmaceutically active agent may be suspended, embedded or dissolved in a biocompatible matrix such as gel. The pharmaceutically active agent may be miscible or immiscible with the biocompatible matrix, in certain embodiments, the pharmaceutically active agent may be encapsulated in a particle such as a liposome, nanopartick or other particle such as, eycfodextran. The gel may be a hydrogel which can be dried and then re-hydrated prior to the expansion of the balloon in vivo or in vitro.

As used herein, the term " pharmaceutically active agent" is interchangeable with the terras "a pharmaceutical agent" or "drug",

The balloon and the biocompatible matrix are enclosed by an expandable cover which conforms to the balloon (as used herein, enclosed, enclosing or encloses refers to

surrounding, covering, enclosing or encapsulating). The expandable cover may entirely enclose the entire balloon or only a. portion of the balloon. There exists an annular space or lumen between the expandable cover and the balloon which may be sealed, i.e., not in fluid communication with the catheter or alternatively, the amiular space or lumen may be in fluid communication with the catheter. Preferably, the expandable cover is semi-permeable or porous when the balloon is in an unexpended state. When the balloon expands, porosity or permeability of the expandable cover to the external environment, e.g., plasma, blood, body fluid, etc. increases. For example, during inflation of the balloon catheter, the expansion of the balloon stretches or radially expands the expandable cover. As a result of such expansion, pores or channels may form in. ihe expandable cover; these pares or ^' c ann ls increase in si¾e or number as the balloon expands. When the coated balloon is initially exposed to an aqueous environment, e.g., plasma or phosphate buffere saline, for a defined period of time, fluid is able to penetrate the expandable cover and begin to soinbiike the matrix. This initial solubilization facilitates expansion of the coating (fluidizes) as ihe expandable balloon is inflated. As ihe balloon expands, plasma or other aqueous fluids, can continue to diffuse into the annular space or lumen between the expandable cover and the balloon. Upon inflation, the coating continues to dissolve, releasing the pharmacetttically active agent through the expandable cover into the body cavity , such as as the artery or vein (as used herein, release refers to release, extrusion, squeezing, burst or di ffusion of the pharmaceutically acti ve agent either alone or encapsulated in a microsphere, liposome, nanoparti e (e.g. , nanogei), cyelodextran or other particle or in conjunction with the biocompatible matrix through the expandable cover), in one embodiment, the coating is initially dehydrated. Once in contact with the plasma or other aqueous fluid, the coating becomes fully rehydrated and then dissolves. The rate of release of the pharmaceutically active agent is variable and is dependent on a number of different variables, including the rehydration process and nature of the biocompatible matrix, the rate of extent of expansion of the balloon and the degree of porosity /permeability of the expandable cover.

Diseases that can be treated with the present balloon, include, but are not limited to, both coronary artery and peripheral artery diseases as well as others. Non-Umiting examples of the diseases or conditions that can be treated by the present balloon or method include atherosclerosis, coronary artery atherosclerosi disease (CAD), peripheral artery

atherosclerosis disease (PAD), narrowing of an artery, etc.

Atherosclerosis is one of the leading causes of death and disability in the world.

Atherosclerosis involves the deposition of fatty plaques on the luminal surface of arteries. The deposition of fatty plaques on the lum al surface of the artery causes narrowing of the cross-sectional area of the artery. Ultimately, this deposi ti on blocks blood flow di stal to the lesion causing ischemic damage to the tissues supplied by the artery. Coronary arteries supply the heart with blood. Coronar artery atherosclerosis disease (CAD) is the among most common, serious, chronic, life-threatening illness in the United States. According to the Centers for Disease Control, 370,000 people die annually from CAD and 733,000 Americans have a heart attack or myocardial infarction (https://www.cdc.gov/heartdi.sease/facts.htm. retrieved, February 5, 2017). Harrowing of .he coronary artery lumen causes destruction of heart muscle resulting, first in angina, followed, by myocardial infarction and -finally death.

Narrowing of the arteries can occur in vessels other than, the coronary arteries, including carotid, aoitoiiiac, infraingumai, distal profunda femoris, distal popliteal, tibial, subclavian and mesenteric arteries. The prevalence of ^' peripheral artery atherosclerosis disease (PAD) depends on the particular anatomic site affected as well as the criteria used for diagnosis of the occlusion, but as many 8,5 million people in the United States are estimated to suffer from PAD Chttp¾:/ w dc.gov/dl¾d^

retrieved, February 5, 20 7) . Traditionally, physicians have used the test of intermittent claudication to determine whether PAD is present.

The present invention also provides for a method of treating any body cavity by releasing a pharmaceutically active agent from an inflatable balloon through an expandable cover into body cavities other than vascular spaces. For example, the genitourinary system, including, the urethra, bladder, ureters, penis and vagina, gastrointestinal system, such as the esophagus, stomach, small intestine or colon, the respiratory system, including., the trachea, bronchi and alveoli can be treated wi th the balloon of the present invention. Vascular spaces other than coronary arteries may also be treated, including, the aorta, vena cava (inferior and superior) or neurovascular arteries, e.g.. carotid arteries, basilar arteries. The coated balloon of the present invention may also be used to create a cavity within a potential space in the body, e.g., muscle, vascular intima or flbrotic tissue. The pharmaceutically active agent is then released into the ne body cavity created from the potential space, e.g., within a muscle.

Other diseases may be treated with the coated balloon of the present invention, including, inflammatory diseases and cancers. Cancers that can be treated with coated balloon of the present invention include, but are not limited to, bladder, lung cancer,, ear, nose and throat cancer, leukemia, colon cancer, melanoma, pancreatic cancer, mammary cancer, prostate cancer, breas cancer, hematopoietic cancer, ovarian cancer, basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; breast cancer; cervical cancer;

choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer; intrae ithelial neoplasm; kidney cancer; larynx cancer; leukemia including acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia; liver cancer lymphoma including Hodgkin's and on-Hodgk n's lymphoma; myeloma; fibroma, neuroblastoma; oral cavity cancer (e.g., lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; renal cancer; cancer of the respiratory system; sarcoma; skin cancer; stomach cancer; testicular cancer; thyroid cancer; uterine cancer ; cancer of the urinary system, as well as other carcinomas and sarcomas.

Inflammatory diseases, include, hut are not limited to, rheumatoid arthritis, systemic lupus eythematosis (SLE), Crohn's diseases or other collagen vascular diseases. Infections diseases resulting from bacteria, viruses or prions may also be treated with the balloon of the present invention.

The structure of the expandable cover is preferably elastkal!y compliant and expandable. The expandable cover may be constructed in the form of a weave, sheet, tube, film, cast, sleeve, tape or any other desired structural configuration which permits the expandable cover to he conformal to the balloon. The expandable cover further comprises a plurality of holes, pores, slits or perforations. Alternatively, the holes, pores, slits or perforations may he formed from a porous network of fibrils, or from a variable density of a fibril matte. Various ty pes of expandable covers may be used, including those which are eiasiomerie and where the pores open when the balloon is inflated (andVor the cover is expanded), and retract when the balloon is deflated (and/or the cover is unexpended). The expandable cover may comprise, e.g. silicone, latex, polyitrethane, and those other materials which are plastically deformed as the material is stretched, thus opening up pores (see discussion of materials, infra.). When the expandable cover is in an unexpanded state, the holes, pores, slits or perforations are substantially closed, so that the permeability of the expandable cover as measured by release of the pharmaceutically active agent from the balloon (e.g., into an aqueous environment) is iess than about 50% (w/w), less than about 25% (w/w), less than about 15% (w/w), less than about 10% (w/w), or less than about 5% (w w) over a defined, period of time as set for the below. As used herein, w/w means th weight of the pharmaceutically active agent released at. my time, t, over total weight of pharmaceutically acti ve agent coated on the balloon; % w/w means w/w X KM).

in vivo release of the pharmaceutically acti ve agent into a vascular space may be simulated in vitro by incubating the balloon which is coated with a pharmaceutically active agent and enclosed wi th an expandable cover in an aqueous bath including a buffer such as phosphate buffered salined (PBS),. The release of the .pharmaceutically active agent to the aqueous bath (e.g., the buffer) after expansion of the balloon is then assayed. Release profiles, both absolute w/w as well as kinetic " ^¾ (see discussion below), of the pharmaceutical acti ve agen t are measured. The concentration of the pharmaceutically active agent in the aqueous environment may he measured using. any means, including, but not limited to, high pressure liquid chromatography (HPLC) or specific immunological assays. For example, the amount of the pharmaceutically acti ve agent released through the expandable co ver within about 1 hour when incubated at about 4°C about 20-25°C or about 37°C in an aqueous environment such as PBS, plasma, blood, a body fluid, or other aqueous medium is assayed. Various time points may he used to assess release of the

pharmaceutically active agent, when, the balloon is in an unexpended state or an expanded state, including, but not limited to, within about 30 seconds, within about 1 minute, within about 2 minutes, within about 3 minutes, within about 4 minutes, within about 5 minutes, within about 6 minutes, within about minutes, within, about 9 minutes, within, about 10 minutes, within about 15 minutes, within about 20 minutes, within about 25 minutes, within about 30 minutes, within about 35 minutes, within about 40 minutes, within about 45 minutes, within about 50 minutes, within about 55 minutes, within about I how, within about. 2 hours, within about 3 hours, within about 4 hours, within abont 5 hours, within about 6 hours, within about 7 hours, within about 8 hour's, within about 1-10 minutes, within about 10 - 100 minutes or within about 50 -200 inutes.

After the expandable balloon has been advanced to the target site, the operator, e.g., the interventional cardiologist, deploys the balloon by inflating it. When the expandable cover is expanded due to expansion of the balloon, the porosity or permeability of the expandable cover increases. As discussed previously, plasma or other aqueous fluids can then diffuse into the annular space or lumen between the expandable cover and the balloon. The coating is then dissolved (totally or partially), releasing the pharmaceutically active agent through the expandable cover into the body cavity, such as as the arter or vein to the pharmaceutically active agent, in one embodiment, the coating is initially dehydrated during application to the balloon and then rehydrated after contact with the aqueous environment, e.g., plasma. When the expandable cover is in an expanded state, the permeability of the expandable cover as measured by release of the pharmaceutically active agent into an aqueous environment is about 100% (w/w), 95% (w w), 90% (w/w), 80% (w/w), 70% (w/w), 60% (w w), 50% (w/w), 40% (w/w), 30% (w/w) or 20% (w/w). The assay for the

pharmaceutically active agent can lie performed as described above at 4°C, 2Q~25°C or 37°C in an aqueous environment such as PBS at 1 hour or for the time periods set form above. Any desired amount of pharmaceutically active agent can be applied to the balloon. For example, the amount of the pharmaeeotkally active agent thai is coated on or

impregnated, on ihe balloon (e.g.. the cover and/or matrix) may range from about 10 to 50,000 μ& including, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 500, 1000, 10,000, 20,000, 30,000, 40,000 and 50,000 pg. The total surface load of the pharmaceutically active agent on the balloon may range from about 1 pg/mur ³ to about 200 pg/mm ² , including, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, 150 or 200 pg/mm ³ . The amounts of the active agent present o the balloon in the biocompatible matrix can range from 2 pg/mm ² to 1 pg/mnr , 2,5 pg/mnr to 5 pg/mnr ⁴ , i pg/rnm" to 2 pg/rnnr, 2 pg/mrrr ⁴ to 15 pg mrrf, 5 pg/mnf to 25 pg/ nf or 25 pg/ n to 40 pg/ nra ^* . Because the coating can be applied in any form, e.g., a tape or wrapping and the annular space or lumen between the balloon and expandable cover may vary as well. Accordingly, the quantity of the pharmaceutically active agent may vary significantly, with loadings of the pharmaceutically active agent ranging up to 10,000 ~ 50,000 pg,

Permeability of the expandable cover may be a function of the porosity of the expandable cover. When the expandable cover is in an expanded state, the permeability or porosity of the expandable cover may range from about 20% to about 400%, from about 50% to about 300%, or irom about 100% to about 200% greater than the permeability or porosity of ihe expandable cover when the expandable cover is in an un.expan.ded or compressed state. To calculate % ranges here, the permeability or porosity in the expanded state is divided by the permeability or porosity, respectively, in the unexpended state and then multiplied by 100. Percentage differences also include, 10%, 20%, 30%, 40%, 50% 60% 70%, 80%, 90 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800% and the like.

"Porosity" refers to a measur of the void, spaces in a material and is measured as a percentage of void space to solid material ranging between 0 - 100%. Porosity may be determined according to the equation: Porosity ~ (1 - dj/cb) x 100, where dj is the density of the material which, is determined from the material weight and the material volume as ascertained from measurements of the sample dimensions, and > is the density of the solid portion of the sample (see, e.g., U.S. Patent No. 7,445,735 and EP 0464163B1). The volume of the sol id portion o f the sample can he measured, for example, using a Quantaehrorne stereopyciioineter (Quantachrome Corp,). The average diameter of th pores of the expandable structure can be determined, by mercury intrusion porosimeity using an Autoscan mercury porosimeter (Quaniachr me Corp.). Mercitry intrusion/Extrusion is based on. forcing mercury (a non-wetting liquid) into a porous material under tightly controlled pressures. Since mercery does not wet most ^' substances and mil not spontaneously penetrate -pores by capillary action, it must be forced into the voids of the sample by applying external pressure. The pressure required to fill the voids is inversely proportional to the size of the pores. Only a small amount of force or pressure is required to fill large voids, whereas much greater pressure is required to fill voids of very small pores. U.S. Patent No. 7,445,735. The porosimetry can also be conducted using other suitable non-wetting liquid besides mercury. Other methods that may be employed to measure porosity include ellipsoraetrie porosimetry, water saturation method, water evaporation method, and nitrogen gas adsorption method. The diameters of the pores in the expandable cover when expanded may range from about 1 μηι to about 100 μιβ, from about 10 μηι to about 100 μχα, from about 20 μ ^η ι to about 80 μτη, from about 40 μηι to about 60 urn or about 20 urn to about 50 μιη.

The pharmaceutically active agent can be uniformly delivered over a period of time, t, to the body cavity. The pharmaceutically active agent may be released through the

expandable cover following zero-order kinetics with no burst effect. As used herein, the term "zero-order kinetics" refers to a release profile where the pharmaceutically active agent is released at a rate independent of time and the concen tration of the pharmaceutically active agent incorporated into the balloon. Zero-order release ensures that a steady amount of pharmaceutically active agent is released over desired length of time, minimizing potential peak/trough fluctuations and side effects, while maximizing the amount of time the

pharmaceutically active agent's concentrations remain within the therapeutic window. The release rate may be calculated using standard methodology,

< >.·

Where drug flu is J and the change i drug concentration over time can be represented as:

w

The term "drug", ^' "pharmaceutically active agent" or "pharmaceutical agent" are used interchangeably here. Release rates may also be diffusion or erosion driven, Fu et at Drug Release Kinetics and Transport Mechanisms of Non-degradab e and Degradable Poly meric Deliy ery Systems, Expert Opin Drug Deli v. 2010 Apr; 7(4); 429-444. Alternatively, the release of the pharmacenticalJy active agent may act as a burst with immediate release into the body cavity. The thickness of the expandable cover may range from about 0.1 μχη to about 300 ,ura or from about I μχη. to about 150 μηι. Other ranges are included herein, such as 50, 100, 150, 200, 250 or 300 μιη. The expandable cover deforms without cracking when it is subjected to stretch or elongation and undergoes plastic and or elastic deformation. After the balloon is deflated, the expandable cover retu rns to i ts imexpanded s tate without ^' being broken, torn, inverted or rolled-back onto itself. The expandable cover may comprise any suitable materials, including synthetic and non-synthetic materials. The expandable cover may also comprise mixtures of synthetic and non-synthetic materials. Examples of the synthetic material, include high density, hig molecular weight polyethylene (B.DHMWPE). ultra high molecular weight polyethylene (UBDHM PE), expanded pp1y(tetfafl«oroethylen,e)

(ePTFE), ethylene vinyl ^' acetate, latexes, ureihaaes, Ouoropolyn er,. _; polyvh yl alcohol (PVA)- cross linked hydroget, pol slioxanes, styrene-ethyiene birtjdene-siyrene block copolymers, aliphatic polyesters, and mixtures and copolymers thereof, polydimethylsiloxane (PDMS) (Silicone) or polyurethane foam, e.g., HYPOL™. The expandable material may be woven as a braid with a latticework of polymeric monofilaments such as a tabular interhrakied sleeve of polymeric nmhifila eni yams, U.S. Patent No. 5 ,957,974,

In one embodiment, the expandabl cover is constructed of medical grade silicone. In another embodiment, the cover is an elastomer, in third embodiment, the elastomer is a high-strength thermoplastic elastomer. This high-strength thermoplastic elasioraer can be a styreme block copolymer, a polyolefm blend, an. elastomeric alloy, a thermoplastic

polyurethane, a thermoplastic copolyester, or a thermoplastic polyamide. The high-strength thermoplastic elastomer may ^' be formed from a polyester-polyether copolymer or a polyamide-polyether copolymer. The high-strength thermoplastic elastomer can also be a nylon. Examples of the non-synthetic material include, but are not limited to, collagen, fibrin, elastin, extracellular matrix components as well as mixtures thereof.

The coating ma be m the form of any biocompatible matrix. The coating may be applied directly on the exterior surface of the balloon, or may be applied on the interior or inner surface of the expandable cover. Alternatively, the pharmaceutically active agent may be disposed between the outer surface of the balloon and interior or inner surface of the expandable cover in a biocompatible matrix. The co ting incorporating the pharmaceutically active agent may also be wrapped around the balioon using a tape which may be in the form of a spiral, spiral -cut tube or spiral-cut wrapping enclosing the balioon. The balloon may be wrapped 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ... » times with the biocompatible matrix. The biocompatible matrix containing the pharmaceutically active agent can be applied to the balloon or expandable cover using standard techniques to cover either the entire or only a partial surface of the balloon or the expandable cover. The coating may form a single layer of a homogeneous mixture of a pharmaceutically active agent(s) and a biocompatible matrix, e.g., gel, or he present in a defined geometric pattern, e.g., a dot matrix pattern.

The coating may form a single layer or multiple layers such as continuous wrapping around the balloon. The baliooa may be dipped or sprayed with a liquid solution comprising at least one pharmaceutically active agent. After each layer is applied, the baliooa may be dried before application of the next layer. The thickness of the layer incorporating the pharmaceutically active agent may range from about Ο.Ιμπι to about 150 um, from about .1 pm to about 1 0 μιη, from about 10 μιη ίο about 50 μ.π.ϊ, or from about 20 μη\ to about 30 μκι. Alternatively, multiple layers of the pharmaceutically active agent/biocompatible matrix composition can. be applied on the surface of the balloon or cover in these or other thickness ranges. For example, different layers of two or more pharmaceutically agents can be coated on the balloon or expandable cover so that a particular pharmaceutically active agent can be released, into the body cavity first, followed by subsequent release of a second

pharmaceutically active agent,

The biocompatible matrix may comprise a water soluble material or water-swel able material The pharmaceutically active agent may be dispersed uniformly or uomrtriformly (e.g., particulates such as liposomes or nanoparticles) within the biocompatible matrix. The biocompatible matrix may comprise a water soluble material which may be dehydrated after application and then rehydrated after insertion into the body cavity by the operator. "Water soluble material" refers to material that dissolves, hydroiyzes, breaks-down, dissolves or disintegrates in contact with water or other aqueous physiological fluid, such as plasma or interstitial fluid. As the balloon expands, the expandable cover also expands, accompanied by an increase in permeability to the plasma or other physiological fluids. The water soluble material within the pharmaceutically active agent coating dissolves and the pharmaceutically active agent is released into the body cavity. The length of time that is needed for the biocompatible matrix to be dissolved ma vary and be less than about 4 hours, 2 hours, less than about I hour, less than about 30 minutes, less than about 10 minutes, less than about 5 minutes, less than about 1 minute, less than about 30 seconds or less than about 5 seconds.

The biocompatible matrix may comprise a mixture of water insoluble and water soluble materials. Examples of such combinations, include shellac and polyvinylpyrolHdone,

I S and -ethyl cellulose and ^' hydroxypropyitnethyl cellulose. The biocompatible matrix may also comprise water sweHable material. Water soluble or water swellabie material may comprise a polysaccharide, such as dextran, alginate, amylose, amySopeetin, carrageenan,

carboxymethyl cellulose, gellan, guar gum, polysaccharide conjugate vaccines, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylroefhyJ cellulose, carboxymethyl cellulose, amylopectin, starch derivatives, hyaluronic acid, starch derivatives, xantan, xyloglucan, chitosan-based hydrogel, pepridoglycan, and progeogl yeans. Water soluble or water swellabie material may also comprise a simple carbohydrate, such as glucose, maltose, lactose, fructose, sucrose, galactose, glucosamine, galactosamine, muramtc acid,

glucruronate, gluconate, fucose, trehalose, a synthetic polymer, such as polyvinyl alcohol, polyv ⁱ nylpyrrolidone,, polyethylene glycol, propylene glycol, polyoxyethylene derivatives, a polypeptide, such as e!asiin, polyvinyl amine or poly(L~i ine), uncros s linked hydrogel, crosslinked. hydrogel, polyacrylie acid or any other cross-linked water swellabie polymers. Examples of hydrogel materials include carboxymethyl cellulose (CMC),

hydroxypropylmethyl cellulose (IIPMC), amylopectin, starch derivatives, hyaluronic acid, or their combinations (WO2Q07US ⁽ X ⁾ 74l23).

The biocompatible matrix that incorporates she pharmaceutical agent may also comprise any desired biocompatible, non-toxic material. Examples of such biocompatible- materials include, polyiiactide-co-gSycolide), polyesters such as poly!actk acid, polyglycolic acid, polyanhydri.de, poiycaprolaetone, polyhydroxybutyrate valerate, or mixtures or copolymers thereof la one embodiment, the biocompatible matrix may further comprise naturally occurring substances such as collagen, fibroneeiia, vitronectin, elastin, iaminin, heparin, fibrin, cellulose, carbon or extracellular malrix components. Polymers which can be used in the matri include poly(lactide-co~giycolide); poly-DL~iacti.de, poly~L-laetide, and/or mixtures thereof and can be of various inherent viscosities and molecular weights. In one embodiment, poly(DL lactide~co-giycolide) can be used. The poly-DL-lactide material can be in the form of homogeneous composition and when solobilized and dried, it can form a lattice of channels in which pharmaceutical substances can be trapped for deli very-' to the tissues. In a further embodiment, the coating composition comprises a nonabsorbable polymer, such as ethylene vinyl acetate (EVAC) , polybutyl- methacrylate (PBMA) and melhylmethacryiate (MMA).

Other examples of bioabsorbabie polymers that may be used with the methods of the present invention include, aliphatic polyesters, biogiass cellulose, chilin collagen copolymers of glycolide, copolymers of lactkie, elastin, tropoelastin, fibrin, glycolide/ S ~laciide copolymers (PGA PLLA), giycoiide trimethylme carbonate copolymers (PGA/TMC), hydr gel lactide te.ramethyl§!yco!ide copolymers, Jactide/trimeihylene carbonate copolymers, lacftdeZ-e-caprolactoiie copolymers, lactide-o-valerolactone copolymers, L- lactlde/ l -lactide copolymers, methyl methacrylate-N-viayl pyrrolidone copolymers, modified proteins, nylon-2 PHBA -hydroxy valerate copolymers (PHBA/HVA),

PLA polyethyleae oxide copolymers, PLA-polyethylene oxide (PELA), poly (amino acids), poly (trimetnylene carbonates), poly bydroxyalkaooaie polymers (PHA), polyialklyeae oxalates), poly(butyle.ne diglycoiate), poly (hydroxy bwtyrate) (PHB), poly(n~ vinyl pyrrolidone) , po.ly(ortho esters), polyalky l~2~cyanoacrylaies, polyanhy drides,

polycya»oacrylates _« polydepsipeptsdes, po ^' tydi ^' hydropyrans, poiy-di -lactide (PDLLA), polyesieramides, polyesters of oxalic acid, polyglycoiide (PGA), polyiminocarbonates, polylaciides (PLA), polyorthoeslers, poly»p-dioxanone (PDO), polypeptides,

polyphosphates, polysaccharides, polyureihanes (PU), polyvinyl alcohol (PVA), poly-β- hydroxypropionate (PHPA), poly-^-hydroxyb tyrate (PBA), poly-o-valerolacione, poly-β- alkanoic acids, poSy-p-malic acid (PMLA), poiy-e-caprolactooe (PCL), pseudo-Poiyi Amino Acids), starch, trimeihylene carbonate (TMC) and tyrosine based polymers. U.S. Pat. No. 7,378,144.

Polymers used for controlled drug delivery may also be used with the coating.

Examples of such polymers, include, poiyatihydrid.es and polyesters, polymers and copolymers of lactic acid, g!ycoiic acid, hydroxybutyrie acid, mandelic acid, caprolactone, sebacic acid, 1 ,3~bis(p~carboxypheiioxy)propaiie (CPP), bis-(p-carboxyphenoxy)methane, dodecaadioic acid (DO), isophthalie acid (ISO), ierephthalic acid, adipic acid, fumaric acid, azeleic acid, pime!ic acid, suberic acid (octanedioic acid), uaconic acid, biphenyl-4,4 - dicarboxylic acid and ben¾ophenone- ,4'-dicarboxylic acid. Polymers may be aromatic, aliphatic, hydrophiiic or hydrophobic.

The polymer forming the biocompatible matrix may comprise a polysaccharide polymer consisting of maltotriose units, also referred to as puilulan. Puilulan is a

poly saccharide polymer consisting of maltotriose units, also known as a- 1,4- ; -l ,6-g! caii. Three glucose units in maltotriose are connected by an a- 1 ,4 g!ycosidic bond, whereas consecutive - maltotriose units are connected to each other by an a- ,6 gryeosidic bond.

Puilulan may be produced from starch by the fm gm A r obasidium puHuhms,

The pharmaceutically active agent may be dispersed within and/or on a sponge-like membrane or layer, made of a non-hydrogel polymer having a plurality of voids. The sponge like membrane or layer alternatively may also be constructed out of a polymer based fibril network or scaffolding, resulting in void spaces ^■ existing within ^' this fibrous or fibril nodal network The phamjaceutically active agent may be infused into the voids of the sponge membrane or lay er that is positioned on the external surface of t he balloon and lie or be disposed between the outer membrane of the balloon and the inner wall of the expandable cover. When the balloon is radially expanded, the sponge membrane or layer stretches around the circumference of the balloon and becomes thinner, open ing and enlargi ng the voids. As a result, the pharmaceutically active agent is expelled or "squeezed out" through the voids of the s onge membrane or layer. The sponge membrane or layer may be prepared by dissolving a non-hydrogel polymer in a solvent and an eiotable particulate material. After the sponge membrane or layer composition is cured, it is exposed to a. solvent, e.g. water or PBS, which causes the particulate material to elute from the polymer, leaving a sponge membrane or layer havisig a plurality of voids therein. The sponge coating is men exposed to a biologically active material to load the sponge membrane or layer with such material. Such material may he loaded into the coating by diffusion or other means. Non-hydrogel polymer(s) useful for forming the sponge membrane or layer are biocompatible. Non- hydrogel polymers are polymers that when a drop of water is added on top of a film of such polymer, the drop will not spread. Examples of such polymers include, without limitation, polyurethanes, polyisobuty ^' leae and its copolymers, silicones, and polyesters. Other suitable polymers include polyolefms, polyisobutylerie, elhylene-alphaolefin copolymers. High

Density High Molecular Weight Polyethelene (HDHMWPE), acrylic polymers and copolymers, vinyl halide polymers and copolymers such as polyvmyl chloride, polyvinyl ethers such as polyvinyl methyl ether, polyvinylidene haiides such as polyvinylidene fluoride and polyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polyvinyl aromaties such as polystyrene, polyvinyl esters such as polyvinyl acetate; copolymers of vinyl monomers, copolymers of vinyl monomers and olefins such as ethylene- methyl methacrylate copolymers.. acrylonitrile-styrene copolymers, ABS resins, ethylene- vinyl acetate copolymers, polyamides such, as Nylon 66 and polycaprolactone, alkyd resins,

polycarbonates, poSyoxyethylenes, polyimides, polyethers, epoxy resins, polyurethanes, rayon-triacetate., cellulose, cellulose acetate, cellulose butyrate, cellulose acetate buiyraie, cellophane, cellulose nitrate, cell ulose propionate, cellulose ^' ethers, carboxymethyl -cellulose, eollagens, chitins, polylactic acid, polyglycolic acid, and . polyiactic acid-polyethylene oxide copolymers. U.S. Patent No. 6773447. US. Patent Publication No. 20040006359.

The biocompatible matrix may also comprise an organogel, such as a poly(ethylene), L~aianine, so.rbit.an monostearate, Eudragit or leci thin organogel . Gupta et al. World J, Pharmacy & Pharnmceutieal Sciences 3(9):150-t63 (201.4). Alternatively, the gels may comprise a sol-gel. Niederherger et al. Metal Oxide Nartopartiele in Organic Solvents.

Synthesis. Formulation. Assembly and Applications. Springer (2009).

The biocompatible matrix may comprise a tbin film. Karki et al. Thin films as an emerging platform for drug delivery. Asian J. Pharmaceutical Sciences 574 (201.6). Thin films comprise a thin and flexible layer of polymer with or without a p!aslicizer. Id. In certain embodiments, a thin film dissolves more rapidly, i.e., quick-dissolve, than other conventional dosage forms, id. Thin films may also be mucoadhesive. Id. The thin film may be formed in any shape or ske. In certain embodiments, the thin films may have a thickness of about 500 μηι to about 1,500 pm; and when dried the thin films may have a thickness from about 3 um to about 250 um. The thin film may comprise polymers including, but not limited to, Hydroxypropyi meihy tceSlulose (HPMC), Carboxymethyl cellulose (CMC),

Hydroxypropyi cellulose (HPC), Poly (vinyl pyrro!idone) (PVP), Poly (vinyl alcohol) (PVA), Poly (ethylene oxide) (PEO), Pultalan, Chitosan, Sodium alginate, Carrageenan, Gelatin, or combinations thereof.

The biocompatible matrix may comprise a bioadhesive. The bioadhes-ve .may be distributed throughout the biocompatible matrix or only around the particles containing the pharmaceutical agent (see discussion of pharmaceutically active agent which may be incorporated into a microsphere, liposomes, nanogeJs and other types of particle-based drug delivery vehicles which are incorporated in the matrix, infra). In certain embodiments, the bioadhesive adheres to the vessel, or body cavity wall. For example, the bioadhesive may comprise an alginate-catechol mixture. astrop et al. PNAS 109; 21444-21449 (2012). In certain embodiments, the bioadhesive may comprise one or more hydroeolloid emulsifying agents. Non-limiting examples ofhydrocoUoid emulsifying agents that may be used include ceiiiiSosie emulsifying agents and acrylic emulsifying agents, including, for example, those which have an alky! group containing from about 10 to about 50 carbon atoms. In certain embodiments, the acrylic emulsifying agents are copolymers of a cartoxylic acid and an acrylic ester (described, for example, in U.S. Patent Nos. 3,915,921 and 4,509,949), including those which are cross-linked. An example of such cross-linked emulsifying agent is

"aayla es Cu it) alkyl aery late crosspoiymef", a cross-linked polymer of acrylic acid and (C s o-se) alkyl acrySates. Aery la.es/C1g.3e alkyl acrylate crosspolymer is available from

Noveon, Inc. (previously 8. P. Goodrich) and is sold under the trade name Peoiulen®.

Aery laies/Cje-sc alkyl acrylate crosspolymer has a small lipophilic portion and a large hydrophile portion, thus allowing for ii to function as a primary e ulsifier for the formation o oil-ift-water emulsions,

of releasing the compounds of the dispersed phase upon contact with a substrate, namely, biological membranes or mucosa and will not re-wet (the oil phase will not re-emttisify upon contact with water). Additional it) formation regarding act ia.es/Cie.3e alkyl acrylate crosspolymer, which is listed in the U.S. Pharmacopeia, is provided in Noveon publications TDS-114, 117, 1 18, 124, 232-3, and 237, and PDS Peraulen 1622.

Alkyi chain cyanoacrylates such as methyl-, eth k isopropyi, butyl and

ociylcyanoacr late may be used as bioadhesives. U.S. Patent No. 8,613,952; see also, Mizrahi et al. Acta Biomaterialia 7:3150-3157 (20,11 ), Other possible bioadhesives include, but are not limited to, ureihaae-based materials as well as adhesives incorporating mussel adhesive proteins, Mehdizadeh et.al. Macromol Biosci, i3(3);271~288 (2013).

hi certain embodiments, the bioadhesive can be prepared by combining: (i) a hiopolymer having one or more first chemically reactive amine groups; (ii) a biocompatible erosslinker having at least two second chemically reactive groups that can chemically react with the one or more first chemically reactive amine groups of the biopoiymer; and (iii) a biocompatible rheological modifier. U.S. ^' Patent Publication No. 20160166728.

The biocompatible matrix may be mixed with a pharmaceutical acceptable excipient, e.g., a carrier, adjuvant and/or diluent, according to conventional pharmaceutical

compounding techniques. The excipiems for modifying, maintaining or preserving, include, for example, the H, osmolariiy. viscosity, clarity, color, isptonJcuy, .odor, sterility,, stability, rate of dissolution, or release, adsorption or penetration of the composition. Suitable excipiems include, but are not limited to, amino acids (such as glycine, giuia rne, asparagine, arginine or lysine); antimicrobials; antioxidant (such as ascorbic acid, sodium sulfite or sodium hydrogen sulfite); buffers (such as borate, bicarbonate, Tris HCi, citrates, phosphates, other organic acids); bulking agents (such as mannitol or glycine), chelating agents (such as ethylenediamine tetraacetie acid .EDTA), ethylene glycol teiraaeetic acid (EGTA)); complexing. gents (such as caffeine, polyvinylpyrrolidone, beta cyclodextrin or hydroxypropyl beta cyclodextrin); fillers; monosaccharides; disaccharides and other carbohydrates (such as glucose, rna iose, or dexlrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring; flavoring and diluting agents; emulsifying agents; hydrophiiie polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; salt forming counterions (such as sodium); preservati es (such as tenzalkoniiun chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, meihylparaben, propylparaben, cMorhextdine, sorbie acid or hydrogen peroxide); solvents (such as glycerin, propylene glycol or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as pluronics, PEG, sorbitan esters, poiysofba.es such as polysorbate 20, polysorbate SO, triton, uomeihanune, lecithin, cholesterol, tyloxapal); stability enhancing agents (sucrose or sorbitol); tonicity enhancing agents (such as alkali metal halides (in one aspect, sodium or potassium chloride, mannitol sorbitol); delivery vehicles; diluents; excipienis and/or pharmaceutical adjuvants. (Remington's Pharmaceutical Sciences, 18th Edition, A. R. Gennaro, ed.,. Mack Publishing Company, 1.990).

The pharmaceutically active agent may be incorporated into a microsphere, liposomes, nanogels and other types of particle-based drug delivery vehicles which are incorporated in the biocompatible matrix. Hoare el al. Polymer 49:1993 - 2007 (2008). For example, Poly(iaciic~co -glycolic acid) nanoparticles can be incorporated within a cross-linkable hyaluronan-based hydrogel matrix, id.

Liposomes are microscopic lipid vesicles that are composed of a central aqueous cavity surrounded by a lipid membrane formed by concentric biiayer(s) (lamellas).

Liposomes are able to incorporate hydrophilic substances (in the aqueous interior) or hydrophobic substances (in the lipid membrane). Liposomes can be unilamellar vesicles ("U V"), having a single lipid bilayer, or multilamellar vesicles ("MLV"), having a series of lipid biiayers (also referred to as "oligo lamellar vesicles"). The multilamellar vesicles typically range in size from 0.2 μιη to 10 p.m in diameter. See e.g., WO 98/006882. The biiayer(s) of liposomes most often comprise phospholipids, but may also comprise lipids including, but not limited to atty acids, fatty acid salts and/or fatty alcohols. The properties of the liposomes depend, among other factors, on the nature of the constituents.

Consequently, if liposomes with certain characteristics are to be obtained, the charge of its polar gro up and/or the length and the degree of saturation of its fatt acid chains must be taken into account. In addition, the properties of liposomes may be modified, e.g., to

incorporate cholesterol and other lipids into the membrane, change the number of lipidie biiayers, or covalently join natural molecules (e.g., proteins, polysaccharides, glycoiipids, antibodies, enzymes) or synthetic molecules (e.g., polyeihyl. glycol) to the surface.. There are numerous combinations of phospholipids, optionally with other lipids or cholesterol, in an aqueous medium that can be used to obtain liposomes. Depending on the method of preparation and the lipids used, it is possible to obtain vesicles of different sizes, structures, and properties. For example, the liposome can be formed jftom. a homologous population of a phospholipid, ^' such as a neutral phospholipid, or a mixture of different types of phospholipids . Examples of phospholipid for making the deli very vehicle include, but are not limited to, phosphatidylcholine (PC), phosphatidylglyceroi (PG), phosphafidyletfaanolamine (PE), phosphatidylserirse (PS), phosphatidic acid (PA), phosphatidylinositol (Pi), egg

phosphatidylcholine (EPC), egg phosphatidylglyceroi (EPG), egg phosphatidylethanoiaraine (EPB), egg phosplratidylserme (EPS), egg phosphatidic acid (EPA), egg phosphatidyl inositol (EPI), soy phosphatidylcholine (SPC), soy phosphatidylglyceroi (SPG), soy

phosphatidyiethanolarnme (SPE), soy phosphatidyiserine (SPS), soy phosphatidic acid (SPA), soy phosphatidyimosito! (SPI), dipalniitoyiphosphatidyicholi.ne (DPPC). 1.,2-dioleoyl- sn-giycero-3-phosphaiidylcholine (DOPC), dimyristoylphosphatidyicholine iDMPC), dipalroitoylphosphatid igiycerol. (DPPG), diolelphosphatidylglycerol ( OPG),

dimyristoylphosphatidyiglycerol (D PG), hexadecylphosphocholine (HE ^' PC), hydrogenated soy phosphatidylcholine (HSPC), distearoyiphosphatidylcho ^' iine (DSPC),

disiearo Iphosphattdylglycerol (DSPG), dioieylphosphatidyiethanolaniine (DOPE), palmitoylstearoytphosphatidyicholine (PSPC), palmitoy tearoylphosphatidyigiycerol

(PSPG), monooleoylphosphatidylethanolamine (MOPE), 1 -palmitoy i-2-oieoyl-sn-giycero-3- phosphatidy Scho ike (POPC), polyethyleneglycol distearoy Iphosphatidy iethanolamine (PEG- DSPE), dipalmitoyiphosphaiidylserine (DPPS), l ,2-dioieoyl-sn-glycero-3-phosphatidyiserine (DOPS), dimyristoyiphospfenidylserine (DMPS), distearoy iphosphatidylserine (DSPS), dipalmitoylphosphatidk acid (DPP A). l,2-dioleoyl-sn~giycero-3-phosphatidic acid (J OPA), dirayristoylphosphatidie acid (DMPA), distearoylphosphatidic acid (DSPA),

dipalmitoylphosphatidylinositol (DPP!), i,2-dioleoyl-sn~giycero-3-phosphatidylinos5tol. (DOPl), dimyristoylphosphatidylinositol (DMPl), distearoylphosphatidylinositol (DSPi), and a mixture thereof.

Alternatively, the pharmaceutically active agent may be incorporated into a nanogel. Vinogradov 2007). Nanogels are a polymer network of charged polyionic segments cross-linked by polyethy lene glycol (PEG) segments. U.S. Patent No. 6,696,089. A wide variety of different pharmaceutically acti ve agents can be iiicoi'porated into the nanogel . Id .

The pharmaceutically active agent may be in the form of a .nanoparticniate suspension, a solid lipid nanoparticie, PLGA nanoparticles or LyoCeils® can be incorporated into or encapsulated in the biocompatible matrix. Hoare et al Hydrogels in drug delivery: Prom-ess and Challenges. Polymer 49:1993-2007 (2008). The nanogel .may be a »a»oparti.cle composed of a erosslmked iiydtopliihc polymer network (hydrogel), Nanogels are most often composed of syn&etic polymers or biopoiymers which are chemically or physically cross-linked which are biocompatible, in yet another embodiment, the nanogels are biodegradable. Methods of obtaining nanogels are known in the art as well as methods for obtaining rianogeis thai are biocompatible arid/or biodegradable (see U.S. Pat. No, 7,727,554). In one aspect, the nanogel comprises a linker that is biodegradable (e.g., wherein enzymes (e.g., physiological enzymes) can degrade the crosslinker, thereby degrading the nanogel). U.S. Patent Publication No. 20160250152, Nanogels (e.g., biodegradable nano gels) can be synthesized using poly mers (e.g., - isopropylacr i amide, -vinyl pytrolidone, pegylated maieic acid or a combination thereof) with a disulfide cross-linker, Nanogels formed using, for example, the above polymers may be about 50 tim in diameter with sustained drug release properties. Nanogels may be formed from N-a!kylacrytamide. In a particular aspect, the N~alkylacrylatnide is poly-N- isopropylacrylaniide. The anogel can further comprises a vinyl monomer and a polyalkylene glycol. For example, the vinyl monomer can be vinyl pyrrol idone and the polyalkylene glycol can be polyethylene glycol. The nanogel can further comprise sodiimi aery late. In particular aspects, the nanogel comprises about 500 to about 1000 mg N-alkylacrylamide. In other aspect, the nanogel can comprise about 100 to abotrt 200 mg of the vinyl polymer and about 50 to about 100 mg of the polyalkylene glycol In yet oilier aspect, the nanogel comprises about 200 mg sodium acrylate. The size of the nanogel particles may vary , ranging from a particle diameter of about 10 mn, 20 ran, 40 nm, 60 am, 80 MI, 100 nra, 120 iim, 140 am, 160 nm, 180 nm, 200 nm, 220 nm, 240 nm, 260 nra, 280 nm, 300 nra, 320 nm, 340 nm, 360 nm, 380 nm, 400 urn, 420 nm, 440 nm, 460 nm, 480 nm, 500 nm, 520 nm, 540 nm, 560 nm, 580 nm, 600 nm, 62 nm, 640 nm, 660 nm, 680 nra, 700 ΒΏΙ, 720 nm, 740 nm, 760 om, 780 nm, 800 am, 820 am, 840 nm, 860 nm, 880 nm, 900 nm, 920 nm, 940 nra, 960 nm, 980 nm or about 1000 nm. In other aspect, the nanogel has a eta potential from, about ^■ -! 0 taV, - 15 mV, -20 mV, -25 mV, -30 mV, -35 mV, or -40 mV. The nanogel has a loading potential of about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1 %, 20% or 25% of the pharmaceutically^ active agent.

m certain embodiments, tlie pharmaceutically active agent: can ^' be encapsulated in a eyclodextfin particles containing cellulose ether with a particle size in the range of SO to ! 000 μ ^η ι. Cyclodextrins are oligomers of anhydroglucose units, which are linked via alpha- 1,4 linkages into a ring shaped molecule. Depending upon the number of the units one refers to these as alpha (6 unit), beta (7 unit) and gamma (8 unit) cyclodexirin. These are conventionally produced item, starch by enxymatic processes. The torroidal structure of the cyclodextrm makes possible the formation of an enclosing complex OH a molecular level .

Pharmaceutically active agents that may be used in the present invention include: (i) pharmacological agents such as, (a) anti-thrombotk agents such as heparin, heparin derivatives, urokinase, and PPack {dexirophenyialanine proline arginine

chloromethylketone); (b) anti-inflammatory agents such as dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine and mesatamine; (c)

antiiieopiastic/a:jriiproiiferative/anti-miotic agents such as sirolimus (or its analogs, bioiiroos, everolirnus or zotarolimus), paclitaxei, 5-ffuorouracil, cisplatin, vinblastine, vincristine, epoihilones, endostatin, angiostatm, angiopeptin, monoclonal antibodies capable of blockin smooth muscle cell proliferation, thymidine kinase inhibitors, rapamyeiB, 40-0-(2- Hydroxyeih l )rapamycin (everolirnus), 40-0-Benzyl «rapamycin, 40-0(4' ^»

Hydroxymerhy 1 )benzy l-raparnycin, 40-0- j 4 ^* -( 1 , .2-DihydroxyethyI) Jbenxyl-rapamycin, 40- Allyl-rapamycin.40-0-[3'-(2,2- Dimethyl- 1, 3-dioxolan-4{S)- yi-prop-2'-en- I'-yl]- 20 rapamycin, ^* -yl),r apamycm 40~0(2Hydroxy) e oxycar¾>nylmetbyl~rapamycin, 40-0-(3~ Hydroxypropyl-rapamyem 40~0~(

(Hydroxy)hexyl-rapaniycin 40-0-(2-(2-Hydroxy)etlioxy]ethyl-rapariiycin, 40-0-((3S)- 2,2Dimethylmoxolan-3-y!jmet yl-taparaycm, 40-0-[ (2S)-2,3- Dibydroxyprop-l-yl}- rapamycin, 40-0-(2- Acctoxy)eihyi-rapamycin, 40-0-(2-Nicotinoyioxy)ethyl-rapamycin ₅ 40- 0-[2~(N-25 Morpholino) acetoxyethy!-rapainycin, 40-0-(2-N-lmida¾o!ylaceioxy)eihyl~ rapamycin, 40~0[ 2~(N -Methyl- N'-piperaziny acetoxyJethyl-rapamycin, 39~0~Desraethyi- 3.9,40-0,0 ethylene- rapamycin, (26R)-2 - Dihydro-40-0-(2-hydrosy)ethyi-rapainyci:n, 28-0 Methyrapamycin, 40~0~(2-Aminoethyl)-rapamycm, 40-0-(2~A£ei ^' aminoet¾yi)-rapamycin 40- 0(2- icotimmiidoet l)-rapamycin, 40-0-{2~( -Methyl- imidaxo-2' yIcarbcthoxamido)eihyl)~ 30 rapamycin, 40-0-(2-Efhoxycarbonylammoethyi}-rapamycin, 40-0-(2-

Tolylsulfonamidoethyl)- rapamycin, 40-(i-(2-(4 ^, .,5'-D!carboethoxy-i^2';3'-iriazoi-I -yl)- ethyl jrapamycin, 42-Epi~(telrazoiyi)rapaniycin (tacrolimus), and 42-[3-hydraxy-2~(hydrox ymethyl)-2-methylpropanoate {rapamycin (temsirolimus) (WO2008/086369) (in various embodiments, the macrolide immunosuppressive drug may be at least 50%, 75%, 90%, 98% or 99% crystalline; (d) anesthetic agents such as Iklocaine, bupivacaine and ropivaeaine; (e) anti-eoagniants such as D-Phe-Pro-Arg•chiotomethyt ketone, an ROD peptide-containing compound, heparin, hirudin, antithrombin compounds, platelet receptor antagonists, anti- thrombin antibodies, anti-platelet recepto antibodies, aspirin, prostaglandin inhibitors, platelet inhibitors and tick antiplatelet peptides; (f) vascular cell growth promoters such as growth factors, transcriptional activators,, and transiatioaai promoters; (g) vascular ceil growth inhibitors such as growth factor inhibitors, growth, factor receptor antagonists, transcriptional repressors, translational repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, Afunctional molecules consisting of a growth factor and a cytotoxin. Afunctional molecules consisting of an antibody and a cytotoxin; (h) protein kinase and tyrosine kinase inhibitors (e. g. , tyrphosttns, genisteiu, quinoxalmes); (i) prostacyclin analogs; (j) cholesterol-lowering agents; (k) angiopoietins; (!) antimicrobial agents such as iric!osan, cephalosporins, aminoglycosides and .nitrofurantoin; (m) cytotoxic agents, cytostatic agents and cell proliferation affeetors; (n) vasodilating agents; and, (o) agents that interfere with endogenous vasoactive mechanisms, (ii) genetic therapeutic agents include anti-sense DMA and RNA as well as D A coding for (a) ami- sense RNA, (b) tRNA or rRNA to replace defective or deficient endogenous molecules, (c) angiogenic factors including growth factors such as acidic and basic .fibroblast growth factors, vascular endothelial growth factor, epidermal growth factor, transforming growth factor a and P, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor a, hepaiocyte growth factor and insulin-like growth factor, (d) cell cycle inhibitors including CD inhibitors, and (e) thymidine kinase ("TK") and other agents useful for interfering with ceil proliferation.

Other pharmaceutically active agents that can be used, include, aearbosc, antigens, beta-receptor blockers, non-steroidal antiinflammatory drugs (NSAID;, cardiac glycosides, aee ylsalicyiic acid, virasiatics, aclarubicm, acyclovir, cisplatro, actmornyein, alpha- and beta-sympatonnmetics, (dmeprazole, altopurino!, aiprostadil, prostaglandins, amantadine, ambroxol, amlodipine, methotrexate, S-aminosalicylic acid, ami tript line, amoxicillin, anastrozole, atenolol, azathioprine, baisaiazide, beclomcthasone, betahistine, bexafibrate, bicalutamide, diazepam and diazepam derivatives, budesonide, bufexamae, buprcnorphine, methadone, calcium salts, potassium salts, magnesium salts, candesartan, c mszepine, captopril, ceMosporins, cetirizine, chenodeoxycholic acid, ursodeoxycholic acid, theophylline and theophylline derivatives, trypsins, cimetidine, clarithromycin, clavulanic acid, clindamycin, cSobutiuol, elonidinc, cotrimoxazoie, codeine, caffeine, vitamin D and derivatives of vitamin D, CQlestyrarnh e, cronioglicic acid, coumarin and eoumariu

derivatives, cysteine, cytarabine, cyclophosphamide, cyclosporin, cyprolerone, cytabarine, dapipra/ole, desogestrel, desontde, dihydralazine, diltiazem, ergot alkaloids, dimenhydrmate, dimethyl sulphoxide, dimettcone, domperidone and domperidan derivatives, dopamine, doxazosin, doxorubicin, doxylamine, dapiprazole, benzodiazepines, diclofenac, glycoside antibiotics, de&iprafttine, econazoSe, ACE inhibitors;, enalapril, ephedrine, epinephrine, epoetin, and epoetin derivatives, morphinass, calcium antagonists, irmotecan, modafrnil, orlistat, peptide antibiotics, phenytoin, rihizoles, risedronate, sildenafil, topiramatc, macrolide antibiotics, oestrogen and oestrogen derivatives, progestogen and progestogen derivatives, testosterone and testosterone derivatives, androgen and androgen derivati es, ethenzamide, etofenamaie, ctofibrate, fcnofibrate, etofylHne, etoposide, famciclovir, famotidine, felodipine, fenoftbrate, fentanyL fentkonazoie, gyrase inhibitors. fluconazole, t¾darabine, fiuarizine, fluoroiH ^' acil, fluoxetine, flurbiprofen, ibuprofen, tliu mide, fluvastatin, follitropin, fonuoterol, fosfomicin, fnrosemide, fusidie acid, gallopamil, ganciclovir, gemfibrozil, gentaroictn, ginkgo. Saint John's wort, glibenekmide, urea derivatives as oral antidiabetics, glucagon, glucosamine and glucosamine derivatives, glutathione, glycerol and glycerol derivatives, hypothalamus hormones, gosere!in, gyrase inhibitors, gitaneihidme, haiofantrine, haloperidoL heparin and heparin derivatives, hyaluronic acid, hydralazine, hydrochlorothiazide and hydrochlorothiazide derivatives, salicylates, hydroxyzine, idarubicin, ifosfamide, imipramine, ittdometacin, indoramine, insulin, interferons, iodine and iodine derivatives, isoconazoie, isoprenaline, glucitol and glucitol derivatives, itraconazole, ketoconazole, ketoprofen, ketotifen, iacidipme, lansoprazole, levodopa, levomethadone, thyroid hormones, lipoic acid and lipoic acid derivatives, iisinopril, ^' hsuride, lofepraraine, lomustine, loperamide, loratadine, roaprotiline, mebendazole, rnebeverine, meclozine, mefenamic acid, mefloquine, meioxkarn, mcpindolol, meprohaniate, meropenem, mesalazinc, mesuxirnide, metamizole, metformin, methotrexate, metbylphemdate, roethylprednisolone, metixene, metoclopramide, rnetoprolol, metronidazole, mianserin, miconazole, minocycline, minoxidil, misoprostol, mitomycin, mizolastinc, moexipril, morphine and morphine derivatives, evening primrose, nalbuphine, naloxone, tilidine, naproxen, narcotine, natamycin, neostigmine, nicergolme, nicethamtde, nifedipine, niflumic acid, nimodipine, nimorazoSe, nimustine, nisoidipme, adrenaline and adrenaline derivatives, norfloxacin, novamine sulfone, noscapine, nystatin, ofloxacin, olanzapine, olsalazine, omeprazole, omocona ole, ondansetron, oxaceprol, oxacillin,

oxiconazole, oxymetazolme, pantoprazole, paracetamol, paroxetine, penciclovir, oral penicillins, pentazocine, penttfylltne, pentoxifylline, perphenazine, pethidine, plant extracts, phenazone, pheniraroine, barbituric acid derivatives, phenylbutazone, phenytoin, p.imozide, pindolol, piperazine, pi acetam, pirenzepine, piribedil, piroxicam, pramipexole, pravastatin, prazosin, procaine, promazine, propiverine, propranolol, propyphenazone, prostaglandins, protionamide, proxyphylline, quetiapine, quinapril, quinaprilat, ramipril, ranitidine, reproteroL reserpine, ribavirin, rifampicin, risperidone, ritonavir, ropinirole, roxatidine, roxithromycin, ruscogemn, mtoside and rutoside derivatives, sabadilla, saibutatnol, salmeierol, scopolamine, selegiline, sertacona/ole, sertmdole, sertralion, silicates, sildenafil, simvastatin, sitosterol, sotalol, spagiumic acid, sparfloxacin, spectinomyem, spiramycin, spirapril, spironolactone, stavud ie, streptomycin, sucralfate, sufentanil, sulbactam, su!phonamides, sulfasalazine, sulpiride, sultmnicillhi, sultiam, sumairiptan, suxamethonium chloride, tacrine, tacrolimus, talioiol, tamoxifen, tauroiidine, tazarotene, tetnaxeparo, teniposicle. tenoxicam, terazosin, terbinafine, terbutaline, terfenadine, terlipressia, tertatolol, tetracycline, teryzoline,

theobromine, theophylline., buiizine, thiama/oSe, phenothiazines, ihiotepa, tiagabine, tiapride, propionic acid derivatives, ticiopidme, timolol, tinidazole, doeonazole, iiogaanine, tioxolone, tiropramide, tizanidine, tolazolinc, tolbutamide, toleapooe, to!naftate, tolperisone, topotecan, torasemide, anttoestrogens, tramadol, tramazoline, trandolapril, tranylcypromine, trapidil, trazodone, triamcinolone and triamcinolone derivatives, txiamierene, trifluperidol, trifiuridine, trimethoprim, trimipramine, tripelenn amine, tripro!idine, trifosfe ide, iTomamadtne,

trometamol, tropalpin, troxemtine, lulobutcrol, tyramine, tyrothricin, urapidit

ursodeoxycholic acid, chenodeoxycholic acid, valaciclovrr, valproic acid, vancomycin, vecuronium chloride, Viagra, venlafaxine, verapamil, vidarabine, vigabatrin, viloazine, vinblastine, vmcamine, vincristine, vmdesme, vinorclbinc, vinpocetine, viquidil, warfarin, xantinol nicotinate, xipara e, zatirkkast, zalcitabine, zidovudine, zoltniiripian, Zolpidem, zoplicone, zoiipme and the like. See, e.g., U.S. Patent os. 6,897,205, 6,838,528 and

6,497,729.

in certain embodiments, mesenchymal stem cell particles, such as exosomes, may be incorporated into the biocompatible matrix or otherwise coated on the balloon. U.S. Patent Publication No. 20151.90430. Mesenchymal stem cell particles may be produced or from, a mesenchymal stem cell (MSC). Such a method may comprise isolating the particle itooi a mesenchymal stem cell conditioned medium (MSC -CM). For example, the mesenchymal stem cell particle may be isolated based on molecular weight, size, shape, composition or biological activity. The conditioned medium may be filtered or concentrated or both during, prior to or subsequent to separation and use, SCs-derived exosomes may be used to treat cardiovascular disease, including, myocardial infarction, reperfusion injury and pulmonary hypertension. Huang et al. Exosomes in. Mesenchymal Stem Cells, a Mew Therapeutic Strategy for Cardiovascular Diseases? lm. J Biol Sei 1 i(2):238-245 (2015).

Alternatively, a variety of ^' DNA or R A vectors may be incorporated into the biocompatible matrix. For example, recombinant viruses include recombinant adeno- associated virus (AAV), recombinant adenoviruses, recombinant lentiviroses, recombinant retroviruses, recombinant poxviruses, and oilier known viruses in the art, as well, as plasmids, eosmids, and phages may be used. Options for gene delivery viral constructs are well known in the art (see, e.g., Ausubel et al, Current Protocols in Molecular Biology, John Wiley & Sons, New York 1989; Kay, M. A., et al, 2001 Nat Medic. 7({):33-40; and Walther W, and Stein ϋ,, 2000 Drugs, 60(2): 249-71 ). Additionally, delivery vehicles such as nanoparticle- atid lipid-based inRNA or protein delivery systems can be used as an alternative to AAV vectors. Further examples of alternative delivery vehicles include lentiviral vectors, lipid- based delivery system, gene gun, hydrodynarak, electroporation or i eofection

microinjection, and biolistics. Various gene delivery methods are discussed in detail by Nayerossadat et al ( Ady Bioroed Res . 2012; 1 ; 27) and Ibraheem et al (int J Pharm. 201 Jan l ;459(l-2):70-83).

The present invention may be used with any balloon catheter stent delivery system, including balloon catheter stent delivery systems described in U.S. Patent Nos. 6,168,61.7, 6,222,097; 6,331,186; 6,478,814; 7,169 J 62 or 20090254064.

The expandable cover may enclose the entire bal loon or only a portion of the balloon.

There exists an annular space or lumen between the expandable cover and the balloon which may be sealed, i.e., not in fluid communication with the catheter or alternatively, may be in fluid conniiunication with the catheter shaft. For example, the balloon catheter system can allow for the release of a fluid into the space or annular lumen between the balloon and the expandable cover. In this embodiment, the annular lumen or space is in commaaication with a fluid delivery lumen extending along the catheter shaft and the aou!ar lumen or space between the inflatable balloon and the expandable cover. Fluid passed through the fluid del ivery lumen in the catheter shaft may be released into the annular lumen or space hydratiiig the dehydrated biocompatible matrix prior to or during insertion into the body cavity.

Balloon catheters such as those described in U.S. Patent Pub. No. 20040006359 may also be used with, the methods of the present invention.

The coating can be applied to a balloon either after the balloon has been compacted for insertion or before insertion. The balloon is compacted by, e.g., crimping or folding. U.S. Pat. Nos, 5,350,361 , 7,308,748 or 7,152,452:. The balloon is delivered to the intervention, site by a delivery device such as a catheter. Balloons can he delivered, removed, and visualized during delivery and/or removal by methods well known in the art, see, e.g., U.S. Pat. Nos. 6,610,013 or 7,171,255. The balloons of the present invention can include, compliant

(expand, e.g., 16-40%, when pressurized), semi-compliant (expand, e.g., 7-1 %, when pressurised), and non-cotHpIiattt balloons {expand,- e.g., 2-7%, when pressurized). The various characteristics, e.g., maximum distensions, i.e. distension from nominal diameter to burst, vary and are well ^' known in the art. Cutting balloons which are also used in angioplasty may be used with the methods and devices of th present invention. The balloon is inflated to a set inflation pressure which is determined by the operator depending on the site and type of balloon. The "'rat ed burst pressure" or "RBP" of the bal loon is the maximum guaranteed pressure to which a balloon can be inflated without failing.

The balloon .may be coated with a lubricant coating before or after application of the pharmaceutically active agent to reduce the coefficient of friction between the

pharmaceutically active agent or biocompatible matrix and the balloon, i.e., sticking. The lubricant coating may be a hydrophiiic or hydrophobic coat. Examples of lubricants to reduce the coefficient of friction used in medical devices include: silicone; colloidal solution of water and lecithin; polypheny ! ethers as electrical connector lubricants; and the solid lubricants molybdenum disulpSiide, PTFE or powdered graphite and boron nitride. The friction coefficients may be reduced as low as 0.00.1 or less. Alternatively, polymers having non-sticky surfaces can be produced by using a surface modifying compound such as Teflon®, ftuoro-containing polymers and copolymers, and the like with vinyl terminal or side groups for chemical solvent resistance and non-sticky surfaces. Polymers hav ing hydrophiiic surfaces can be produced by using a surface modifying compound such as

polyvinylpyrrolidone, PVA, PEG,, and the like. I addition, polymers having a low surface friction can be produced by using a surface modifying compound such as

■polyvinylpyrrolidone, PVA, PEG, Teflon®, and the like.

In one embodiment, the balloon L I is positioned on a guidewire 1.2 (Figure I). The guidewire 1.2 can have marker bands i .3, 1.4 positioned at either end of the balloon. The balloon can be in an expanded or inflated 2, 1 (Figure 2), allowing release or extrusion of biocompatible matrix or hydrogel 2,2. After introduction into the blood vessel, the balloon may be positioned adjacent to a atherosclerotic plaque. The balloon is introduced into the blood vessel or body cavity in a folded or pleated (or uninflated) state prior to inflation, 3.1., 3.2, 3.3, 3.4 (guidewire 3.5) (Figure 3). The balloon is completely enclosed or enveloped in an expandable cover 3.6, As the balloon inflates, the pleats unfold and after full expansion, the balloon is completely unfolded (inflated), in the unexpended state, the pleats of the balloon wrap around the body of the balloon which is positioned over the guidewire. The balloon may contain 3, , 5, 6, 7, 8, 9, 10 ... n pleats; the pleated size ratio to (he inflated balloon can be 2, 3, 4, 5, 6, 7, 8. 9, 10. 20 or 30. After ^■ expansion, the slits or pores in the expandable cover enlarge 4.1 (Figure 4), allowing for extrusion of the biocompatible .matrix into the body cavity 4,2. This extrusion is shown in a doseup view as 5.1 (Figure 5). A cross section view of the balloon after expansion is shown in Figure 6. The balloon 6.1 surrounds the guidewire 6.2. The enlarged slits/pores are shown as 6.3, Through these slits or pores, the biocompatible matrix 6.4 is extruded.

The biocompatible matrix can be formed from a spiral wrap 7,1 which surrounds, encloses or envelops the balloon 7,2 (Figure 7). The wrapping with the expandable cover 8.3 of the pleated balloon 8.2 is shown in Figure 8. The matrix, 9.1 , wrapped spirally around the balloon 9.2 is enclosed with a expandable cover 9.3 which contains slits/pores 9.4 through which the matrix can be extruded (Figure 9).

The subjects that can be treated using the medical device and methods of this invention are mammals, including, but. not limited to, a human, horse, dog, cat, pig, rodent, monkey and the like.

The following are examples of the present in vention and are not to be construed as limiting.

Examples

Example 1 - Balloon Coatings (Paditaxel)

(a) 90% paclitaxel 10% Mpeg-PLGA in chloroform - Paditaxel was mixed in chloroform to a w/v concen tration of 1.5% (15 mg/mL). The polymer was mixed in chloroform to a w concentratio of 1.5% (15 mg/mL). The two solutions were then combined in the ratio of 90: 10 respectively.

(b) 90% paclitaxel/10% Mpeg-PDLA in chloroform - Paditaxel was mixed in chloroform to a w v concentration of 1.5% (15 mg/mL). The polymer was mixed in chloroform to a w/v concentration of 1.5% (15 mg/mL). The two solutions were then combined in the ratio of 90; 10 respectively.

(e) 90% paclitaxel/10% lohexol in Distilled (DJ) Water - Paditaxel was mixed in. acetone to a w/v concentration of 1.5% (15 mg/mL). lohexol was mixed in deionized water io a w v concentration of 1.5% (15 mg/mL). The two solutions were then combined in the ratios of 90:10 or 95:5 where applicable. (d) ^' 90% paeiitaxeI/10% Urea in tl Water - Paclitaxei was .mixed in chloroform to- a w/v concentration of L5% (15 .mg/mL). The urea was mixed in de-ioni/.ed water to a w/v concentration of 1.5% (15 mg/mL). The two solutions we e: then combined in the^atio Of

90: 10 respectively.

(e) Coating of Balloons - 3.0 mm x 15 mm Sapphire® balloons were- coated with the formulations listed above. Balloons were coated with target doses were 1 μ^ΓαττΤ, 2 pg/ronr and 3 μ nim^. Coated baliooas were folded and sheathed, immediately after coating.

(i) Solubility Studies - Glass slides wil l be coated with the various formulations. The coating will then be scraped off the glass slide into a crucible. The coating will then be weighed on the analytical balance (T/N 1 160). Phosphate buffered saline (PBS) will be added to the pre-weighed coating to make a 10 mg/mL solution. The solution will then, be vortexed for 3 minutes and filtered. 1 ml of solution will be extracted and filtered into a test tube using a 3 mL syringe and a 13 mm 0.45 pm PTFE filter, i ml of methanol will then be added to the filtered PBS and "vortexed" for 20 sees in order to dissolve an paclitaxei present A. Ini ^' l sample will then be analyze for drug (paclitaxei) content

Example 2 - Balloon Coatings (Sirolimus)

(a) 90% sirolimus/ 10% Mpeg-PLGA in chloroform - Si.ro! sinus will be mixed in chloroform to a w/v concentration of 1.5% (15 mg mL). The polymer will be mixed in chloroform to a w/v concentration of 1.5% (15 mg mL). The two solutions will then be combined in the ratio of 90; 10 respectively,

(b) 90% sirolimus/10% Mpeg-PDLA in chloroform - Sirolimus will be mixed in chloroform to a w/v concentration of 1.5% (15 mg/mL). The polymer will be mixed in chloroform to a w/v concentration of 1, 5% (15 mg/mL). The two solutions will then be combined in the ratio of 90: 10 respectively.

_. (c) 90% s.irol.imus/i 0% lohexoi in ^' Distilled (DI) Water ~ Sirolimu will be mixed, in acetone to a w/v concentration of 1.5% (15 mg mL). lohexoi will be mixed in deionized water to a w/v concentration of 1.5% (15 mg/mL). The two solutions will then be combined in the ratios of 90: 10 or 95:5 where applicable.

(d) 90% sirolimus/10% Urea in D.l Water - Sirolimus will be mixed in chloroform to a w/v concentration of 1,5% {15 mg/mL). The urea will be mixed in de-ionl¾ed wate to. a w/ concentration of 1.5% (15 mg/mL). The two solutions wiltthen fee combined in the -ratio of 90; 1 respectively.

(e) Coating of Balloons - 3.0 mm % 15 mm Sapphire® balloons will be coated with, the fomtulations listed above. Balloons will be coated with target doses such as I ug mnf , 2 pg/rom ² and 3 μ g/ram ² . Coated balloons will be folded and sheathed immediately with the expandable cover after coating.

(f) Solubility Studies - Glass slides will be coated with the various formulations. The coating will then be scraped off the glass slide int a crucible. The coating will then be weighed on the analytical balance (T N i 160). Phosphate buffered saline (PBS) will be added to the pre-weighed coating to make a 10 mg/mL solution. The solution will then he vortexed for 3 minutes and filtered, I ml of solution will be extracted and filtered into a test tube using a 3 niL syringe and a 13 mm 0.45 pm PTFE filter. 1 mi of methanol will be then added to the filtered PBS and vortexed for 20 sees in order to dissolve any sirolimus present. A I nil sample will then be analysed for dmg (sirolimus) content,

Example 3 - Elation Profile

(a) Elation Profile Kinetics - The coated balloon, with and without the expandable cover, will be placed in different 1 ml aliquots of PBS at 37°C for a series of defined times, e.g., 30 seconds, 1. 2, 3, 4, 5, 1 , .15, 30, 60 and 120 minutes in order to generate an elution profile over time. Aliquots of PBS will then be analyzed by high pressure liquid chromatography (HPLC) to establish sirolimus concentrations in solution at each time point. Calibration standards containing known amount of sirolimus will be used to determine the amount of sirolimus eluted. The multiple peaks present for sirolimus (also present in the calibration standards) will be added to give the amount of sirolimus eluted at that time period (in absolute amount and as a cumulative amount eluted). High pressure liquid chromatography (HPLC) analysis will then performed using Waters .HPLC system.

Example 4 ^« Clinical Simulation Test

(a) In-Vitro Mass Loss Test: The coated balloon with the expandable cover, prepared as in. Example 2, will be weighed on a microbalance and then secured to a balloon catheter. A segment of optically clear TYGON® tubing will be filled with phosphate buffered saline (PBS) and immersed in a water bath at 37 in order to to mimic physiological conditions of deployment in the body cavity of a subject. The coated balloon will be inserted into the tubing and the balloon will be inflated to at least about 25% to about 70% below the balloon's rated burst pressure (e.g., 5-15 aim) for 30 seconds.. 1 , 2, 3, 4, 5, 10, 1.5, 30, 60 or 120 minutes. The balloon will be deflated and then removed from the tubing. After drying, the balloon will be further dried and weighed on a microbalance. A comparison of the pre- and post-deployment weights indicates how much coating is freed, dissociated, and/or transferred from the balloon.

(b) In- Vitro Testing for Distal flow: The coated balloon, prepared in Example 2, will be secured to a guidewire iiicorporating a porous filter of 100 p pore size. A segment of ΤΥΟΟΝ Cubing will be filled with PBS and -immersed in a water bath at 37 C. The coated balloon enclosed with the expandable cover will be inserted into the tubing. The flow of PBS through the TYGO robing will be started, the distal filter will be deployed and the balloon will be inflated to at least 25% Co about 70% below the balloon's rated burst pressure (e.g., 5- 15 aim) for 30 seconds, 1 , 2, 3, 4, 5, 1 , .15, 30, 6 o 12 urinates. The balloon will be deflated and removed from the tubing. The .filter will be deployed for S minutes after removal of the balloon and the flow of PBS will b halted, the tubing cut adjacent to the epoxy seal, the filter retrac ted and removed from the tubing. The content of the filter will be analysed for the presence of sirolimus containing particles.

Example S ~ Expanding Coated Balloon in Yucatan lnswine Arteries

A coated balloon will be prepared and then secured to a balloon catheter. Briefly, a balloon will be dip-coated in a coating composition (e.g., described in Example 1 or

Example 2). The balloon will then be dried, folded, and secured to a balloon catheter.

A. segmen t of resected coronary artery from Yucatan miniature swine will be positionally fixed and filled with PBS. The coronary artery will then be immersed in a water bath at 37°C in order to mimic physiological conditions of deployment in a subject. The coated balloon will be inserted into the tubing and the balloon will be inflated to at least about 25% to about 70% below the balloon's rated burst pressure (e.g.., 5-1 atm). for 30 seconds, 1 , 2, 3, 4, 5, 1 , 15, 30, (SO or 120 minutes. The balloon will be deflated and removed from the artery. The section of artery exposed to the deployed balloon will be cut a way from the remainder of the artery section, placed into a tissue homogeuizer and the homogenized material extracted with methylene chloride to make up 25 raL total volume of rinsings which will be. collected in a flask for analysis. Analysis by HPLC as described above will be performed to determine the amount of sirolimus transferred from the balloon through the expandable cover to the coronary arter ' at each time point.

Sirolimus will also be extracted from the balloon by placing it in a. 5 mL glass test tube containing I mL of methanol and vortexhig for approximately 20 seconds. The balloon will be removed from the test tube and the contents of the test tube will he filtered into a 1 mL autosampler vial using a 3 ml, syringe and 0.45 micron filter. Strolimiis concentrations wit! be assayed by HPLC,

Example 6 - Optical Microscopy and Scanning Electron. Microscopy (SEM) of the Balloon and Coating

A coated balloon will be prepared using a coating composition, e.g., described in Example 1 or Example 2. The balloon will, be coveted with an expandable cover and immersed in PBS at 37*C. The coated balloon will be inserted into the ΤΥ60ΜΦ tubing as described above .and the balloon will be inflated to at least about 25% to about 70% below the balloon's rated burst p essure (e.g.. 5-15 aim) for about 30 seconds, 1, 2, 3, 4, 5, 10, 15, 30, 60 or .120 minutes. The balloon will be deflated and removed from, the TYOONdt? tubing. SEM and Optical microscopy will be performed on the balloon and the expandable cover to determine physical changes occurred to the soifaces of the balloon and the expandable co ver associated with transfer, disassociation, and displacement of the coating.

Example 7 - In vivo Analysis of Active Pharmaceutical Agent at site of Application

A group of 10 New Zealand white rabbits will beprepared for a Seldinger procedure using a balloon coated with a formulation of sirolimus with total loading of sirolimus of approximately, 20 - 60 pg. The coated balloon will then enclosed by the expandable cover and then placed in the coronary artery. The covered and coated balloon catheter will be positioned with the assistance of fluoroscopy. Six animals will be subjected to the procedure using a coated balloo thai does not have sirolimus in the coating. After deployment and removal of the balloon, 2 control anitna ^' iswill be sacrificed at i hour post deployment and serum and tissue samples will be collected. The 3 remaining control animals will be sacrificed at 56 days post deployment. During the course of the study, serum sample will be collected from control and drag-treated animals every five days. The drug treated animals, 3 each, will be sacrificed at 1 hour, 24 ^' hours, 7 days, 14 days, 28 days, 42 days and 56 days post-deployment. The tissue and serum samples will be subjected to analysis for sirolimus concentration by HPLC as described above. The scope of the present invention is Ho limited, by hat has beers, specifically shown arid .described ^' hereinabove. Those skilled is th art will recogniz that there are suitable alternatives to the depicted examples of materials, : configurations,; constructions and

dimensi ns. Numerous references, including patents and various publications, are cited and discussed in the description of this invention. The citMio and discussion of such references is provided merely to clarify the description of the present invention and is not an admission thai any reference is prior art to the invention described herein. All. references cited and discussed- la this specification are. incorporated herein by reference an their entirety.

Variations, 'modifications and other implementations of what is described herein will occur to those of ordinary skill in the art without departing .from the spirit and scope of the invention.. While certai embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications may be made without. departing from the spirit and scope of the invention. The matter set forth in the foregoing description and .accompanying drawings is offered by way of illustration only and not as a limitation.