DRUG ELUTING BALLOON

Field of Invention The current invention relates to various drug eluting balloons that may be inserted into a lumen in the body of a subject to deposit a drug composition at a desired site of action.

Background The listing or discussion of a prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

Coronary/Peripheral Artery Disease is a common circulatory problem in which plaque builds up in the arteries and limits blood flow to parts of the body. A typical treatment for this condition includes artery bypass surgery, stent placement or balloon angioplasty. In the case of stent placement and balloon angioplasty, some patients develop a new narrowing of the vessel wall at the site of intervention after a few months, which narrowing is known as restenosis. Recognition of the problems associated with stenosis and restenosis resulted in the development of drug eluting stents to combat said conditions. A drug eluting stent is designed to release one or more drugs for a sufficiently long period of time to inhibit cell hyper-proliferation (and hence stenosis/restenosis). However, the use of drug eluting stents poses a risk of inflammation due to chronic irritation caused by having a permanent implant. Thus, a device capable of providing immediate delivery of a therapeutic composition to the site of treatment, with the device being removed entirely from the site of action would be preferred over a permanent implant - even if said implant were able to be resorbed over time.

In recent years, the concept of a drug eluting balloon (DEB), or drug coated balloon (DCB), has been introduced and DEBs have been used as angioplasty balloons in both percutaneous transluminal angioplasty (PTA) and percutaneous transluminal coronary angioplasty (PTCA). A drug eluting balloon is coated with an active agent. In practice, the DEB acts by transferring an active agent to the vessel wall when the balloon is inflated and pressed against the vessel wall at the desired site of action. The procedure for using a DEB generally entails:

(1 ) an uncoated balloon catheter is inserted into a body lumen and used for prediction to ensure a clear pathway for delivery of the drug coated balloon catheter, which helps to prevent transit loss from the DEB. The uncoated balloon is then removed;

(2) a drug coated balloon catheter is then introduced through a guiding catheter/sheath through the pre-cleared lumen towards the site of action;

(3) the drug coated balloon catheter is positioned at the site of action (e.g. a lesion in a blood vessel);

(4) the balloon is inflated to a predetermined size to radially compress against an atherosclerotic plaque in the lesion to remodel the vessel wall; and

(5) the balloon is deflated and retracted through the guide sheath or catheter.

While DEBs as a class show promise, there remain a number of problems that need to be solved - both with the DEB itself and the associated procedure. These problems are discussed below.

(1 ) For DEB, one or more drugs are directly coated onto the external surface of the balloon, which surface is usually exposed to circulating blood (or other bodily fluids) during use. Given this exposure, the DEB delivery system can suffer from a significant loss of drug while the drug coated balloon is manipulated towards a stenotic or occlusive lesion - these losses may be exacerbated by the distance that the DEB has to travel to reach the site of action, as well as the different diameters and tortuosity of the lumen(s) in question en route to a lesion. Further, a high percentage of drug is usually lost when the balloon catheter passes through the introducer sheath and/or guide catheter and/or the torturous blood vessel before it even reaches the lesion. Therefore, the drug loss differs on a case-by-case basis, and is often uncontrollable, leading to unpredictability. This unpredictability results in a different DEB efficacy for each patient, leading to inconsistent clinical treatment outcomes. If a high amount of drug loss occurs during catheter transit through the lumen of a patient, then large aggregates of particles or patches of the drug coating may break off from the balloon surface and enter the blood stream of the patient. This could potentially result in the blockage of a lumen of the body, for example, the patient's vascular capillary system, causing a distal embolization.

(2) Currently, almost all DEB companies directly apply the drug coating onto the balloon surface. The traditional balloon materials are PET, pebax and nylon, which are hydrophobic and non-elastic. Due to the hydrophobic nature of the drug, such as paclitaxei, the interaction between the balloon surface and the drug is generally very strong. Therefore, after the balloon is inflated at the site of action, it may be difficult to transfer the drug particles that remain from the balloon surface to the lesion. Hence, to achieve low drug loss and high drug transfer, two types of technology are applied to DEBs: (a) the use of small molecule additives to improve release of the drug from the surface of the balloon; or (b) to treat the balloon surface to become hydrophilic by using mechanical or chemical methods. Both methods try to weaken the interfaciai interaction between the drug and the balloon surface to improve drug transfer. However, this will also weaken the adhesion of the drug to the balloon surface during transit, potentially leading to increased loss of drug during transit. Since drug adhesion and drug transfer are contradictory, the drug-coated balloons currently available in the market are unable to strike a balance between high drug transfer (at the site of action) and low drug loss {en route to said site). Currently, drug coating technologies developed based using either approach (a) or (b) above cannot maximize drug transfer while minimizing drug loss. (3) Most DEB catheters require pre-dilation of the site of action. This is done by using a standard balloon angioplasty before application of the DEB to ensure a clear pathway for delivery. Such a pre-treatment adds to the cost and time needed to perform the procedure. Thus, there remains need for improved DEBs that tackle one or more of the problems outlined above.

Summary of Invention Aspects and embodiments of the invention are set out below.

In a first aspect of the invention, there is provided a drug delivery device comprising:

a balloon catheter shaft having an inflation lumen, both having a proximal end and a distal end;

a balloon having a proximal end, a distal end and a working portion therebetween, where the proximal end of the balloon is coupled to and in fluid communication with the distal end of the inflation lumen, where the balloon during use or inflation has a cylindrical shape along the whole of its working portion;

a first sheath having a proximal end and a distal end; and

a therapeutic agent coating on a surface of the balloon facing the first sheath, wherein the first sheath is provided in a first position that wholly covers the balloon and is movable relative to the balloon to a second position that fully exposes the balloon. In embodiments of the first aspect of the invention:

(a) the balloon material may be compliant, semi-compliant or non-compliant (e.g. the balloon material is semi-compliant or non-compliant);

(b) the therapeutic agent coating may comprise a therapeutic agent selected from one or more of the group consisting of an antiproliferative, immunosuppressive, anti- angiogenic, anti-inflammatory, and anti-thrombotic agent (e.g. the therapeutic agent may be selected from one or more of the group consisting of paclitaxel, rapamycin, everolimus, zotarolimus, umirolimus, tacrolimus, and pimecrolimus (such as a therapeutic agent selected from one or more of the group consisting of paclitaxel, rapamycin, zotarolimus and umirolimus, such as paclitaxel and rapamycin)), optionally wherein:

(I) the therapeutic agent coating may further comprise an excipient, selected from one or more of the group consisting of tartaric acid, a sugar, and a sugar alcohol (e.g. the pharmaceutically acceptable carrier may be selected from one or more of the group consisting of fructose, glucose, sucrose, lactose, maltose, erythritol, threitol, arabitol, ribitol, mannitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, more particularly, xylitol, tartaric acid, and sorbitol (such as selected from one or more of the group consisting of fructose, glucose, sucrose, mannitol, or more particularly, sorbitol, or yet more particularly xylitol, and tartaric acid)); and/or

(II) the therapeutic agent coating may further comprise an adhesion balance layer or base coating layer directly on the balloon, comprising a hydrophilic polymer and/or a hydrophilic compound, optionally wherein the hydrophilic compound is selected from one or more of the group consisting of a sugar, a sugar alcohol, and polyethylene glycol (e.g. the hydrophilic compound has a molecular weight of less than 1 ,000 Daltons and is selected from one or more of the group consisting of fructose, glucose, sucrose, lactose, maltose, erythritol, threitol, arabitol, ribitol, mannitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, xylitol, sorbitol and polyethylene glycol (such as selected from one or more of the group consisting of fructose, glucose, sucrose, xylitol, mannitol, and sorbitol));

(c) the balloon may be partially or fully covered by the therapeutic agent coating layer (e.g. the balloon may be fully covered by the therapeutic agent coating layer);

(d) the device may further comprise a first hypotube having a proximal end and a distal end, where the distal end of the hypotube is connected to the proximal end of the first sheath, optionally wherein the first hypotube has a longitudinal slot at or adjacent to its distal end and running towards its proximal end, suitable for movement of a Y-shaped junction therethrough (e.g. one branch of the Y-shaped junction may comprise a second hypotube that is connected to the proximal end of an inflation lumen/balloon catheter shaft and the other branch may comprise a guidewire lumen);

(e) the first sheath may have a marker band, optionally a radiopaque market band;

(f) when inflated, the whole working length of the balloon may have a consistent diameter;

(g) the first sheath may have a first surface facing the balloon and a second surface opposed to the balloon and may further comprise a lubricious coating on the first and/or second surface;

(h) the device may further comprise a polymer film (e.g. a non-elastic polymer film) having a first end, a second end and a middle potion, where the first end is connected to the first sheath, the second end is connected to the proximal end of the balloon and the middle portion extends along the first surface of the sheath when the sheath is in the second position, optionally wherein the middle portion is folded and extends along the first surface of the sheath when the sheath is in the second position.

In a second aspect of the invention, there is provided a use of a therapeutic agent a therapeutic agent selected from one or more of the group consisting of an antiproliferative, immunosuppressive, anti-angiogenic, anti-inflammatory, and anti-thrombotic agent (e.g. the therapeutic agent may be selected from one or more of the group consisting of paclitaxel, rapamycin, everolimus, zotarolimus, umirolimus, tacrolimus, and pimecrolimus (such as a therapeutic agent selected from one or more of the group consisting of paclitaxel, rapamycin, zotarolimus and umirolimus, such as paclitaxel and rapamycin)) in the preparation of a drug delivery device according to the first aspect of the invention and any technically sensible combination of its embodiments for the treatment of a disease or condition that causes narrowing or obstruction of a body lumen (e.g. arteries or veins).

In a third and fourth aspect of the invention, there is, respectively, provided:

(a) a drug delivery device according to the first aspect of the invention and any technically sensible combination of its embodiments for the treatment of a disease or condition that causes narrowing or obstruction of a body lumen (e.g. arteries or veins); and (b) a method of treatment or surgery using a drug delivery device according to the first aspect of the invention and any technically sensible combination of its embodiments to treat a disease or condition that causes narrowing or obstruction of a body lumen (e.g. arteries or veins). For example, in the method of (b), the steps may comprise: (1 ) optionally, an uncoated balloon catheter is introduced for pre-dilation to ensure a clear pathway for delivery of a drug coated balloon catheter;

(2) a drug delivery system according to any one of Claims 1 to 5 is introduced;

(3) the distal region of the drug coated balloon is positioned at a lesion and the first sheath is retracted in a proximal direction to expose the balloon, or the distal region of the drug coated balloon is positioned before the lesion and the balloon is advanced and positioned at the lesion, thereby exposing the balloon;

(4) the balloon is inflated to a predetermined size to radially compress against an atherosclerotic plaque in the lesion to remodel the vessel wall;

(5) the balloon is deflated; and

(6) the drug coated balloon delivery system is retracted directly, or the first sheath is pushed forward or the balloon is retracted into the first sheath before the drug coated balloon delivery system is retracted. In a fifth aspect of the invention, there is provided a drug delivery device comprising:

a balloon having a proximal end and a distal end;

a first elastic film configured or configurable to at least partly surround the balloon; and

a therapeutic agent coating on the second surface of the elastic film, wherein when the first elastic film is configured to at least partly surround the balloon, it has a first surface facing the balloon and a second surface facing away from the balloon and the first elastic film can expand to at least 1 .1 times its original dimension upon inflation of the balloon. In embodiments of the fifth aspect of the invention:

(a) the device may be a catheter balloon for a balloon catheter or a balloon catheter;

(b) the balloon material may be compliant, semi-compliant or non-compliant (e.g. the balloon material may be semi-compliant or non-compliant);

(c) the first elastic film may expand from 1 .1 to 20 times (e.g. from 1 .5 to 10 times, e.g. from 2 to 5 times) its original upon inflation of the balloon;

(d) wherein the first elastic film primarily expands in a radial direction;

(e) the first elastic film may be made from a material comprising silicone, thermoplastic elastomers or mixtures thereof, optionally wherein the material further comprises a scaffold material that limits longitudinal expansion of the elastic film;

(f) the first elastic film may be a continuous film, a mesh, or a film with a number of holes; (g) the first elastic film may surround the balloon and is bonded to said balloon at or adjacent to the proximal and distal ends of the balloon, optionally where the device may further comprise a third sheath that surrounds the first elastic film and balloon, where the third sheath and/or the balloon are moveable relative to each other, such that the first elastic film and the balloon can be exposed from the third sheath, so that the first elastic film can be expanded to at least 1 .1 times its original dimension upon inflation of the balloon (optionally, the third sheath may comprise a non-elastic polymeric material);

(h) the device may further comprise a first sheath, having a first surface facing the balloon and a second surface facing away from the balloon, where the first elastic film forms at least part of the first sheath and where the first sheath and/or balloon are moveable relative to each other, such that the balloon can be exposed from the first sheath, optionally wherein the device may further comprise a second sheath that surrounds the first sheath, where the second sheath and/or the first sheath are moveable relative to each other and the balloon, such that the first elastic film, which forms part of the first sheath, can be exposed from the second sheath, so that the first elastic film can be expanded to at least 1 .1 times its original dimension upon inflation of the balloon, optionally where the second sheath comprises a non-elastic polymeric material;

(i) the device further comprises a first sheath that is moveable relative to the balloon, such that it can cover at least part of the balloon in a first position and expose the balloon in a second position,

the first elastic film has a first end, a second end and a middle potion,

where the first end of the first elastic film is connected to the first sheath, the second end is connected to the distal end of the balloon and, when the first sheath is in the first position, the middle portion of the first elastic film extends along the first surface of the first sheath, optionally wherein when the first sheath is in the first position, the middle portion of the first elastic film is folded and extends along the first surface of the first sheath

(j) the therapeutic agent coating may comprise a therapeutic agent selected from one or more of the group consisting of an antiproliferative, immunosuppressive, anti- angiogenic, anti-inflammatory, and anti-thrombotic agent (e.g. the therapeutic agent may be selected from one or more of the group consisting of paclitaxel, rapamycin, everolimus, zotarolimus, umirolimus, tacrolimus, and pimecrolimus (such as a therapeutic agent selected from one or more of the group consisting of paclitaxel, rapamycin, zotarolimus and umirolimus, such as paclitaxel and rapamycin)), optionally wherein:

(I) the therapeutic agent coating may further comprise an excipient, selected from one or more of the group consisting of tartaric acid, a sugar, and a sugar alcohol (e.g. the pharmaceutically acceptable carrier may be selected from one or more of the group consisting of fructose, glucose, sucrose, lactose, maltose, erythritol, threitol, arabitol, ribitol, mannitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, more particularly, xylitol, tartaric acid, and sorbitol (such as selected from one or more of the group consisting of fructose, glucose, sucrose, mannitol, or more particularly, sorbitol, or yet more particularly xylitol, and tartaric acid)); or

(II) the therapeutic agent coating may further comprise an adhesion balance layer or base coating layer directly on the second surface of the elastic film, comprising a hydrophilic polymer and/or a hydrophilic compound, optionally wherein the hydrophilic compound is selected from one or more of the group consisting of a sugar, a sugar alcohol, and polyethylene glycol (e.g. the hydrophilic compound has a molecular weight of less than 1 ,000 Daltons and is selected from one or more of the group consisting of fructose, glucose, sucrose, lactose, maltose, erythritol, threitol, arabitol, ribitol, mannitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, xylitol, sorbitol and polyethylene glycol (such as selected from one or more of the group consisting of fructose, glucose, sucrose, xylitol, mannitol, and sorbitol)).

A sixth aspect of the invention relates to a use of a therapeutic agent selected from one or more of the group consisting of an antiproliferative, immunosuppressive, anti-angiogenic, anti-inflammatory, and anti-thrombotic agent (e.g. the therapeutic agent may be selected from one or more of the group consisting of paclitaxel, rapamycin, everolimus, zotarolimus, umirolimus, tacrolimus, and pimecrolimus (such as a therapeutic agent selected from one or more of the group consisting of paclitaxel, rapamycin, zotarolimus and umirolimus, such as paclitaxel and rapamycin)) in the preparation of a drug delivery device according to the fifth aspect of the invention and any technically sensible combination of its embodiments for the treatment of a disease or condition that causes narrowing or obstruction of a body lumen (e.g. arteries or veins).

In a seventh and eighth aspect of the invention, there is, respectively, provided:

(a) a drug delivery device according to the fifth aspect of the invention and any technically sensible combination of its embodiments for the treatment of a disease or condition that causes narrowing or obstruction of a body lumen (e.g. arteries or veins); and (b) a method of treatment or surgery using a drug delivery device according to the fifth aspect of the invention and any technically sensible combination of its embodiments to treat a disease or condition that causes narrowing or obstruction of a body lumen (e.g. arteries or veins). Drawings

The invention may be more completely understood in consideration of the following description of various embodiments of the invention in connection with the accompanying drawings.

Fig. 1 (a) depicts a balloon that may be suitable for use in the current invention.

Fig. 1 (b) depicts a balloon that may be suitable for use in the current invention further connected to, or integrally formed with, a balloon catheter shaft.

Fig. 2(a) is a conceptual drawing of the drug delivery system for Design 1

Fig. 2(b) is a conceptual drawing of the drug delivery system for Design 2

Fig. 2(c) is a conceptual drawing of the drug delivery system for Design 3

Fig. 3(a) is a side view of an example of drug delivery system (Design 1 ) for PTA

Fig. 3(b) is a side view of an example of drug delivery system (Design 1 ) for PTA

Fig. 3(c) is a side view of an example of drug delivery system (Design 1 ) for PTCA

Fig. 3(d) is a side view of an example of drug delivery system (Design 1 ) for PTA with a polymer film

Fig. 4 is a side view of a slotted hypotube with a longitudinal slot through the hypotube Fig. 5 is a top view of a slotted hypotube with a longitudinal slot through the hypotube Fig. 6 is a cross-sectional side view of the port for flushing

Fig. 7 is a cross-sectional front view of the tip

Fig. 8 depicts a guidewire exit port that is at the proximal end of a balloon

Fig. 9A depicts a top view of a guidewire exit port in an outer sheath of an embodiment of the invention.

Fig. 9B depicts a cross-section view of a guidewire exit port in an outer sheath of an embodiment of the invention.

Fig. 9C depicts a top view of a guidewire exit port in an outer sheath of an embodiment of the invention.

Fig. 9D depicts a cross-section view of a guidewire exit port in an outer sheath of an embodiment of the invention.

Fig. 10A is a side view of an example of drug delivery system (Design 2) for PTA whereby the elastic film encompassing the balloon is coupled near the proximal and distal end of the balloon

Fig. 10B is a side view of an example of drug delivery system (Design 2) for PTA whereby the elastic film encompassing the balloon is coupled to a sheathe

Fig. 10C is a side view of an example of drug delivery system (Design 2) for PTA whereby the elastic film is folded and coupled to a balloon and a sheath Fig. 1 1 A is a side view of an example of drug delivery system (Design 3) for PTA whereby the elastic film encompassing the balloon is coupled near the proximal and distal end of the balloon and an outer sheathe is used to enclose the balloon and elastic film

Fig. 1 1 B is a side view of an example of drug delivery system (Design 3) for PTA whereby the elastic film encompassing the balloon is coupled to a middle sheathe and an outer sheathe is used to enclose the balloon and elastic film

Fig. 1 1 C is a side view of moving mechanism of outer sheath, middle sheath and the catheter shaft in drug delivery system (Design 3).

Fig. 1 1 D is a side view of an example of drug delivery system (Design 3) for PTA / PTCA consisting of said PTA / PTCA and a sheathe whereby the sheathe consists of an inner sheathe which the elastic film is coupled to and an outer sheathe.

Description Fig. 1 (a) depicts a balloon that may be suitable for use in the current invention, while Fig. 1 (b) depicts said balloon attached to, or integrally formed with, a balloon catheter shaft. As depicted in Fig. 1 (a), the balloon 1 comprises a balloon body 2, which may be made of a suitable material as discussed in more detail hereinbelow, and two balloon shafts 3, 4 at the ends 5, 6 of the balloon. As shown in Fig. 1 (b), one of the balloon shafts 3 may be connected to a balloon catheter 7, while the other balloon shaft 4 may contain the tip 8 of the balloon catheter.

When used herein, the term "proximal end" refers to the end furthest from the tip 8, while "distal end" refers to the end closest to said tip.

When referred to herein, the "ends" of a balloon may refer to the portion of a balloon including two tapered portions that are subsequently, respectively, attached to a balloon shaft. The "working portion" of a balloon, when used herein, may refer to the non-tapered portion of the balloon between the two tapered ends of the balloon.

For purpose of explanation and illustration, and not limitation, Figs. 2(a) to (c) show the basic concepts of embodiments of the invention that can be used for the drug delivery system disclosed herein. As shown in Fig. 2(a), a drug delivery system 10 may comprise a balloon 11 with a therapeutic agent 20 coated on its outer surface 12. An outer sheath 30 is positioned outside the balloon 11. The outer sheath 30 can protect the therapeutic agent coated balloon and minimize drug loss during transit of the drug delivery system. This system may be referred to herein as Design 1 .

A possible method of treatment or surgery of a subject using balloon according to Design 1 may comprise the steps of:

(1 ) optionally, an uncoated balloon catheter is introduced for pre-dilation to ensure a clear pathway for delivery of a drug coated balloon catheter;

(2) a drug delivery system according to Design 1 is introduced;

(3) the distal region of the drug coated balloon delivery system is positioned at a lesion and the outer sheath may be retracted in a proximal direction to expose the DEB or the distal region of the drug coated balloon delivery system is positioned before the lesion and the balloon catheter is advanced and positioned at the lesion and the DEB is exposed;

(4) the balloon is inflated to a predetermined size to radially compress against an atherosclerotic plaque in the lesion to remodel the vessel wall;

(5) the balloon is deflated;

(6) the drug coated balloon delivery system may be retracted directly. The outer sheath may be pushed forward or the balloon catheter is retracted into the outer sheath before the drug coated balloon delivery system is retracted.

It will be appreciated that other methods within the remit of a physician/surgeon may also be used to achieve the desired surgery or therapy. It will also be appreciated that the above method may be applicable to the treatment of any disease or condition that causes a narrowing or obstruction in a lumen of the body, such as, but not limited to, blood vessels (e.g. arteries, capillaries and veins).

During this process, the therapeutic agent coating layer on the surface of the balloon in Design 1 is protected by the outer sheath as the drug delivery system passes through the introducer sheath or the lumen before it reaches the desired site of action. The therapeutic agent coating in the drug delivery system can transit through lumen of the body with different diameters, different tortuosity and different distances without significant drug loss before it reaches the site of action. The therapeutic agent coating layer is only exposed to body fluid or tissue at step (3). The drug loss in this process is well-controlled as it mainly depends on friction between the therapeutic agent coating layer and the inner surface of outer sheath. With a lubricious inner liner on the outer sheath, the drug loss during outer sheath retraction is minimal. As shown in Fig. 2(b), a drug delivery system 10 may alternatively comprise a balloon 11 with an elastic film 40 over the balloon 11 . The elastic film 40 is coated with therapeutic agent 20 on its outer surface 41 . The drug transfer is significantly enhanced by using both mechanical force that arises from expansion of the elastic film 40 and intermolecular interactions between the elastic film 40 and the therapeutic agent coating layer 20. This system may be referred to herein as Design 2.

The elastic film 40 surrounds the balloon and it will expand as the balloon is inflated, resulting in pressure being exerted on the elastic film. As the therapeutic coating layer on the surface of the elastic film is rigid and is not as elastic as the elastic film, the adhesion of the therapeutic agent coating layer to the film is weakened by the mechanical force/pressure exerted by the inflated balloon. Thus, when the therapeutic coating layer touches the tissue of the body at the desired site of action, the therapeutic coating layers tends to detach from the elastic film and adhere to the tissue instead.

As shown in Fig. 2(c), a drug delivery system 10 may alternatively comprise a balloon 11 with an elastic film 40 over the balloon 11 . The elastic film 40 is coated with therapeutic agent 20 on its outer surface 41 . An outer sheath 30 is located on top of the elastic film to protect the balloon and film. The outer sheath 30 can protect the therapeutic agent coated balloon and minimize drug loss during transit of the drug delivery system. The drug transfer is significantly enhanced by using both mechanical force that arises from expansion of the elastic film 40 and intermolecular interactions between the elastic film 40 and the therapeutic agent coating layer 20. The drug loss during transit and the resulting drug transfer are exceptionally well-controlled in this embodiment. This system may be referred to herein as Design 3.

General features of Designs 1 to 3 will now be discussed hereinbelow. It will be appreciated that these features may be generally applicable, unless otherwise stated. When used herein, the term "comprising" is intended to require all components mentioned to be present, but to allow further components to be added. It will be appreciated that the term "comprising" also covers the terms "consisting of" and "consisting essentially of" as subsets, which are limited to only the components mentioned or to only the component mentioned along with some impurities, respectively. For the avoidance of doubt, it is explicitly contemplated that every use of the word "comprising" may be replaced with "consisting of" and "consisting essentially of" and variants thereof. In aspects and embodiments of the invention, the balloon may be a catheter balloon for a balloon catheter or may be a balloon catheter, for example as depicted in Fig. 1 . The balloon may be formed from a compliant, semi-compliant or non-compliant material. The term "compliant" as used herein relates to a material that can expand and stretch with increasing pressure to several times its original size during use as a balloon. Complaint balloons may be made from such materials as silicone, latex and thermoplastic elastomer (TPEs) etc. The term "semi-compliant" and "non-compliant" as used herein relates to a material for a balloon that can retain its designed size and shape even as the internal balloon pressure increases beyond that required to fully inflate the balloon. When such materials are used to make a balloon, the balloons may be thin walled and exhibit high tensile strength, with relatively low elongation. Such balloons are made from materials like polyethylene terephthalate (PET), po!yamides (e.g. Pebax™ and nylon 12 or DURETHAN™ or CRISTAMID™), polyurethane, polyethylene (PE) (for example, Marlex™ high-density polyethylene, Marlex™ low-density polyethylene, and a linear low density polyethylene such as REXELL™), polypropylene (PP), poiyetherimide (PEI), polytetrafluoroethylene (PTFE), ethylene tetrafiuoroethylene (ETFE), fiuorinated ethylene propylene (FEP), polyoxymethylene (POM), polybutylene terephthalate (PBT), polyvinylchloride (PVC), polyether-block-amide (PEBA, for example, available under the trade name PEBAX™), polyefheretherketone (PEEK), polyimide (PI), poiyphenylene sulfide (PPS), polyphenylene oxide (PPO), poly(ethylene naphthalenedicarboxylate) (PEN), polysulfone, perfluoro(propyl vinyl ether) (PFA), or mixtures, combinations, copolymers thereof, and the like.

When an outer sheath 30 is present in a design, it is movable relative to the balloon that is covers. As described herein, the outer sheath may be movable in a proximal direction to expose the coating or the balloon may be movable in a distal direction to become unprotected from the outer sheath. The moving distance of the outer sheath relative to balloon catheter may be equal to the length of the expandable balloon or above. The outer sheath can be single layer or multilayer tube. For example, single layer tube are selected from but not limited to polyethylene (PE), Pebax, polyurethane (PU) and Nylon. The multilayer tube may be selected from but not limited to dual layer and tri-layer tube. For example a dual layer tube with an outer layer and an inner layer or tri-layer tube with an outer layer, a middle layer and an inner layer. For the dual layer structure, the inner layer can be attached to or formed with the outer layer. The material for outer jacket may be chosen from PE, Pebax, PU and Nylon. The inner liner may be chosen from polytetrafluoroethylene (PTFE), fiuorinated ethylene propylene (FEP), perfiuoroalkoxy polymeric material (PFA), PE, Pebax, polyurethane, and Nylon. Lubricious materials which may facilitate the sliding between the inner catheter balloon and the outer sheath are preferred. The preferred material for the inner liner may be selected from but are not limited to PTFE, PFA, FEP or HDPE. A tri-layer tube may include an outer layer, a middle layer and an inner layer. The tri-layer tube may be a braided tube which provides high torque, high pushability, steerability and kink resistance. The middle layer may be a braided wire layer. The materials for the wires may be 304 stainless steel, 316 stainless steel, polyester, nylon and nitinol. The wire density may be 10 to 250 picks per inch, with wire size 0.0005"-0.004" for round wire and 0.0005"x0.003" to 0.002"x0.007" for flat wire. The middle layer can also be formed by using one type of wire or two types of wires. For example, the middle braided layer may be formed by two types of wires, such as yarn and stainless steel. Alternatively, the middle layer can be coil construction. The material for outer jacket may be chosen from but not limited to PE, Pebax, PL) and Nylon. The inner liner may be chosen from PTFE, FEP, PFA, PE, Pebax, polyurethane, and Nylon. Lubricious materials which may facilitate the sliding between the inner catheter shaft and the outer deployment sheath is preferred. The preferred material for inner liner may be PTFE, PFA, FEP or HDPE. The outer sheath can have different material at different part of the sheath. For example, the outer sheath can be a braided tube coupled with a dual layer tube. The dual layer tube may have the same outer diameter but larger inner diameter as compared with that of the braided tube. The therapeutic agent coating layer may be selected from one or more of the group consisting of an antiproliferative, immunosuppressive, anti-angiogenic, anti-inflammatory, and anti-thrombotic agent (e.g. the therapeutic agent may be selected from one or more of the group consisting of paclitaxel, rapamycin, everolimus, zotarolimus, umirolimus, tacrolimus, and pimecrolimus (such as a therapeutic agent selected from one or more of the group consisting of paclitaxel, rapamycin, zotarolimus and umirolimus, such as paclitaxel and rapamycin)).

The therapeutic agent may further comprise an excipient, which may be selected from but not limited to one or more of the group consisting of tartaric acid, a sugar, and a sugar alcohol (e.g. the pharmaceutically acceptable carrier may be selected from one or more of the group consisting of fructose, glucose, sucrose, lactose, maltose, erythritol, threitol, arabitol, ribitol, mannitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, more particularly, xylitol, tartaric acid, and sorbitol (such as selected from one or more of the group consisting of fructose, glucose, sucrose, mannitol, or more particularly, sorbitol, or yet more particularly xylitol, and tartaric acid)). The therapeutic agent coating layer may further comprise an adhesion balance layer or base coating layer laid directly on the outer hydrophobic surface of the balloon, comprising a hydrophilic polymer and/or a hydrophilic compound. The hydrophilic compound may be selected from one or more of the group consisting of a sugar, a sugar alcohol, and polyethylene glycol (e.g. the hydrophilic compound with a molecular weight of less than 1 ,000 Daltons may be selected from one or more of the group consisting of fructose, glucose, sucrose, lactose, maltose, erythritol, threitol, arabitol, ribitol, mannitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, xylitol, sorbitol and polyethylene glycol (such as selected from one or more of the group consisting of fructose, glucose, sucrose, xylitol, mannitol, and sorbitol)). The adhesion balance layer may be applied using any suitable method, such as, but not limited to, spray coating, immersion or dip-coating and the like.

It will be appreciated that the therapeutic agent coating layer, may be applied by mixing together the therapeutic agent and, optionally, an excipient and coating the substrate (e.g. the elastic film or balloon surface) with the mixture, which may include a solvent to enable coating to take place. Methods suitable to achieve the coating include, but are not limited to, spray coating, immersion or dip-coating and the like. The elastic film 40, when present, has an inner and outer surface, where the inner surface faces or is in contact with balloon. The outer surface may be directly covered by a therapeutic agent coating layer or coated with an adhesion balance layer at the bottom and a therapeutic agent coating layer on the top, such agents are as described hereinbefore. The elastic film 40, when present, may be expanded and stretched with increasing pressure within the balloon during inflation. The elastic film may cover the balloon in a number of alternative ways. For example, the elastic film can be an elastic film tube that covers the balloon like a sleeve. The elastic film tube may have a proximal end and a distal end, where both ends of the elastic film tube may be coupled to the respective ends of the balloon, or to the balloon shafts. Alternatively, the elastic film can be an elastic film tube that is coupled to a sheath, for example as described in more detail below with regard to Fig. 10B. The sheath with elastic tube is movable relative to the balloon.

In all embodiments and aspects of the invention where elastic film 40 is present in the form of a tube, it may expand radially when the balloon is inflated. Additionally, the elastic tube can be made from polymer film that may optionally further comprise a scaffold within the film. The scaffold minimise the ability of the elastic film to expand longitudinally, such that the elastic film primarily expands in a radial direction. The material of the scaffold may be chosen from, but not limited to, 304 stainless steel, 316 stainless steel, nylon, PET, polyamide and nitinol, where the material is aligned to minimise longitudinal expansion, but not to affect radial expansion.

The elastic 40 film may be made from materials including, but not limited to, silicone, thermoplastic elastomers, chosen from thermoplastic vulcanizates (TPV), thermoplastic copolyesters (COPE), polyether block amides (PEBA), thermoplastic polyurethane (TPU), thermoplastic elastic olefin (TEO), styrene ethylene butylene styrene (SEBS). It may be made from biocompatible materials including but not limited to polyolefin copolymers and polyethylene, poly(lactide-co-caprolactone), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(L-lactide-co-caprolactone) (PLLCL)polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLLA), poly(glycolide-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), poly(L-lactide-co-D,L-lactide) (PLDLLA), poly(L-lactide-co-glycolide) (PLGA), poly(D,L- lactide-co-glycolide), poly (D-lactide) (PDLA), poly(trimethylene carbonate) (PTMC), poly(lactide-co-trimethylene carbonate) (PLTMC), poly(glycolide-trimethylene carbonate), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB), polyhydroxyalkanoates (PHA), poly(phosphazene), poly(butylene succinate) (PBS) and its PLA copolymers, ethyl glycinate polyphosphazene, polycaprolactone-co-butylacrylate, a copolymer of polyhydroxybutyrate, a copolymer of poly(trimethylene carbonate).

The thickness of the elastic film may be 0.001 mm to 2 mm (e.g. 0.05mm to 1 mm).

Specific embodiments of Designs 1 -3 will now be discussed with reference to Figures 3 to 1 1 . Embodiments of Design 1 may comprise:

a balloon catheter shaft having an inflation lumen both having a proximal end and a distal end;

a balloon having a proximal end, a distal end and a working portion therebetween, where the proximal end of the balloon is coupled to and in fluid communication with the distal end of the inflation lumen, where the balloon during use or inflation has a cylindrical shape along the whole of its working portion;

a first sheath having a proximal end and a distal end; and

a therapeutic agent coating on a surface of the balloon facing the first sheath, wherein the first sheath is provided in a first position that wholly covers the balloon and is movable relative to the balloon to a second position that fully exposes the balloon. A first embodiment of Design 1 is provided in Fig. 3(a), which device is a drug delivery system for percutaneous transluminal angioplasty. The drug delivery system 100 includes a catheter shaft 110 having proximal (close to handle 140) and distal (close to tip 155) end portions. In this embodiment, the catheter shaft includes a guidewire lumen 120 and an inflation lumen 130. The guidewire lumen 120 extends to a proximal guidewire port 141 positioned on the side of handle 140. A guidewire can be introduced through the guidewire port 141 .

As depicted in Fig 3(a), a Y-shape junction 173 is formed at the proximal end of the inflation lumen 130 with another branch for guidewire lumen 120. The inflation lumen 130 may be further coupled to a hypotube 160 at the proximal end. Both the hypotube 160 and inflation lumen 130 may be in fluid communication with the inner chamber of the expandable balloon 150. The fluid is introduced into the fluid lumen through a luer adaptor 142 or the like located at the proximal end of the handle 140. The inflation lumen 130 can supply an inflation medium under positive pressure and can withdraw the inflation medium under negative pressure from the expandable balloon 150. The balloon 150 during usage or inflation has a cylindrical shape along its whole working length (i.e. the portion of the balloon intended to contact the body lumen in operation) with a consistent diameter. A tip 155 is coupled to the distal end of the expandable balloon 150.

The outer deployment sheath 180 may cover the whole catheter shaft except the tip 155. A slotted hypotube 171 may be connected to the proximal end of the outer deployment sheath 180. Fig. 4 shows that a slotted hypotube has a distal end 174 and a proximal end 173. The slotted hypotube further contains a longitudinal slot 177 that runs from a position close to the distal end 174 towards the proximal 173 in a longitudinal direction, as shown in Fig 4. The longitudinal slot 177 allows the relative longitudinal movement of the Y-shape junction along said longitudinal slot 177. The Y-shaped junction may contain a second hypotube (not shown) that runs through the handle up to the Y-shaped junction. The second hypotube may provide a housing within the handle for an inflation lumen 160. The second branch of the Y-shaped junction may contain a guidewire lumen. Fig. 4 also shows that the slotted hypotube structure may further include at least one or more cuts or slits 175 to increase the flexibility of the hypotube towards its distal end. A strain relief device 185 may be located at the distal end of the handle 140. The strain relief has a channel that allows the slotted hypotube 171 to reside within it, so that the slotted hypotube 171 can move relative to the strain relief. The strain relief provides adequate stress distribution during usage of the delivery system and is also intended to avoid undesired bending of the slotted hypotube 171. Fig 3(a) shows a triangle clamp shell 172 positioned in the handle 140. The triangle clamp shell 172 has a Y-shape junction, with one branch for guidewire lumen and another branch for the slotted hypotube 171 and the second hypotube, connected to the outer deployment sheath 180 and the inner inflation lumen 130, respectively. The triangle clamp shell 172 may be used to facilitate the relative and independent movement of catheter shaft 110 and outer deployment sheath 180. The handle 140 may also include an actuation member 145 that is configured to shift the longitudinal position of the catheter shaft member relative to the deployment sheath 180. For example, when the distal region of the drug delivery system is positioned at lesion, the actuation member 145 can be moved backward by a clinician in order to accomplish proximal retraction of the deployment sheath 180, thereby exposing balloon 150 to the lesion. After balloon 150 is deflated and before drug delivery system 100 is retracted from the body, the actuation member 145 can be moved forward by a clinician in order to move outer sheath forward to cover the deflated balloon 150. The outer deployment sheath can be provided with a generally constant outer and inner diameter. Alternatively, the outer deployment sheath can define a first inner diameter at its proximal end and a second different inner diameter at its distal end. The first diameter can be smaller than the second diameter, and vice versa. By tuning the inner diameter of the outer sheath, and the outer diameter of the (uninflated) balloon, the friction force generated between balloon 150 and the outer sheath 180 may be reduced, which can reduce drug loss when the outer sheath 180 moves backward. Alternatively or additionally, the inner diameter of the outer sheath may be coated in a second material that acts as a balloon cover. This second material may be selected from a material known to reduce friction, such as PTFE or other lubricious materials mentioned herein.

The outer sheath 180 may further include at least one radioopaque marker band 156 on the distal end, as shown in Fig. 3(a). This allows the clinician to precisely locate the catheter within the body. It will be appreciated that the use of a radioopaque marker band is generally applicable in all aspects and embodiments of the invention described herein.

It is necessary to evacuate the air inside the outer sheath before the drug delivery system is inserted into a blood vessel. Generally, the clinician injects water into the proximal end of the outer sheath and let water flow out from the distal end of the sheath to accomplish this air removal. This is to prevent the formation of air bubbles in the blood vessels of a subject during the implantation procedure. In the drug delivery system 100, there may be at least one port 183 located on the outer deployment sheath, as shown in Fig 6. In this configuration, the drug delivery system can be flushed (e.g. to remove air bubbles trapped inside the outer sheath 180) by infusing fluid through the catheter sheath through the ports 183. The water will then flush out from both the distal and proximal ends of the outer sheath 180. At the proximal end of the outer sheath 180, the fluid may be flushed out through slotted hypotube 171 . At the distal end of the outer sheath, the fluid may be flushed out through flats or channels 156 which are located on the tip 155 (see Fig. 7), which may allow the fluid to be flushed out of the sheath by passing through the gaps between catheter shaft 110 and outer deployment sheath 180. This may be desirable because flats or channels 156 may allow a clinician to evacuate air bubbles that may be trapped near the balloon 150. An alternative embodiment of the drug delivery system 200, in accordance with the general principles of Design 1 , for percutaneous transluminal angioplasty is provided in Fig. 3(b), which embodiment includes a catheter shaft 210 having a proximal end portion and a distal end portion. In this embodiment, the catheter shaft includes a guidewire lumen 220, extending across the entire length of the inner tubular member. An adaptor or manifold 240 can be provided at the proximal end of the handle 230. The adaptor can be a Y-shape luer connecter with one branch (e.g. proximal to adaptor 242) connected to a guidewire lumen 220, with the other branch (e.g. proximal to adaptor 241 ) connected to an inflation lumen 250.

As depicted in Fig. 3(b), the catheter shaft 210 has an inflation lumen 250 and a guidewire lumen 220. The inflation lumen 250 surrounds the guidewire lumen 220 and further formed a Y-shape junction at the proximal end of the inflation lumen 250. The Y-shape junction is located at the end of the handle 230. A hypotube 265 may surround proximal portion of the inflation lumen 250. Only the inflation lumen 250 is in fluid communication with the inner chamber of the expandable balloon 260. Fluid is introduced into the fluid lumen through a luer adaptor 241 or the like located at the proximal end of the handle 230. The inflation lumen 250 can supply an inflation medium under positive pressure and can withdraw the inflation medium under negative pressure from the expandable balloon 260. The guidewire lumen 220 is connected to the adaptor 242 through the Y-shape junction. A tip 255 is coupled to the distal end of the expandable balloon 260.

The outer deployment sheath 280 covers the whole catheter shaft except for tip 255. A flexible hypotube 271 (with slits 275 at its distal end) is connected to the proximal end of the outer deployment sheath. This design can increase the flexibility of a metal hypotube and enhance pushability and crossibility for the whole system. The relative movement between the outer sheath and catheter shaft is achieved through the movement of the hypotube 265 and a second hypotube 271. A strain relief device 285 may be located between the handle 230 and the hypotube 271 , which functions in a similar manner described above in relation to the device disclose in Figure 3(a). The handle 230 may include an actuation member 235 that is configured to shift the longitudinal position of the catheter shaft member relative to the deployment sheath 280. For example, when the distal region of the drug delivery system is positioned at a lesion, the actuation member 235 can be moved backward by a clinician in order to accomplish proximal retraction of the deployment sheath 280 and expose the balloon 260 to the lesion. After balloon 260 is deflated and before the drug delivery system 200 is retracted from the body, the actuation member 235 can be moved forward by a clinician in order to move the outer sheath forward to cover the deflated balloon 260. The outer deployment sheath 280 has a similar configuration to that shown in drug delivery system 100 and is intended to function in a similar way.

A further embodiment of a drug delivery system 300, in accordance with the general principles of Design 1 , for percutaneous transluminal coronary angioplasty is provided by Fig. 3(c), which embodiment includes a catheter shaft 310 and an outer sheath 380, both of which have a proximal end portion and a distal end portion. In this embodiment, as depicted in Fig 3(c), the catheter shaft 310 has an inflation lumen 350 and a guidewire lumen 320. The guidewire lumen extends through the balloon 360 from a distal end of the balloon to a guidewire exit port 321 that is at the proximal end of the balloon, as shown in Fig. 8. A guidewire 322 can be introduced into guidewire lumen through the exit port 321. The inflation lumen 350 surrounds the guidewire lumen 320 and further extends out from the exit port 321.

As shown in Fig. 3(c), a hypotube surrounds the inflation lumen 350 at the proximal end thereof. Only the inflation lumen 350 is in fluid communication with the inner chamber of the expandable balloon 360. The fluid is introduced into the fluid lumen through a luer adaptor 340 or the like located at the proximal end of the handle 330. The inflation lumen 350 can supply an inflation medium under positive pressure and can withdraw the inflation medium under negative pressure from the expandable balloon 360. A tip 355 is coupled to the distal end the expandable balloon 360.

The outer deployment sheath 380 covers the whole catheter shaft except the tip 355. A hypotube 371 with slits, similar in structure to that used in system 200 of Fig. 3(b), is connected to the proximal end of the outer deployment sheath. A strain relief device 385 may be located between the handle 330 and the hypotube 371 , which functions in the similar manner as described previously. The outer sheath may have an opening 381 at its distal region to allow guidewire 322 to further extend out from the exit port 321 , as shown in Figs. 9A-D. The opening can be a slot (Figs. 9A and 9B) or a circle (Figs. 9C and 9D). An adaptor can be provided at the proximal end of handle 330. The adaptor can be a luer connecter 340 that is connected (or connectible) to the inflation lumen 350. The handle 330 may include an actuation member 335 that is configured to shift the longitudinal position of the catheter shaft member relative to the deployment sheath 380. The guidewire 322 may move together with catheter shaft along the slot 381 in the outer sheath 380.

For both PTA and PTCA, a polymer film may be added to the balloon catheter, which has a first end, a second end and a middle portion. The polymer film is preferably made from a non-elastic polymer, though elastic polymers may still be used. The first end is connected to the outer sheath and the second end is connected to the proximal end of the balloon, while the middle portion may be folded or non-folded and extends along the inner surface of the sheath when the sheath is retracted. The handle's working mechanism is similar for PTA and PTCA. Fig. 3(d) is based on drug delivery device 100 as an example of this polymer film's placement and use. The first end 161 of the polymer film is connected to the outer sheath 180, the second end 163 of the film is connected to the proximal end of the balloon. When the outer sheath 180 is retracted, the middle portion of the polymer film will extend along the inner surface of the sheath. By using this design, there is little chance of introducing a bubble into the blood system. It will be appreciated that such a polymer film may be generally applicable to other aspects and embodiments of the invention where there are one or more sheaths.

The materials used in the catheter shaft, including the guidewire lumen, the inflation lumen and the tip are chosen from any suitable material, which includes, but is not limited to, polymer materials such as nylon, polyurethane, PEEK, PTFE, PVDF, PEBAX, PE. The outer deployment sheath can be constructed of a single layer of a suitable material. For example, suitable materials can include, but are not limited to, polymer materials such as nylon, polyurethane, PEEK, PTFE, PVDF, PEBAX, PE or dual-layer and tri-layer materials selected from the list from nylon, polyurethane, PEEK, PTFE, PVDF, PEBAX, PE. Again, these materials may be generally applicable throughout similar components in other aspects and embodiments of the current invention unless specifically stated.

The hypotube or slotted hypotube may be made from a material that comprises a metal or a plastic. Metals that may be used to form the hypotube include, but are not limited to, stainless steel including 302, 304V, 316L or nitinol. Plastics that may be used to form the slotted hypotube include, but are not limited to, polymeric materials such as nylon, polyurethane, PEEK, PTFE, PVDF, PEBAX or PE. As illustrated in Fig. 5, a slot 177 may be located in a longitudinal direction at one side of the hypotube, which facilitates the movement of the hypotube coupled to the inner catheter shaft. The width of the slot may be sufficient to enable the movement of the hypotube together with the guidewire lumen. The slotted hypotube may further include one or more cuts or slits to improve the flexibility of the hypotube. The pattern in the slotted hypotube may be achieved by laser-cutting or any other suitable method. These features may be generally applicable across all aspects and embodiments of the invention.

In the embodiments discussed herein, the expandable balloon may be provided in a folded configuration and covered by the deployment sheath. When in use, and at the site of action, the outer deployment sheath is retracted to a length which is at least equivalent to the total length of the expandable balloon and the tip to allow the balloon to be deployed.

It will be appreciated that when the device of Design 1 as described herein is used, it is consumed, in that the drug coating is left in the lumen of a patient. As such, the device may be suitable for the use of a therapeutic agent as defined hereinbefore in the preparation of a drug delivery device according to the concept of Design 1 , for example with reference, but not limited, to the particular embodiments discussed herein.

Embodiments of Designs 2 and 3 may relate to a drug delivery device comprising:

a balloon having a proximal end and a distal end;

a first elastic film configured or configurable to at least partly surround the balloon; and

a therapeutic agent coating on the second surface of the elastic film, wherein when the first elastic film is configured to at least partly surround the balloon, it has a first surface facing the balloon and a second surface facing away from the balloon and the first elastic film can expand to at least 1 .1 times its original dimension upon inflation of the balloon.

When used herein, "configured to" may refer to a fixed configuration of components that enables the desired expansion of the first elastic film, as described in respect of Fig. 10A below. Alternatively, "configured to" may refer to components that may move from a first spatial arrangement to a second spatial arrangement, wherein the first (e.g. see Fig. 10B) or second spatial arrangement (see Fig. 1 1 B) enables the desired expansion of the first elastic film, while the other spatial arrangement is not capable of achieving this effect. It will be appreciated that "configurable to" refers to the ability of a device to move between said spatial arrangements and that the device may be supplied for use in either the first or the second spatial arrangement. It will be appreciated that the device may be a catheter balloon for a balloon catheter or a balloon catheter. The balloon material may be compliant, semi-compliant or non-compliant. In particular embodiments of Designs 2 and 3, the balloon material may be semi-compliant or non-compliant.

The expansion of the elastic film may be from 1 .1 to 20 times (e.g. from 1 .5 to 10 times, e.g. from 2 to 5 times) its original diameter upon inflation of the balloon. Without wishing to be bound by theory, it is believed that when the balloon is inflated, the therapeutic agent coating on the elastic film is stretched as the elastic film expands and is therefore placed under a mechanical pressure, causing the coating to break. This mechanical breaking of the therapeutic agent coating may contribute to a greater than expected transference of drug to the desired site of action. In addition, the elastic film may be chosen to have a suitable balance of chemical properties (e.g. hydrophilic and hydrophobic properties), such that the intermolecular interaction between the elastic film and the therapeutic agent coating is sufficiently strong enough to prevent detachment of the drug in transit, but not so strong as to interference with the transference of the drug at the site of action (e.g. when additionally under mechanical pressure from the inflation of the balloon).

An embodiment of the invention with regard to drug delivery system in accordance with the principles of Design 2 is shown in Fig. 10A. In this embodiment, the drug delivery system 400 includes a catheter shaft 410 having a proximal end portion and a distal end portion. In this embodiment, the catheter shaft includes a guidewire lumen 420 and an inflation lumen 430. The catheter shaft 410 is coupled with a balloon 450 at its distal end. An elastic film 440 surrounds balloon 450 and is conjugated with the proximal and distal end of the balloon shaft 455, as shown in Fig. 10A. The therapeutic agent coating layer 460 is on the surface of the elastic film 440. When referring to coupling of the elastic film to the proximal end of the balloon, this may refer to direct bonding of the elastic film to the tapered proximal end of the balloon, the proximal balloon shaft or to the catheter shaft. When referring to coupling of the elastic film to the distal end of the balloon, this may refer to direct bonding of the elastic film to the tapered distal end of the balloon, the proximal balloon shaft or to tip of the catheter shaft. It will be appreciated that these points of coupling/bonding may be generally applicable unless otherwise stated when an elastic film is described as being coupled to a balloon directly herein. Methods of coupling the elastic film include, but are not limited methods of heat- bonding the elastic film to the points of attachment discussed herein.

A possible method of treatment or surgery of a subject using balloons according to Design 2 of the kind shown in Fig. 10A, where the elastic film is bound to the balloon, may comprise the steps of:

(1 ) optionally, an uncoated balloon catheter is introduced for pre-dilation to ensure a clear pathway for delivery of drug coated balloon catheter;

(2) a drug delivery system according to Design 2 without a sheath and it variants is introduced;

(3) the distal region of the drug delivery system is positioned at a lesion or the distal region of the drug delivery system is positioned before the lesion;

(4) the balloon is inflated to a predetermined size to radially compress against an atherosclerotic plaque in the lesion to remodel the vessel wall, which results in expansion of the elastic film and transference of the drug from the film to the lesion;

(6) the balloon is deflated and the elastic film is recovered; and

(7) the drug delivery system is retracted.

A further embodiment of a drug delivery system in accordance with the principles of Design 2 is shown in Fig. 10B. The drug delivery system 500 includes a catheter shaft 510 having a proximal end portion and a distal end portion. In this embodiment, the catheter shaft 510 includes a guidewire lumen 520 and an inflation lumen 530. An elastic film 540 surrounds balloon 550. The proximal end of the elastic film is coupled to a sheath 545. The sheath 545 can move relative to the catheter shaft 510, which results in relative movement of the elastic film 540 and the balloon 550. The therapeutic agent coating layer 560 is on the surface of the elastic film 540. The assembly of the device is similar to drug delivery system 100 and 200. Either handle design can be applied drug delivery system 500. Fig. 10B shows the design similar to the drug delivery system 100. A possible method of treatment or surgery of a subject using balloons according to Design 2 of the kind shown in Fig. 10B, where the elastic film forms part of a sheath over the balloon, may comprise the steps of:

(1 ) the drug coated balloon delivery system according to Design 2 where the elastic film forms a sheath over at least part of the balloon, is introduced and advanced to just before the lesion;

(2) the balloon is advanced forward, without the sheath, for pre-dilation to ensure a clear pathway for delivery of drug; (3) the balloon is deflated;

(4) the balloon may be retracted into the sheath and the sheath together with the balloon catheter are advanced to the lesion, or the sheath may be advanced to cover the balloon at the lesion (the sheath covering the balloon being the elastic film);

(5) the balloon is inflated to a predetermined size to radially compress against the atherosclerotic plaque of the lesion to remodel the vessel wall, such that the elastic film is expanded and drug is transferred from the film to the lesion;

(6) the drug coated balloon delivery system may be retracted directly. A further embodiment of a drug delivery system in accordance with the principles of Design 2 is shown in Fig. 10C. In this embodiment, the elastic film 540 may have a first end 511 , a second end 512 and a middle portion 513, wherein the first end 511 is connected to the sheath 545, the second end 512 is connected to the distal end of the balloon 551 , the middle portion 513 may extend along the inner surface of the sheath when the sheath 545 covers the balloon (it will be appreciated that the middle portion may be provided in a folded configuration along the inner surface of the sheath when the sheath covers the balloon). The therapeutic coating layer 560 is exposed as the sheath 545 is retracted. Methods described hereinbefore may be applicable to this embodiment. A separate pre-dilation balloon catheter can be saved in the case that the elastic film is coupled with the sheath. The relative movement between the sheath and balloon catheter enables the balloon catheter to be used for pre-dilation and drug delivery. It will be appreciated that pre-dilation is an optional step and it use depends on the clinician's preference and the patient's clinical circumstances.

It will be appreciated that other methods within the remit of a physician/surgeon may also be used to achieve the desired surgery or therapy using the variants of Design 2 mentioned herein. It will also be appreciated that the above method may be applicable to the treatment of any disease or condition that causes a narrowing or obstruction in a lumen of the body, such as, but not limited to, blood vessels (e.g. arteries, capillaries and veins).

It will be appreciated that when the device of Design 2 as described herein is used, it is consumed, in that the drug coating is left in the lumen of a patient. As such, the device may be suitable for the use of a therapeutic agent as defined hereinbefore in the preparation of a drug delivery device according to the concept of Design 2, for example with reference, but not limited, to the particular embodiments discussed hereinbefore. An embodiment of the invention according to the principles of drug delivery system Design 3 is shown in Fig. 1 1 A. The drug delivery system 600 includes a catheter shaft 610 having a proximal end portion and a distal end portion. In this embodiment, the catheter shaft includes a guidewire lumen 620 and an inflation lumen 630. The inflation lumen 630 is coupled with a balloon 650 at the distal end of the inflation lumen. An elastic film 640 is surrounds the balloon 650. The elastic film maybe bonded to the proximal and distal ends of the balloon shaft 655, as shown in Fig. 1 1 A or bonded to balloon body or catheter shaft. The elastic film may be surrounds the balloon as a sleeve or may be further folded with the balloon. The therapeutic agent coating layer 660 is on the surface of the elastic film 640. The outer sheath 680 covers the whole catheter shaft. The outer sheath 680 can be moved backward by a clinician in order to accomplish proximal retraction of deployment sheath. The outer sheath 680 can also be moved forward by a clinician in order to accomplish proximal retraction of catheter shaft back into the sheath following deployment. A possible method of treatment or surgery of a subject using balloons according to Design 3, of the kind shown in Fig. 1 1 A, where the elastic film is bound to the balloon, may comprise the steps of:

(1 ) optionally, an uncoated balloon catheter is introduced for pre-dilation to ensure a clear pathway for delivery of drug coated balloon catheter;

(2) the drug delivery system according to Design 3, where the elastic film is bound to the balloon, is introduced;

(3) the distal region of the drug delivery system is advanced to and positioned at a lesion and the outer deployment sheath is retracted in proximal direction and the therapeutic agent coating layer on the elastic film is exposed, or the distal region of the drug delivery system is advanced and positioned before the lesion and the balloon catheter is advanced and positioned at the lesion, thereby exposing the therapeutic agent coating layer on the elastic film as well;

(4) the balloon is inflated to a predetermined size to radially compress against the atherosclerotic plaque of the lesion to remodel the vessel wall, such that the elastic film is expanded and drug is transferred from the film to the lesion;

(7) the balloon is deflated and the elastic film is recovered, leaving the thereapeutic agent in position on the lesion;

(8) the drug delivery system is retracted, either without covering the balloon and film with the sheath, or after doing so.

During this process, the therapeutic agent coating layer on the surface of the film is protected by the outer sheath as the drug delivery system passes through the torturous blood vessel before it reaches the lesion. The therapeutic agent coating in the drug delivery system can transit through blood vessels with different diameters, different tortuosity and through different distances without any drug loss until it reaches the lesion. As the therapeutic agent coating layer is only exposed to body fluid or tissue at step (3), the drug loss in this process is well-controlled. This control can be further improved by reducing the friction between the therapeutic agent coating layer and the inner surface of outer sheath. For example, a lubricious inner lining can be added to the outer sheath, to minimise drug loss on transit of the balloon out of the outer sheath. Drug transmission is significantly enhanced by using both mechanical force that arises from expansion of the elastic film and reduced bonding force between the elastic film and the therapeutic agent coating layer.

An alternative embodiment of drug delivery system in accordance with the principles of Design 3 is shown in Fig. 1 1 B. The drug delivery system 700 includes a catheter shaft 710 having a proximal end portion and a distal end portion. In this embodiment, the catheter shaft 710 includes a guidewire lumen 720 and an inflation lumen 730. An elastic film 740 is located over the balloon 750. The proximal end of the elastic film is coupled to a middle sheath 745. The middle sheath 745 can move relatively to the catheter shaft 710, which results in relative movement of the elastic film 740 and the balloon 750. The therapeutic agent coating layer 760 is on the surface of the elastic film 740. The outer sheath 780 covers the middle sheath and can move relatively to the catheter shaft 710 and the middle sheath 745. The therapeutic agent coating layer 760 on the surface of the balloon 750 is protected by the outer sheath 780 as the drug delivery system passes through the introducer sheath or the torturous blood vessel before it reaches a lesion. The therapeutic agent coating in the drug delivery system can therefore transit through blood vessels with different diameters, different tortuosity and through different distances without any drug loss en route to the lesion. The therapeutic agent coating layer is only exposed to body fluids and/or tissues when the outer sheath 780 is retracted. Thus, the drug loss in this process can be well-controlled, provided that friction between the therapeutic agent coating layer 760 and the inner surface of outer sheath 780 is controlled during retraction of the outer sheath. With a lubricious inner liner material, the drug loss during outer sheath retraction is minimal. In addition, drug transmission to the site of action is significantly enhanced by using both mechanical force that arises from expansion of the elastic film and the intermolecular interactions between the elastic film 740 and the therapeutic agent coating layer 760. Fig. 1 1 C shows a hub 711 attached to the catheter shaft 710 which can be pulled back and forward to allow movement relative to the middle sheath 745 and outer sheath 780. The outer sheath 780 is connected to the slider 712, so the slider 712 can move the outer sheath 780 relative to the middle sheath 745 and catheter shaft 710. The middle sheath 745, which the elastic film 740 is connected to at the distal end, is connected to the handle body, which cannot be moved in this embodiment. It will be appreciated that other suitable arrangements can be devised.

A possible method of treatment or surgery of a subject using balloons according to Design 3, of the kind shown in Fig. 1 1 B and 1 1 C, where the elastic film forms part of a middle sheath, may comprise the steps of:

(1 ) the drug coated balloon delivery system is advanced to just before the lesion and then balloon catheter is advanced forward from the protection offered by the outer and inner sheaths for pre-dilation to ensure a clear pathway for delivery of drug, or the balloon catheter is introduced in an advanced position before the sheaths and is advanced to the lesion, where it is used to clear a pathway for drug delivery;

(2) the balloon catheter is deflated;

(3) the balloon may be retracted into the middle sheath which houses the elastic film and the middle sheath together with balloon catheter are advanced to lesion, or the outer sheath and middle sheath both may be advanced to cover the balloon and the outer sheath may be retracted and expose the elastic film and balloon;

(4) the balloon is inflated to a predetermined size to radially compress against the atherosclerotic plaque of the lesion to remodel the vessel wall, such that the elastic film is expanded and drug is transferred from the film to the lesion;

(5) the balloon is deflated and the elastic film is recovered, leaving the drug behind on the lesion;

(6) the drug delivery system may be retracted directly or the outer sheath may be pushed forward to cover the balloon and the middle sheath of the balloon and middle sheath are retracted into the outer sheath before the drug coated balloon delivery system is retracted.

In the method described above, it will be appreciated that the device of Fig. 1 1 B, may be supplied:

(a) with the balloon in an advanced position relative to the middle sheath 745 and outer sheath 780;

(b) with the balloon covered by the sheath 745, with both balloon and middle sheath in an advanced position relative to the outer sheath 780; or (c) with the balloon in covered by both the middle sheath 745 and outer sheath

780.

A separate pre-dilation balloon catheter can be saved in the case that the elastic film is coupled with the middle sheath. The relative movement between the middle sheath and balloon catheter enables the balloon catheter to be used for pre-dilation and drug delivery.

A yet further alternative embodiment of a drug delivery system in accordance with the principles of Design 3 is shown in Fig. 1 1 D. The drug delivery system 800 includes a balloon catheter (e.g. PTCA catheter 810 or a PTA catheter 815) and a sheath 820. The sheath is composed from an inner sheath 821 and an outer sheath 822. The inner sheath 821 has an elastic film 825 at its distal end, which may cover at least a portion of the balloon 870. The therapeutic agent coating layer 860 is on the surface of the elastic film 825. An outer sheath 822 surrounds the inner sheath 821 and thereby the balloon. The inner sheath 821 and the outer sheath 822 can move together or can have relative movement to each other. The sheath 820 and PTCA balloon catheter 810 or PTA balloon catheter 815 may be introduced separately.

It will be appreciated that other methods within the remit of a physician/surgeon may also be used to achieve the desired surgery or therapy using the variants of Design 3 mentioned herein. It will also be appreciated that the above method may be applicable to the treatment of any disease or condition that causes a narrowing or obstruction in a lumen of the body, such as, but not limited to, blood vessels (e.g. arteries, capillaries and veins). It will be appreciated that when the device of Design 3 as described herein is used, it is consumed, in that the drug coating is left in the lumen of a patient. As such, the device may be suitable for the use of a therapeutic agent as defined hereinbefore in the preparation of a drug delivery device according to the concept of Design 3, for example with reference, but not limited, to the particular embodiments discussed hereinbefore.

Examples Example 1 Test articles were coated with the same drug coating formulation and coating method. Test Articles

Device A is a drug delivery device prepared similar to Fig 3(a).

Device B is a drug delivery device prepared similar to Fig 10(c).

Device C is a drug delivery device prepared similar to Fig 10 (a).

Device D is a typical balloon catheter.

Method

In-vitro testing methods were adapted from Seidlitz et al. (2013) In Vitro Determination of Drug Transfer from Drug-Coated Balloons PLoS ONE8(12): e83992 (doi:10.1371/journal. pone.0083992).

The following changes were made:

• A silicon tube was used for the model vessel wall.

• Imaging of the model vessel wall was not carried out, and thus the balloons were not treated with fluorescent substances.

• Drug contents were extracted in ACN and analysed using UV-spectrometer at 227nm.

• Balloons were inflated to pressure of 12atm.

• Drug remaining on the balloon were then also analysed, so that the drug loss during introduction and transit of the balloon were also deduced.

Results

As shown in Fig. 12, Device A, which has the outer sheath, have a significantly lower drug loss compared to Device D, a typical balloon catheter. Device C, consisting an elastic film, also have a significantly lower drug loss compared to Device D, a typical balloon catheter. Device B, consisting of both an elastic film and an outer sheath, have a more significantly lower drug loss compared to Device D, a typical balloon catheter. Device B also has a lower drug loss compared to both Device A and C. Example 2

Test articles were coated with the same drug coating formulation and coating method. Test Articles

Device C is a drug delivery device prepared similar to Fig 10 (a).

Device D is a typical balloon catheter. Method

In-vitro testing methods were adapted from Seidlitz et al. (2013) In Vitro Determination of Drug Transfer from Drug-Coated Balloons PLoS ONE8(12): e83992 (doi:10.1371/journal. pone.0083992).

The following changes were made:

• A silicon tube was used for the model vessel wall.

· The delivery route is shortened.

• Imaging of the model vessel wall was not carried out, and thus the balloons were not treated with fluorescent substances.

• Drug contents were extracted in ACN and analysed using UV-spectrometer at 227nm.

• Balloons were inflated to pressure of 12atm.

Results

As shown in Figure 13, Device C, which comprises of an elastic film, has significantly more drug attached to the silicon tube compared to Device D, a typical balloon catheter. The results depicted in Figure 2 clearly show that the device designs described in hereinbefore significantly improves the drug transfer at the site of action.