WO2019009809A1

WO2019009809A1 - Drug delivery balloon catheter

Info

Publication number: WO2019009809A1
Application number: PCT/SG2018/050328
Authority: WO
Inventors: Jingnan LUO; Honglei WANG; Moses Lee
Original assignee: Vascuros Medical (shanghai) Co Ltd; Vascuros Medical
Current assignee: Vascuros Medical (shanghai) Co Ltd; Vascuros Medical
Priority date: 2017-07-05
Filing date: 2018-07-04
Publication date: 2019-01-10
Anticipated expiration: 2020-01-05
Also published as: CN111491687A; CN111491687B

Abstract

The current invention relates to the provision of drug eluting balloons and balloon catheters, where the drug coating is protected by a sheath.

Description

DRUG DELIVERY BALLOON CATHETER

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/introducer 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 introducer sheath or guiding

An advantage associated with DEBs is that they avoid late thrombotic problems whilst also reducing early restenosis, simplifying the procedure and reducing the dual antiplatelet duration. Thus, DEBs are an innovative solution with a high potential impact on the treatment of patients. However, 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) Inconsistent, unpredictable and significant drug loss.

For DEBs, 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) Insufficient, uncontrollable and unpredictable drug release, transfer and uptake. Once at the site of application, drug transfer is required to be very fast, as the drug has to be released within from thirty seconds to a few minutes. Therefore, the ideal coating should be easily, rapidly and fully releasable at the site of action. This requires the balloon and the drug to have a weak adhesion during drug transfer to ensure drug transfer, though a weak adhesion creates issues in getting the drug to the site of action. The traditional balloon materials are PET, pebax and nylon, which are hydrophobic. As both the drug and balloon surface are generally hydrophobic, the interaction (adhesion) between the drug and balloon surface is quite strong. In addition, the drug molecules also adhere to each other, such that even drug molecules that are not in contact with the balloon surface exhibit a strong adhesion to the balloon (through their adhesion to other drug molecules (direct or indirect) that are adhered to the balloon surface). This adhesion makes it difficult to rapidly and fully release the drug from the balloon surface, which leads to low drug transfer and uptake. A number of methods have been used to try to weaken the interfacial interaction between the drug molecules themselves as well as drug molecules to the balloon surface to improve drug release and transfer. These methods include: (a) the use of small molecule additives to reduce adhesion; (b) treating the balloon surface to become hydrophilic by using mechanical or chemical methods; or (c) forming drug particles on the balloon surface instead of a drug layer. However, these methods weaken the drug's stability on the surface of the balloon and also can increase high, unpredictable and uncontrollable drug loss. If drug loss during transition needs to be minimized, then the coating stability has to be enhanced, in that case, the drug release and transfer will not be optimal because the composition will be more adhered to the surface of the balloon. Therefore, reducing drug loss (drug stability on balloon) during transit and drug release/transfer at the site of action are contradictory. The drug-coated balloons currently available in the market cannot achieve a high drug release and transfer (at the site of action), low drug loss during navigation (en route to said site) and hence predictable drug delivery.

(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.

(4) In addition, significant and uncontrollable drug loss en route to the desired site of action may lead to large drug coating particles or even patches of the drug coating being released into the bloodstream, which may result in the blockage of a lumen of the body, for example, a patient's vascular capillary system, causing a distal embolization. Thus, there remains need for improved DEBs that tackle one or more of the problems outlined above.

Summary of Invention The current invention solves one or more of the problems outlined hereinbefore. Thus, in a first aspect of the invention, there is provided a fixed wire catheter balloon delivery device comprising:

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

a wire having a proximal segment and a distal segment;

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;

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

a therapeutic agent coating on a surface of the balloon facing the sheath,

wherein:

the sheath is provided in a first position that wholly covers the balloon and is movable relative to the balloon to a second position that exposes at least a portion of the balloon; and part or whole of the distal section of the wire is irreversibly coupled to the distal end of 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 may be semi-compliant or non-compliant);

(b) the balloon during use or inflation may have a cylindrical or non-cylindrical shape along the whole of its working portion;

(c) 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 (more particularly, the therapeutic agent may be selected from one or more of the group consisting of paclitaxel, rapamycin, zotarolimus and umirolimus (e.g. paclitaxel and rapamycin)));

(d) 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 excipient 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 (more particularly the excipient may be 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));

(e) the balloon catheter shaft may have a tip at the distal end of the shaft, where the tip has a proximal end facing towards the shaft and a distal end facing away from the shaft and the distal end of the outer sheath and the proximal end of the tip proximal may further comprise an interlock mechanism;

(f) the distal end of the sheath may be flared relative to the rest of the sheath, such that the distal end has an outer diameter that is larger than the rest of the sheath by from 0.1 % to 75%;

(g) the sheath may have an inner lumen and further comprises a suction mechanism in contact with said inner lumen to prevent the formation of air bubbles when the device is used, optionally wherein the suction mechanism may comprises an o-ring bound to the inner lumen at a proximal position relative to the balloon in the first position;

(h) the balloon may be partially or fully covered by the therapeutic agent coating layer;

(i) the distal segment of the wire may have a tip and the tip is in front of the distal end of the balloon.

It will be appreciated that any technically combination of the first aspect of the invention with any (or all) of embodiments (a) to (i) are specifically contemplated. In a second aspect of the invention, there is provided a use of a therapeutic agent as defined in embodiment (c) of the first aspect of the invention 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 aspect of the invention, there is provided 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 fourth aspect of the invention, there is provided 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), optionally wherein the disease or condition is a vascular condition or a non-vascular condition (e.g. prostatic hyperplasia (BPH), urethral strictures, ureteral strictures, prostate cancer, esophageal strictures, sinus strictures, biliary tract strictures, asthma and chronic obstructive pulmonary disease (COPD)).

In an embodiment of the fourth aspect of the invention, there is provided a method of treatment or surgery, wherein the method comprises 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 the first aspect of the invention (and any technically sensible combination of its embodiments) 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. Further aspects and embodiments of the invention are provided in the following clauses.

1. A rapid exchange drug delivery catheter balloon 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;

an exit port for a guidewire lumen in the balloon catheter shaft spaced apart in the proximal direction from the proximal end of the balloon;

a guidewire lumen, where the guidewire lumen runs co-axially through the inflation lumen from a proximal end that extends through the exit port to a distal end that extends through the distal end of the balloon;

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

a therapeutic agent coating on a surface of the balloon facing the sheath,

wherein:

the sheath is provided in a first position that wholly covers the balloon and is movable relative to the balloon to a second position that exposes at least a portion of the balloon; and

the sheath further provides a longitudinal opening that accommodates the exit port and enables the relative movement of the sheath with respect to the balloon from the first position to the second position.

2. The device according to Clause 1 , wherein the sheath has an inner lumen with a first inner diameter, where at least one segment of the inner lumen has a second diameter that is smaller than the first diameter.

3. The device according to Clause 2, wherein the second diameter is less than or equal to 0.010" larger than an outer diameter of the inflation lumen.

4. The device according to Clause 2 or Clause 3, wherein each second diameter is independently formed by a neck-down portion or an o-ring bound to the inner lumen.

5. The device according to any one of Clauses 2 to 4, wherein two or three segments of the inner sheath lumen have the second diameter, optionally wherein the longitudinal opening has a proximal end and a distal end and one segment is positioned adjacent to each end of the longitudinal opening.

6. The device according to any one of the preceding clauses, wherein the balloon material is compliant, semi-compliant or non-compliant (e.g. the balloon material is semi- compliant or non-compliant); and/or the balloon during use or inflation has a cylindrical or non-cylindrical shape along the whole of its working portion.

7. The device according to any one of the preceding clauses, wherein the therapeutic agent coating comprises a therapeutic agent selected from one or more of the group consisting of an antiproliferative, immunosuppressive, anti-angiogenic, anti-inflammatory, and anti-thrombotic agent.

8. The device according to Clause 7, wherein the therapeutic agent is selected from one or more of the group consisting of paclitaxel, rapamycin, everolimus, zotarolimus, umirolimus, tacrolimus, and pimecrolimus.

9. The device according to Clause 8, wherein the therapeutic agent is selected from one or more of the group consisting of paclitaxel, rapamycin, zotarolimus and umirolimus (e.g. paclitaxel and rapamycin)).

10. The device according to any one of the preceding clauses, wherein the therapeutic agent coating further comprises an excipient, selected from one or more of the group consisting of tartaric acid, a sugar, and a sugar alcohol.

11. The device according to Clause 10, wherein the excipient 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, more particularly, xylitol, tartaric acid, and sorbitol.

12. The device according to Clause 10 or Clause 11 , wherein the excipient is 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. 13. The device according to any one of the preceding clauses, wherein the balloon catheter shaft has a tip at the distal end of the shaft, where the tip has a proximal end facing towards the shaft and a distal end facing away from the shaft and the distal end of the outer sheath and the proximal end of the tip proximal further comprise an interlock mechanism. 14. The device according to any one of the preceding clauses, wherein the distal end of the sheath is flared relative to the rest of the sheath, such that the distal end has an outer diameter that is larger than the rest of the sheath by from 0.1 % to 75%. 15. The device according to any one of the preceding clauses, wherein the balloon is partially or fully covered by the therapeutic agent coating layer. 16. The device according to any one of the preceding clauses, wherein the distal segment of the wire has a tip and the tip is in front of the distal end of the balloon.

17. Use of a therapeutic agent as defined in Clause 8 or Clause 9 in the preparation of a drug delivery device according to any one of Clauses 1 to 16 for the treatment of a disease or condition that causes narrowing or obstruction of a body lumen (e.g. arteries or veins).

18. A drug delivery device according to any one of Clauses 1 to 16 for the treatment of a disease or condition that causes narrowing or obstruction of a body lumen (e.g. arteries or veins).

19. A method of treatment or surgery using a drug delivery device according to any one of Clauses 1 to 16 to treat a disease or condition that causes narrowing or obstruction of a body lumen (e.g. arteries or veins), optionally wherein the disease or condition is a vascular condition or a non-vascular condition (e.g. prostatic hyperplasia (BPH), urethral strictures, ureteral strictures, prostate cancer, esophageal strictures, sinus strictures, biliary tract strictures, asthma and chronic obstructive pulmonary disease (COPD)).

20. A method of treatment or surgery according to Clause 19, wherein the method comprises 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 any one of Clauses 1 to 13 is introduced;

(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.

21. A fixed wire catheter balloon delivery device comprising:

a wire having a proximal segment and a distal segment;

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

a therapeutic agent coating on a surface of the balloon facing the sheath,

wherein:

the sheath is provided in a first position that wholly covers the balloon and is movable relative to the balloon to a second position that exposes at least a portion of the balloon; and part or whole of the distal section of the wire is irreversibly coupled to the distal end of the balloon. 22. The device according to Clause 21 , wherein the balloon material is compliant, semi- compliant or non-compliant (e.g. the balloon material is semi-compliant or non-compliant); and/or

the balloon during use or inflation has a cylindrical or non-cylindrical shape along the whole of its working portion.

23. The device according to Clause 21 or Clause 22, wherein the therapeutic agent coating comprises a therapeutic agent selected from one or more of the group consisting of an antiproliferative, immunosuppressive, anti-angiogenic, anti-inflammatory, and antithrombotic agent.

24. The device according to Clause 23, wherein the therapeutic agent is selected from one or more of the group consisting of paclitaxel, rapamycin, everolimus, zotarolimus, umirolimus, tacrolimus, and pimecrolimus. 25. The device according to Clause 24, wherein the therapeutic agent is selected from one or more of the group consisting of paclitaxel, rapamycin, zotarolimus and umirolimus (e.g. paclitaxel and rapamycin)). 26. The device according to any one of Clauses 21 to 25, wherein the therapeutic agent coating further comprises an excipient, selected from one or more of the group consisting of tartaric acid, a sugar, and a sugar alcohol.

27. The device according to Clause 26, wherein the excipient 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, more particularly, xylitol, tartaric acid, and sorbitol.

28. The device according to Clause 26 or Clause 27, wherein the excipient is 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.

29. The device according to any one of Clauses 21 to 28, wherein the balloon catheter shaft has a tip at the distal end of the shaft, where the tip has a proximal end facing towards the shaft and a distal end facing away from the shaft and the distal end of the outer sheath and the proximal end of the tip proximal further comprise an interlock mechanism.

30. The device according to any one of Clauses 21 to 29, wherein the distal end of the sheath is flared relative to the rest of the sheath, such that the distal end has an outer diameter that is larger than the rest of the sheath by from 0.1 % to 75%.

31. The device according to any one of Clauses 21 to 30, wherein the sheath has an inner lumen and further comprises a suction mechanism in contact with said inner lumen to prevent the formation of air bubbles when the device is used, optionally wherein the suction mechanism comprises an o-ring bound to the inner lumen at a proximal position relative to the balloon in the first position.

32. The device according to any one of Clauses 21 to 31 , wherein the balloon is partially or fully covered by the therapeutic agent coating layer.

33. The device according to any one of Clauses 21 to 32, wherein the distal segment of the wire has a tip and the tip is in front of the distal end of the balloon. 34. The device according to Clause 21 , wherein the sheath has an inner lumen with a first inner diameter, where at least one segment of the inner lumen has a second diameter that is smaller than the first diameter.

35. The device according to Clause 34, wherein the second diameter is less than or equal to 0.010" larger than an outer diameter of the inflation lumen.

36. The device according to Clause 34 or Clause 35, wherein each second diameter is independently formed by a neck-down portion or an o-ring bound to the inner lumen.

37. The device according to any one of Clauses 35 to 36, wherein two or three segments of the inner sheath lumen have the second diameter. 38. Use of a therapeutic agent as defined in Clause 23 or Clause 24 in the preparation of a drug delivery device according to any one of Clauses 21 to 37 for the treatment of a disease or condition that causes narrowing or obstruction of a body lumen (e.g. arteries or veins). 39. A drug delivery device according to any one of Clauses 21 to 37 for the treatment of a disease or condition that causes narrowing or obstruction of a body lumen (e.g. arteries or veins).

40. A method of treatment or surgery using a drug delivery device according to any one of Clauses 21 to 37 to treat a disease or condition that causes narrowing or obstruction of a body lumen (e.g. arteries or veins), optionally wherein the disease or condition is a vascular condition or a non-vascular condition (e.g. prostatic hyperplasia (BPH), urethral strictures, ureteral strictures, prostate cancer, esophageal strictures, sinus strictures, biliary tract strictures, asthma and chronic obstructive pulmonary disease (COPD)).

41. A method of treatment or surgery according to Clause 40, wherein the method comprises the steps of:

(2) a drug delivery system according to any one of Clauses 21 to 37 is introduced;

(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.

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 is a conceptual drawing of a drug delivery system.

Fig. 3a is a side view of an example of the Initial Design of the drug delivery system of Fig. 2. Fig. 3b is a side view of a slotted hypotube with a longitudinal slot through the hypotube for use in the drug delivery system of Fig. 2.

Figure 4 is the design of a conventional rapid exchange balloon shaft.

Figure 5 depicts a drug delivery system 1100 according to the current invention.

Figure 6a depicts a drug delivery system 200 according to the current invention.

Figure 6b depicts a drug delivery system 3100 according to the current invention.

Figure 7a depicts the device with the actuation member 145 positioned at the initial position of the device in Fig. 6a.

Figure 7b depicts the device with the actuation member 145 positioned at the withdrawn position of the device in Fig. 6a.

Figure 8a depicts an example of a device having a distal region with a straight wire tip.

Figure 8b depicts an example of a device having a distal region with a bending wire tip.

Figure 8c depicts an example of a device having a distal region with a coil wire tip.

Figure 9 depicts a delivery system with a tapered wire and inflation lumen.

Figure 10a depicts the design of a balloon tip suitable for use in the current invention.

Figure 10b depicts a ring structure with longitudinal ridges present at a distal region of an outer sheath suitable for use in the current invention. Figure 10c depicts the cross-sectional design of the balloon tip and distal end of the outer sheath disclosed in Figures 10a and 10b.

Figure 1 1a depicts a distal region of the delivery system, of which the outer sheath tip is straight.

Figure 1 1 b depicts a distal region of the delivery system, of which the outer sheath tip is flared.

Figure 12 depicts a delivery system with a changing outer diameter of outer sheath.

Figure 13a depicts a PTCA rapid exchange catheter shaft according to the current invention without an outer sheath.

Figure 13b depicts a PTCA drug delivery system 600 according to the current invention, where the balloon is covered by the outer sheath.

Figure 13c depicts the outer sheath movement of a PTCA drug delivery system 600 according to the current invention, where the balloon is in a fully exposed position.

Figure 13d depicts a PTCA drug delivery system 700 according to the current invention, where the balloon is covered by the outer sheath.

Figure 13e depicts a PTCA drug delivery system 700 according to the current invention, where the balloon is pushed forward and exposed.

Figures 14a and b depicts a suction mechanism inside the sheath at a position A and a position B, respectively.

Figure 15a depicts a PTCA rapid exchange catheter fitted with an O-ring system.

Figure 15 b depicts a PTCA rapid exchange catheter fitted with narrowing sections.

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.

Before dealing with the balloon catheter of the current invention, it is useful to consider the design disclosed in unpublished US provisional application No. 62/423475 (hereinafter referred to as the Initial Design). While this Initial Design can achieve predictable and significantly reduce drug loss, while also providing controllable and sufficient drug release and transfer, it suffers from some other issues which make it challenging for use in certain circumstances, as will be discussed below.

Fig. 2 is a drug delivery system 10 provides the unifying concept between the devices of the Initial Design and those of the current invention. The drug delivery system of Fig. 2 comprises a balloon 11 with a therapeutic agent 20 coated on its outer surface 12 (not shown in Fig. 2). 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.

Fig. 3a provides a detailed view of the Initial Design, which device is a drug delivery system for percutaneous transluminal angioplasty and percutaneous transluminal coronary 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. 3a, 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 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 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 balloon 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. 3b 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. 3b 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. 3a 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. 3a. 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.

The design described above is called an design. The balloon catheter of the current invention may also be used in a Rapid Exchange (RX) design. In a conventional OTW design, two lumens (guidewire and inflation) run throughout at least the length of the catheter exposed from the handle (in the current invention's OTW designs, only a guidewire with no lumen is used). In contrast, in an RX catheter, only the inflation lumen runs throughout the length of the catheter exposed from the handle. This is because the guidewire (and the associated guidewire lumen) is introduced through a rapid exchange exit port positioned somewhere between the handle and the balloon. A conventional RX balloon catheter is shown in Fig, 4. Such conventional RX catheters comprise a catheter shaft defining an inflation lumen 51 having a proximal end and a distal end, a balloon 54 having a proximal end and a distal end, an inner shaft defining a guidewire lumen and a hypotube 52. The distal end of the guidewire lumen is joined to the distal end of the inflatable balloon. The inflation lumen is in fluid communication with the inflatable balloon and the hypotube. The distal end of the inflatable balloon is sealed by the proximal end of the catheter tip S3, and the guidewire shaft 56 is coupled only to the catheter tip S3 and the distal end of the inflatable balloon. A guidewire lumen (that houses a guidewire shaft) is bonded to the inflation lumen to form an exit port 55. As disclosed above, the standard balloon catheter contains three basic elements:

1) an inner lumen which having a passage way through which the guidewire can be slideably moved;

2) a balloon which is to open up arteries; and

3) an inflation lumen over the inner lumen which has fluid convection with inflatable balloon. Therefore, the balloon catheter profile of a standard balloon catheter with inflation lumen is basically determined by: the inner lumen; the wall thickness of the inner tube; the gap between the inner tube and inflation tube; the wall thickness of the inflation tube; and the balloon folding profile.

In contrast, the balloon catheter profile of the Initial Design is determined by: the inner lumen; the wall thickness of the inner tube; the gap between the inner tube and the inflation tube; the wall thickness of the inflation tube; the balloon folding profile; the gap between the inflation tube/balloon and the outer sheath; and the outer sheath wall thickness. The wall thickness of the movable outer sheath is usually from 0.003" to 0.005", which leads to a profile increase of from 0.006" to 0.010" (excluding the gap between the balloon/inflation tube and the outer sheath). This means that due to the addition of a movable outer sheath, the profile of the Initial Design DCB catheter is bigger than a conventional DCB catheter. For example, a drug coated balloon may be compatible with one of the 5F (for a 4.0 mm balloon diameter), the 6F (for a 5.0-6.0 mm balloon diameters), and the 7F (for a 7 mm balloon diameter) introducer sheaths. When a drug coated balloon is fitted with an outer sheath as in the Initial Design drug coated balloon catheter, it may be compatible with 6F (for a 4.0-5.0 mm balloon diameter), and 7F (for a 6.0-7.0 mm balloon diameters) introducer sheaths. It is the similar for other balloon diameters, such as for a balloon having a 2-3.5mm balloon diameter. This makes it challenging to use this Initial Design drug coated balloon catheter for some small, tortuous and complicated arteries, as it will be difficult to deliver such a large-profile balloon catheter to a lesion located in such arteries.

It is noted that the purpose of the inner lumen is to create a channel or passage that can be used to slide the balloon catheter into a vessel over the guidewire, making it easy and convenient to insert the balloon catheter. The size of commercial guidewires are standardised and the most commonly used smallest one is 0.014". Therefore, to be compatible with commercially available guidewires, the diameter of the inner lumen of balloon catheter must complement these standardised guidewire sizes and this means that a balloon catheter of the Initial Design, which includes an outer sheath, will prove challenging to use to reach some lesions in small-diameter arteries.

The current invention seeks to solve this problem while maintaining the outer protective sheath. It is believed that the design discussed below can be applied to smaller and complicated lesions, so that a drug can be delivered predictably and in a sufficient amount to the site of the lesion, while causing less trauma to a patient. The present invention overcomes the disadvantages above by:

(1) removal of the inner tube which is used as a guidewire lumen from conventional balloon catheter;

(2) integration of a wire to balloon catheter; and

(3) integration of a moveable outer sheath.

The above design maintains a low profile through removal of the inner tube wall and the inner lumen (i.e. the use of a fixed wire balloon catheter). As will be appreciated, these advantages relate to OTW catheter systems.

The purpose of (1) and (2) is to reduce the profile of the OTW balloon catheter and simplify surgery. The purpose of (3) is to achieve a consistent and efficient drug delivery to the site of the lesion. By removal of the inner tube, the total profile can be reduced 0.008-0.012", which compensates for the increase in profile by inclusion of an outer sheath (i.e. 0.006- 0.008"). There is no real size constraint from the guidewire, as it will be replaced with a fixed wire that is integrated to form a monolithic whole with the balloon catheter. Thus, the profile of the entire device is reduced, making it suitable for use in smaller arteries and/or more complex arteries.

General design features of the Designs of the current invention will now be discussed hereinbelow. It will be appreciated that these features may be generally applicable to both OTW and RX balloon catheters, 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, arlex™ high-density polyethylene, Marlex™ low-density polyethylene, and a linear low density polyethylene such as REXELL™), polypropylene (PP), polyetherimide (PEI), po!ytetrafluoroethylene (PTFE), ethylene tetrafiuoroethylene (ETFE), f!uorinated ethylene propylene (FEP), po!yoxymethylene (POM), po!ybutylene terephthalate (PBT), polyvinylchloride (PVC), po!yether-biock-amide (PEBA, for example, available under the trade name PEBAX™), polyetheretherketone (PEEK), po!yimide (PI), poiyphenylene sulfide (PPS), polyphenylene oxide (PPO), poly(ethylene naphthalenedicarboxylate) (PEN), polysulfone, perfiuoro(propyi vinyl ether) (PFA), or mixtures, combinations, copolymers thereof, and the like. The balloon during use may be cylindrical in shape or have a non-cylindrical shape in its inflated configuration along the whole working length.

The outer sheath 30 (see Fig. 2), is movable relative to the balloon that it 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 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), fluorinated ethylene propylene (FEP), perfluoroalkoxy 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, PU 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. Preferably, a tri-layer tube may include an outer polymer layer, an inner polymer layer and reinforce layer positioned between outer layer and inner layer. The inner layer provides a low coefficient of friction surface to reduce the forces required to deploy the balloon catheter shaft, which significantly helps to prevent drug coating being scratched off. The inner liner may be chosen from PTFE, FEP, PFA, PE, Pebax, polyurethane, and Nylon. Lubricious material 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. Other suitable polymers for inner and outer layer include any suitable material known to those skilled in the art. The middle reinforce layer may be a wire reinforcing layer. The reinforcing layer is preferably made from stainless steel. It may be braided wire or coil wire or both. The proximal region of the reinforcing layer may be made from braided wire and the distal region may be made from coil wire. The configuration of braid layer can be changed to change system performance. This is achieved by changing the pitch of the braid, the shape of the individual braidwires, the number of braidwires, and the braid wire diameter. Additionally, coils could be incorporated into the sheath enhance system flexibility. The material for outer layer may be chosen from but not limited to PE, Pebax, PU and Nylon. The outer sheath can have different material at different part of the sheath. The outer layer can be a series of fused transitions decreasing in material durometer from proximal to distal along outer layer of the sheath. For example, the material in the proximal region may be pebax 72D, while the material in the distal region may be pebax 53D. The inclusion of transitions of varying material durometers can effectively enhance catheter's pushability. This means that the catheter is able to transmit a force applied by the physician at a proximal location on sheath to the distal tip, which aids in navigation across tight stenotic lesions within the vascular anatomy. It also gives the sheath better flexibility at distal region, which makes it easier to reach target artery. The sheath design also gives the sheath better resistance to elongation and necking as a result of tensile loading during sheath retraction. The catheter's performance can be tuned through changing the multilayer structure of the outer sheath. The wall thickness of the outer sheath has to be kept as low as possible, so as to keep the profile of the whole device low.

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 materials used in the catheter shaft, including 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.

A 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. A slot 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 balloon catheter. 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. As will be noted in more detail below, the slotted hypotube does not need to include a Y-shaped segment, as there is no separate guidewire.

Specific embodiments of the OTW Design of the current invention will now be discussed with reference of Figures 5 to 12.

Embodiments of the fixed wire catheter balloon delivery device Design of the current invention may comprise:

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

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

a therapeutic agent coating on a surface of the balloon facing the sheath,

wherein:

When used herein, the term "a second position that exposes at least a portion of the balloon" refers to a position where at least a section of the working portion of the balloon is exposed from the sheath, such that it can inflate and deposit the drug on a lumen. For the avoidance of doubt, the terms "first position" and "second position" are used herein to refer to the intended function of the balloon and are not intended to place any limit on how the balloon is presented for commercial sale. While the balloon may conveniently be fully covered by the sheath in a commercial package for sale, the balloon may also be partly or wholly exposed.

When used herein, the phrase "the sheath is provided in a first position that wholly covers the balloon and is movable relative to the balloon to a second position that exposes at least a portion of the balloon" is intended to cover either the forward movement of the balloon, while keeping the sheath generally stationary or, more particularly, the retraction of the sheath while keeping the balloon generally stationary. In both cases, the sheath moves relative to the balloon.

Figures 5 and 6 depict two drug delivery systems according to the current Design, 1100 and 200, respectively, both comprise a balloon catheter shaft, a tip, a wire, an outer sheath and a handle.

In Fig. 5, drug delivery system 1100 includes a catheter shaft 1150, having proximal end (close to handle 1170) and distal (close to tip 1108) end portions. The device also has an outer sheath 1140 that in a first position that wholly encloses a balloon catheter 1150. The balloon catheter shaft 1150 is composed of a balloon 1130 and an inflation tube 1180. The balloon 1130 has a distal leg 1120 and a proximal leg 1122. The inflation tube 1180 is conjugated at the proximal leg 1122 of the balloon 1130 and is in fluid communication with the inner chamber of the balloon 1130. A fluid may be introduced into the fluid lumen through a luer adaptor 1160 or the like located at the proximal end of the handle 1170. The inflation tube 1180 can supply an inflation medium under positive pressure and can withdraw the inflation medium under negative pressure from the balloon 1130. A therapeutic agent 1155 is coated on the outer surface of balloon 1135. The wire 1110 has four segments as shown in Fig. 5(c). The first segment 1102 is embedded in the inflation tube 1180 as shown in cross- section Fig. 5(a). The proximal portion of the first segment is coterminous with the end of the inflation tube 1180. The middle segment 1106 of wire 1110 is located in the balloon 1130 (e.g. the balloon centre as depicted) and penetrate through the distal tip 1125. Segment 1104 is a connector portion between segment 1102 and segment 1106. The distal segment 1108 is conjugated to the distal leg 1120 of the balloon and extends over a tip 1125. As part of the wire 1110 is embedded within the inflation tube 1180 and part of the wire is irreversibly conjugated to the balloon distal leg 1120, the wire is partially in contact with the inflation medium. As the distal end of the wire is conjugated with the balloon's distal leg 1120, when the outer sheath 1140 is retracted, there is no relative movement between the wire 1110 and the balloon catheter shaft 1150 during navigation of the device. In other words, the balloon catheter described here is a fixed wire balloon catheter.

The luer adaptor 1160 of this embodiment is conjugated to both the proximal end of inflation tube 1180 and the proximal end of hypotube 1195. The hypotube 1195 covers the part of the inflation tube 1180 that is located inside the handle. An actuation member 1145, conjugated with the proximal end of the outer sheath 1140, is surrounds part of hypotube 1195. The actuation member 1195 is configured such that the actuation member 1145 can be shifted together with the outer sheath 1140 along the longitudinal direction of the handle as shown in Figure 7. For example, Figure 7a shows the device with the actuation member 1145 positioned at the initial position. When the distal region of the drug delivery system is positioned at a lesion, the actuation member 1145 can be moved backward (relative to the balloon) by a clinician in order to accomplish proximal retraction of the outer sheath 1140, thereby exposing balloon 1130 to the lesion (shown in Figure 7b). After balloon 1130 is deflated and before drug delivery system 1100 is retracted from the body, the actuation member 1145 can be moved forward by a clinician in order to move outer sheath forward to cover the deflated balloon 1130. The clinician can also retract the drug delivery system directly after balloon deflation. Similar to drug delivery system 1100, system 200 is shown in Figure 6 and is also composed of a balloon catheter shaft 250 comprising a balloon 230 and an inflation tube 280, a tip 225, a wire 210, an outer sheath 240 and a handle 270. The main difference between the balloon catheter of design 1100 and that of design 200 is the wire and inflation tube design. In system 1100, the inflation tube 1180 is a double lumen tube, while in system 200, the inflation tube is a single lumen tube. The wire 210 is in the embodiment of this second design is located at the center of both inflation tube 280 and balloon 230, as shown in cross- section Figure 6. The detailed structure of handle 270 is not shown as it is the same as system 1100 and operates in the same manner as described hereinbefore.

System 3100 is similar to drug delivery system 1100, but the catheter shaft design is different, as shown in Fig. 6b. The balloon catheter shaft 3150 is composed of a balloon 3130 and an inflation tube 3180. The luer adaptor 3160 of this embodiment is conjugated to only the proximal end the hypotube 3195 (not shown in the drawing). The balloon 3130 has a distal leg 3120 and a proximal leg 3122. The inflation tube 3180 is conjugated at the proximal leg 3122 of the balloon 3130 and is conjugated at the distal end of the hypotube 3195. There will be fluid communication with the inner lumen of the hyptobue 3195, inflation tube 3180 and balloon 3130. The proximal end of wire 3110 is conjugated to the distal of hypotube 3195. The distal end of wire 3110 is conjugated with the balloon distal leg 3120. The wire has a tapered shape at its distal portion.

Figures 5 and 6 therefore show different design embodiments of the current invention which differ on how the wire is conjugated to the rest of the DCB system.

One of the purposes of conjugating the wire to the balloon tip is to improve the trackability and torque of the device. In other words, this arrangement enables the device to more easily navigate a vessel, such as small and torturous vasculature associated with lesions of arteries. The wire is composed of a main wire 2215 and a tip 2216 which is located at the distal end of the tip 2215, as shown in Figure 8a.

In general, the main wire 2215 is flexible and may, for example, be constructed of a stainless steel material, such as a grade 304 surgical stainless steel. The wire may have a uniform diameter longitudinally or the wire may include segments having tapered configurations of varying diameters. The tapered diameters of these segments may, for example, be selected to provide a desired degree of wire flexibility. For example, the wire may be thicker at the proximal region and may be thinner at the distal region. The diameter may range from 0.005" to 0.035" along the length of the wire. For example, as shown in Figure 8a, the main wire body may have several tapered segments. The first main body 2201 of the wire embodied in Figure 8a has a diameter D1 and a first tapered segment 2203 that tapers down to a second segment 2205 with diameter D2, and a second tapered segment 2207 that tapers down to a third segment 2209 with diameter D3. The tapered segment 2207 may be located at the distal end of the balloon tip 2225. The third segment 2209 can be the wire core of the wire tip. The wire can only have fewer or more segments with taper regions, which is not shown in the drawings.

The tip of the wire can have several configurations as shown in Figure 8. For example, it can have a bending structure (Figure 8b), or straight tip (Figure 8a) or a straight tip with coil (Figure 8c). It also can be a bending coil structure which is not shown in the drawings. The length of the tip may be from 0.5 to 50cm in length, though it is generally preferably from 1 to 20 cm. The portion located at the balloon region may be covered by a polymer jacket with a very thin wall thickness such as from 0.0005 to 0.005". The polymer jacket may have a constant outer diameter (OD) or an OD with tapered profile that follows the OD of the metal wire. For the coil structure, the ends of coil can be secured at segment 2207 and at the distal segment 2209 respectively. The coil's OD and ID may follow the shape of the inner segment. The coil is like a spring which is able to resume its helical configuration after being deflected. The change of configuration of the wire distal region will change the stiffness of the wire at that region. Thus, the coil design aims to increase the stiffness and improve the trackability of the whole device. A bend may be present as in the wire tip as shown in Figure 8b. The inner bend radius R1 can, for example, be from 0.10 mm to 1.70 mm. The outer bend radius R2 can, for example, be from 0.40 mm 2.10 mm. The bending wire tip feature may be especially suited to traverse a partial or total occlusion of the vessel. If the main wire has a tapered configuration, the inflation lumen may follow the profile of the wire. As shown in Figure 9, the wire 311 has large diameter D4 at proximal segment 312 and a small diameter D5 at distal segment 313, which is inside the inflation tube 380. The inflation tube also has two different segments 381 and 382. The segment 381 also has bigger diameter D6 than that of segment 382, D7.

The wire may also include one or more markers constructed of a radiopaque material, such as gold, platinum, iridium or a combination thereof, such as a platinum-iridium alloy, which can be easily viewed on x-rays. There are two possible ways to achieve this:

(1) the polymer cover jacket may be made from polyamide or heat shrinkage FEP tube, PET tube etc. Marker bands may be swaged over the polymer cover jacket. The rest of the portion of wire can be covered or uncovered; (2) the marker band may be coated directly on the surface of the wire. The inclusion of markers facilitates monitoring the progression of the whole device in a blood vessel; and

(3) the marker band may be swagged directly on the wire.

Example locations for markers are illustrated generally at 2217 and 2218 in FIG. 8a.

The balloon tip, shown in Figure 10a can be made from polyethelyene, Pebax, polyurethane, and Nylon. The distal tip has a tapered shape. The balloon tip is used to:

(1) ensure the crossibility of the device;

(2) prevent drug coating from loss; and

(3) ensure that the torque from proximal can be transfer to the distal tip.

If there is no distal tip or the maximal profile A1 (Figure 10c) is too small, the blood flow will infuse into the outer sheath and flush away part of the drug coating. The profile of tip can fit into the inner lumen of the outer sheath directly. Alternatively, there may be an interlock mechanism between the tip and the outer sheath. As shown in Figure 10b, there is a ring structure with longitudinal ridges present at the distal region of the outer sheath. The shape and the number of the ridges can vary for different designs. The general idea is that the structure on the tip can match with the ridges of the outer sheath and is locked in place (Figure 10c). There is no relative rotational movement between the tip and the other sheath. Since the tip is conjugated with the balloon catheter and the wire, once the proximal portion of the outer sheath is turned during navigation, the whole device can be turned together, including the wire tip. It is very important that the torque can be transferred to the wire tip so the delivery system can be transferred through torturous blood vessels reach the lesion.

The outer sheath is movable relative to the balloon. 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 less than, or equal to the length of the balloon or above. In other words, the balloon can be inflated when it is fully exposed, or when it is only partially exposed. The outer 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 and the outer sheath may be reduced, which can reduce drug loss when the outer sheath 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 deployment sheath may have two different diameters. Additionally, it may be flared at the distal region. This is important if the device's distal region is to be located in a torturous blood vessel. The outer sheath always has some stiffness. When it bends, the edge of the tip will tend to scratch the balloon surface during outer sheath retraction and lead to undesired drug loss, as shown in Figure 11 a. With a flared outer sheath tip, the edge won't contact the balloon even it is in a curvature, as shown in Figure 11 b. The flare percentage of OD may be between 0.1 % to 75%. Further details of materials and layers of outer sheaths that may be used herein (e.g. multilayer sheaths, such as dual layer and trilayer sheaths) is provided hereinbefore. The mechanical properties of the device are not only affected by the materials used in the construction of the outer sheath, but are also affected by the dimension and the design of the outer sheath. For example, the wall thickness of the outer sheath may affect the pushability and the torque of the whole system. The thicker the wall is, the better the pushability and the torque are. On the other hand, the wall thickness will affect the profile of the whole device. As shown in Figure 12, the outer sheath 440 can have two segments 441 and 442 with different outer diameters. Segment 441 with bigger diameter at the proximal end will improve the pushability of the delivery system, while segment 442 with a smaller diameter at the distal end can keep the profile low, which allows the delivery system to have a low distal profile and reach the occlusion and lesion.

As noted above, the general principles and components of the OTW systems discussed above may also be applied to rapid exchange balloon catheter for percutaneous transluminal coronary angioplasty. Thus there is also disclosed a rapid exchange drug delivery catheter balloon device comprising:

an exit port for a guidewire lumen in the balloon catheter shaft spaced apart in the proximal direction from the proximal end of the balloon; a guidewire lumen, where the guidewire lumen runs co-axially through the inflation lumen from a proximal end that extends through the exit port to a distal end that extends through the distal end of the balloon;

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

a therapeutic agent coating on a surface of the balloon facing the sheath,

wherein:

The term "guidewire lumen" is as conventionally defined and provides a lumen for the insertion and removal of a guidewire for use in positioning the catheter balloon system at a desired site of action. Given the presence of a guidewire lumen, the RX balloons disclosed herein may be conventionally sized, as described above.

The term "exit port" as used herein refers to an opening in the inflation lumen that admits the guidewire lumen into the interior of the inflation lumen. As will be appreciated, as the inflation lumen is required to provide a fluid to the balloon to inflate it, the opening in the inflation lumen is sealed by at least the wall of the guidewire lumen by any suitable means, such as bonding. Such arrangements are disclosed in the inserts in Figures 13b and 13c. In some embodiments, the inflation lumen opening may have extension tube that is then bonded together with guidewire lumen's wall to form a fluid-tight seal.

The RX devices disclosed herein which will now be discussed with reference to Figures 13a-c. Fig. 13a and Fig. 13c depict a balloon catheter according to this embodiment, where the balloon has been fully exposed, while Fig. 13b, depicts the same embodiment, but with the balloon covered by a sheath as described hereinabove. Fig. 13a depicts a balloon catheter shaft 610 without the outer sheath, the shaft having a proximal end portion and a distal end portion. The shaft of Fig. 13a also includes an inflation lumen 650, a hypotube connection portion or an extension of inflation lumen 623 (which is optional), a guidewire lumen 620, a guide wire 622 (not shown) a balloon 660 and a hypotube 670. As depicted, the inflation lumen 650 is proximally bonded with hypotube 670 via the hypotube connection portion 623. The hypotube 670 surrounds the hypotube connection portion 623 at its proximal end and the inflation lumen surrounds its distal end, such that only the inflation lumen 650, the hypotube connection portion 623 and the hypotube 670 are in fluid communication with the inner chamber of the expandable balloon 660. As will be appreciated, the hypotube connection portion 623 is entirely optional and may be omitted from the catheter shaft, in which case the hypotube 670 surrounds the inflation lumen 650 at the proximal end thereof, such that only the inflation lumen 650 and the hypotube 670 are in fluid communication with the inner chamber of the expandable balloon 660.

As shown in the inserts of Figs. 13b and 13c, the guidewire lumen 620 extends from the distal end of the balloon 660 to and extends out through an exit port 621 , which is depicted as being located in the inflation lumen 650, but it may equally be located in the hypotube connection portion 623 or the hypotube 670. The exit port 621 is formed by bonding the hypotube connection portion 623, inflation lumen 650 and guidewire lumen 620 together. As will be appreciated, this arrangement means that the inflation lumen 650 surrounds the guidewire lumen 620 that is internally positioned in the catheter shaft 610.

Fig. 13b and Fig. 13c depict a fully-functional delivery system, which in addition to the balloon shaft 610 further includes a handle 630 and an outer sheath 680. The outer sheath 680, has a proximal end attached to an actuation member portion 645 of handle 630 and a distal end that covers the balloon 660 (the outer sheath also covers the inflation lumen and hypotube extending out from the handle). The actuation member 645 is configured to shift the longitudinal position of the catheter shaft member relative to the deployment (or outer) sheath 680. The outer sheath 680 has a longitudinal slot (or opening) 681 that also has a proximal end and a distal end. When the balloon is covered by the outer sheath (as depicted in Fig. 13b), the exit port abuts or is adjacent to the proximal end of the long slot 681. When the balloon is deployed, the actuation member 645 retracts the outer sheath (such that a portion of the outer sheath is retained in the handle), resulting in the movement of the long slot 681 back towards the handle until the exit port 621 abuts the distal end of the long slot, thereby arresting further retraction. The effect of this arrangement is that the guidewire essentially maintains its absolute position while the outer sheath is retracted. As will be appreciated, the long slot may have any suitable size that enables at least the desired portion of the balloon 660 to be uncovered. In particular embodiments, the long slot may be sized so at to allow for the balloon to be fully exposed, while in others it may be sized to only allow a portion of the balloon to be exposed if that is a desired outcome. In the above embodiment, the outer sheath is retracted, while the balloon and guidewire maintain their original positions. It will be appreciated that it is also possible to maintain the original position of the outer sheath, while extending both the guidewire and balloon using actuation member attached to the catheter shaft. Delivery system 700 in Figure 13d and 13e has similar outer and inner shaft design. The difference is that the actuation member 745 is joined to hypotube 735. With guidewire 722 in place, the actuation member 745 can be pushed forward to shift the balloon forward. The guidewire exit from the guidewire lumen extension tube 721 can move forward longitudinally along the slot 781 on the outer sheath 780.

Fluid can be introduced into the fluid lumen through a luer adaptor 640 or the like located at the proximal end of the handle 630 (see Fig. 13b and Fig. 13c). The inflation lumen 650 can supply an inflation medium under positive pressure and can withdraw the inflation medium under negative pressure from the expandable balloon 660. A tip 655 is coupled to the distal end of the expandable balloon 660.

Advantages associated with the current invention's rapid exchange design of balloon catheter include integration:

(a) with a thin moveable outer sheath; and

(b) of narrowing means (e.g. O-rings or narrowing of the lumen) to overcome issues such as bubbles. To get to small and complicated lesions, it is always advantageous to have catheters or delivery systems that are as small as possible. This is so that the devices can reach into smaller vessels, and to cause less trauma to the patient. This is different to traditional drug coated balloon systems which are exclusively delivered by a system that uses a separate guidewire, meaning that drug coated balloons invariably require a guidewire lumen. In the current OTW design, the wire is conjugated to the system (i.e. the wire and the balloon form a monolothic whole), so it is not necessary to include a guidewire lumen. This leads to the advantages of being able to provide a balloon folding profile that is much lower than that provided in the traditional design and, most importantly, enables an outer sheath to be placed over the balloon catheter without affecting balloon catheter's profile.

A hydrophilic coating may partially or fully coat the outer surface of the device, including the wire coil that is extended out. This will facilitate catheter tracking process and improve its pushability. Examples of suitable hydrophilic materials are provided hereinbefore. In the embodiments discussed herein, the 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 balloon and the tip to allow the balloon to be deployed.

It will be appreciated that when the device of the current design 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 Initial Design, for example with reference, but not limited, to the particular embodiments discussed herein. A possible method of treatment or surgery of a subject using balloon according to the current design may comprise the steps of:

(2) a drug delivery system according to Initial Design 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;

(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). This also includes non-vascular applications, such as benign prostatic hyperplasia (BPH), urethral strictures, ureteral strictures, prostate cancer, esophageal strictures, sinus strictures, biliary tract strictures, asthma and chronic obstructive pulmonary disease (COPD).

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 uniformity is well- controlled due to a uniform delivery of drug coating to the lesion, which also significantly enhances drug transfer and uptake.

As there is always gap between the outer sheath and the inflation tube, there is an air column between them. The conventional way to prevent air bubbles entering a blood vessel (and hence prevent an air embolism) would be to use a sterile fluid to flush through the gap so as to evacuate air from the system. As drug is coated on the balloon and is between balloon and outer sheath, the conventional way of flushing the gap with fluid may cause drug loss. Therefore to avoid this issue, a suction mechanism can be attached to the handle of the device in such a way that it is in fluid communication with the relevant gap, which can prevent air bubbles created during application without flushing the gap. As shown in Fig. 14, an inflation tube 520 is located inside an outer sheath 510. There is a rubber o-ring 530 bound to the inner lumen of the outer sheath, which in this example acts as the suction mechanism in combination with the inner lumen and the inflation tube/balloon. Position A refers to the initial position. Position B refers to the withdrawn position. When outer sheath is withdrawn relative to the balloon, the volume of the air trapped inside the system expands and so the pressure within the lumen will suddenly drop. The blood will be pushed into the space between outer sheath and the air will be prevented from infiltrating the delivery system. Component 530 may not be necessary in some cases, as long as there is a tight fit between outer sheath 510 and inner tube 520. In RX devices described herein (e.g. as depicted in Figs. 13a-c), the suction mechanism described above is not applicable because it is not a closed system. However, the closed portions of the outer sheath 680 may still contain air columns and therefore a system is needed to prevent such air bubbles from exiting the outer sheath and entering the bloodstream without flushing the gap between the inflation lumen 650 and the outer sheath. Given this, the inner lumen of the outer sheath can contain one or more areas that are narrower than the rest of the outer sheath's inner diameter to limit the movement of any air column in the other portions of the outer sheath towards the slot. In other words, the outer sheath generally has an inner diameter value X and the narrower areas are narrower by a value Y, such that these narrower areas have a diameter X-Y. Said narrower areas in the inner diameter of the outer sheath may have a diameter that is less than or equal to 0.010" larger than the outer diameter of the inflation lumen 650. Conventional inflation lumens may have an outer diameter of from 0.03" to 0.05". Any suitable means to introduce such narrower sections may be used. For example, o-rings, headings or neck-down portions may be used to reduce the inner diameter of the outer sheath. As will be appreciated, when more than one narrower portion is present in an RX device, any suitable combination of these examples may be used.

Fig. 15a depicts an o-ring system where o-rings 690 are fitted at three positions of the outer sheath 680. As shown an o-ring 690 is fitted adjacent to the outer sheath portion that covers the balloon and two further o-rings 690 are positioned adjacent to the proximal and distal ends of the slot 681. It will be appreciated that an integrated beading may achieve the same effect. Fig. 15b depicts a neck-down system where neck-down portions 695 are fitted at three positions of the outer sheath 680. As shown a neck-down portion 695 is fitted adjacent to the outer sheath portion that covers the balloon and two further neck-down portions 695 are positioned adjacent to the proximal and distal ends of the slot 681. The function of the o- rings 690 or neck-down portions 695 is to separate the gap between the outer sheath and the inflation tube into several small compartments, such that when the outer sheath is retracted, the air column is locked between the outer sheath and the inflation tube by the o- rings 690 or neck-down portions 695 and prevent air bubbles escaping through the slot. The number of o-rings 690 or neck-down portions 695 can be varied from case to case. As will be appreciated, only two narrower areas in the outer sheath may be needed to prevent escape of an air column through the longitudinal opening (i.e. either side of the longitudinal opening).

As will be appreciated, the use of such narrowing areas may also be applied to the OTW systems described herein. In such systems, the narrowing sections may be positioned to prevent the exit of air bubbles by application of the principles discussed above.

Examples

Example 1

Transition loss/navigation loss

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 6b. The outer sheath distal tip is flared as shown in Fig. 11 b.

Device B is a drug delivery device is a normal DEB. No outer sheath is presented.

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 acetonitrile and analysed using UV-spectrometer at 227nm.

· Balloons were inflated to pressure of 12 atm.

• The catheter was delivered to the lesion site. The system was then flushed with an appropriate amount of water. The water was collected and the drug concentration was evaluated. The transition loss or navigation loss is equivalent to the total drug content inside the collected water divided by the total drug dose.

· Three samples were tested for each group.

Results

The transition loss of device A is <5%, while the transition loss of device B is 30-50%. The transition loss of device B is significantly higher than device A. The wide range of transition loss of device B shows that the transition loss is uncontrollable and unpredictable as compared to that of device A.

Example 2

Unsheathing loss

Device C is a drug delivery device prepared similar to Fig 6b. The outer sheath distal tip is straight as shown in Fig. 11a.

Device D is a drug delivery device prepared similar to Fig 6b. The outer sheath distal tip is flared as shown in Fig. 11 b.

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.

· Balloons were inflated to pressure of 12atm.

• The outer sheath was retracted at a curved channel. The system was then flushed with an appropriate amount of water. The water was collected and the drug concentration was evaluated. The unsheathing loss of the drug coating is equivalent to the total drug content inside the water divided by the total drug dose.

· Three samples were tested for each group.

Results

The unsheathing loss of device C is 5-10% and the unsheathing loss of device D is less than 2%. This indicates that the normal tip edge will press against and scratch-off the drug coating in a torturous path, while the flared tip can avoid tip edge contact with the coating. Therefore, the unsheathing loss will be minimized by using a flared tip design.

Claims

1. A rapid exchange drug delivery catheter balloon device comprising:

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

a therapeutic agent coating on a surface of the balloon facing the sheath,

wherein:

2. The device according to Claim 1 , wherein the sheath has an inner lumen with a first inner diameter, where at least one segment of the inner lumen has a second diameter that is smaller than the first diameter.

3. The device according to Claim 2, wherein the second diameter is less than or equal to 0.010" larger than an outer diameter of the inflation lumen.

4. The device according to Claim 2 or Claim 3, wherein each second diameter is independently formed by a neck-down portion or an o-ring bound to the inner lumen.

5. The device according to any one of Claims 2 to 4, wherein two or three segments of the inner sheath lumen have the second diameter, optionally wherein the longitudinal opening has a proximal end and a distal end and one segment is positioned adjacent to each end of the longitudinal opening.

6. The device according to any one of the preceding claims, wherein the balloon material is compliant, semi-compliant or non-compliant (e.g. the balloon material is semi- compliant or non-compliant); and/or

7. The device according to any one of the preceding claims, wherein the therapeutic agent coating comprises a therapeutic agent selected from one or more of the group consisting of an antiproliferative, immunosuppressive, anti-angiogenic, anti-inflammatory, and anti-thrombotic agent.

8. The device according to Claim 7, wherein the therapeutic agent is selected from one or more of the group consisting of paclitaxel, rapamycin, everolimus, zotarolimus, umirolimus, tacrolimus, and pimecrolimus.

9. The device according to Claim 8, wherein the therapeutic agent is selected from one or more of the group consisting of paclitaxel, rapamycin, zotarolimus and umirolimus (e.g. paclitaxel and rapamycin)).

10. The device according to any one of the preceding claims, wherein the therapeutic agent coating further comprises an excipient, selected from one or more of the group consisting of tartaric acid, a sugar, and a sugar alcohol.

11. The device according to Claim 10, wherein the excipient 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, more particularly, xylitol, tartaric acid, and sorbitol.

12. The device according to Claim 10 or Claim 11 , wherein the excipient is 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.

13. The device according to any one of the preceding claims, wherein the balloon catheter shaft has a tip at the distal end of the shaft, where the tip has a proximal end facing towards the shaft and a distal end facing away from the shaft and the distal end of the outer sheath and the proximal end of the tip proximal further comprise an interlock mechanism.

14. The device according to any one of the preceding claims, wherein the distal end of the sheath is flared relative to the rest of the sheath, such that the distal end has an outer diameter that is larger than the rest of the sheath by from 0.1 % to 75%.

15. The device according to any one of the preceding claims, wherein the balloon is partially or fully covered by the therapeutic agent coating layer.

16. The device according to any one of the preceding claims, wherein the distal segment of the wire has a tip and the tip is in front of the distal end of the balloon.

17. Use of a therapeutic agent as defined in Claim 8 or Claim 9 in the preparation of a drug delivery device according to any one of Claims 1 to 16 for the treatment of a disease or condition that causes narrowing or obstruction of a body lumen (e.g. arteries or veins).

18. A drug delivery device according to any one of Claims 1 to 16 for the treatment of a disease or condition that causes narrowing or obstruction of a body lumen (e.g. arteries or veins).

19. A method of treatment or surgery using a drug delivery device according to any one of Claims 1 to 16 to treat a disease or condition that causes narrowing or obstruction of a body lumen (e.g. arteries or veins), optionally wherein the disease or condition is a vascular condition or a non-vascular condition (e.g. prostatic hyperplasia (BPH), urethral strictures, ureteral strictures, prostate cancer, esophageal strictures, sinus strictures, biliary tract strictures, asthma and chronic obstructive pulmonary disease (COPD)).

20. A method of treatment or surgery according to Claim 19, wherein the method comprises the steps of:

(2) a drug delivery system according to any one of Claims 1 to 13 is introduced;

(5) the balloon is deflated; and

21. A fixed wire catheter balloon delivery device comprising:

a wire having a proximal segment and a distal segment;

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

a therapeutic agent coating on a surface of the balloon facing the sheath,

wherein:

22. The device according to Claim 21 , wherein the balloon material is compliant, semi- compliant or non-compliant (e.g. the balloon material is semi-compliant or non-compliant); and/or

23. The device according to Claim 21 or Claim 22, wherein the therapeutic agent coating comprises a therapeutic agent selected from one or more of the group consisting of an antiproliferative, immunosuppressive, anti-angiogenic, anti-inflammatory, and anti-thrombotic agent.

24. The device according to any one of Claims 21 to 23, wherein the therapeutic agent coating further comprises an excipient, selected from one or more of the group consisting of tartaric acid, a sugar, and a sugar alcohol.

25. The device according to any one of Claims 21 to 24, wherein the balloon catheter shaft has a tip at the distal end of the shaft, where the tip has a proximal end facing towards the shaft and a distal end facing away from the shaft and the distal end of the outer sheath and the proximal end of the tip proximal further comprise an interlock mechanism.

26. The device according to any one of Claims 21 to 25, wherein the distal end of the sheath is flared relative to the rest of the sheath, such that the distal end has an outer diameter that is larger than the rest of the sheath by from 0.1 % to 75%.

27. The device according to any one of Claims 21 to 26, wherein the sheath has an inner lumen and further comprises a suction mechanism in contact with said inner lumen to prevent the formation of air bubbles when the device is used, optionally wherein the suction mechanism comprises an o-ring bound to the inner lumen at a proximal position relative to the balloon in the first position.

28. The device according to any one of Claims 21 to 26, wherein the sheath has an inner lumen with a first inner diameter, where at least one segment of the inner lumen has a second diameter that is smaller than the first diameter.

29. Use of a therapeutic agent as defined in Claim 23 in the preparation of a drug delivery device according to any one of Claims 21 to 28 for the treatment of a disease or condition that causes narrowing or obstruction of a body lumen (e.g. arteries or veins).

30. A drug delivery device according to any one of Claims 21 to 29 for the treatment of a disease or condition that causes narrowing or obstruction of a body lumen (e.g. arteries or veins).

31. A method of treatment or surgery using a drug delivery device according to any one of Claims 21 to 28 to treat a disease or condition that causes narrowing or obstruction of a body lumen (e.g. arteries or veins), optionally wherein the disease or condition is a vascular condition or a non-vascular condition (e.g. prostatic hyperplasia (BPH), urethral strictures, ureteral strictures, prostate cancer, esophageal strictures, sinus strictures, biliary tract strictures, asthma and chronic obstructive pulmonary disease (COPD)).

32. A method of treatment or surgery according to Claim 31 , wherein the method comprises the steps of:

(2) a drug delivery system according to any one of Claims 21 to 37 is introduced;

(5) the balloon is deflated; and