Balloon catheter

Abstract

One example of the present disclosure describes a balloon catheter comprising a catheter shaft, a first ballon and a second ballon. The catheter shaft extends from a proximal end to a distal end and has an inflation port and a drug injection port. The first balloon is mounted to the catheter shaft and coupled to the inflation port. The second balloon is mounted to the catheter shaft and surrounds the first balloon. The second balloon is coupled to the drug injection port. A space between the second balloon and the first balloon defines an annular lumen for receiving a drug injected through the drug injection port. The second balloon has a plurality of apertures for allowing the drug to flow out of the second balloon to a treatment site on a patient. The plurality of apertures have a non-uniform arrangement.

Description

Balloon CatheterTechnical Field

[0001] The present disclosure relates to a balloon catheter. Certain examples relate to a balloon catheter for delivering a drug to a treatment site on a blood vessel of a patient.Background

[0002] Angioplasty is a procedure used to widen blocked or narrowed coronary arteries. A balloon catheter may be inserted into the artery and the balloon inflated to widen the artery walls. The inflated balloon squashes fatty deposits (known as a plaque) against the artery wall, enabling blood to flow through the artery more freely once the deflated balloon is removed. In some cases a stent (a mesh tube) is placed on the balloon before inflation, expands with the balloon to contact the artery walls and remains in place after the balloon is removed.

[0003] A relatively new approach is to use a drug coated balloon, which is coated with solid drug particles for treating the artery walls. For example, after the artery walls have been expanded by an inflation balloon, the inflation balloon may be removed and a drug coated balloon inserted and inflated to contact the artery walls. The drug may be an anti-proliferative medication to help prevent restenosis, which is a re-narrowing of the blood vessel after treatment. The balloon may optionally also be coated with an excipient to aid in drug transfer.

[0004] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each of the appended claims.Summary

[0005] A first aspect of the present disclosure provides a balloon catheter comprising: a catheter shaft extending from a proximal end to a distal end, the catheter shaft having an inflation port and a drug injection port; a first balloon mounted to the catheter shaft, the first balloon being coupled to the inflation port; a second balloon mounted to the catheter shaft, the second balloon surrounding the first balloon and being coupled to the drug injection port; a space between the second balloon and the first balloon defining an annular lumen for receiving a drug injected through the drug injection port; wherein the second balloon has a plurality of apertures for allowing the drug to flow out of the second balloon to a treatment site on a patient; and wherein the plurality of apertures having a non-uniform arrangement.

[0006] A second aspect of the present disclosure provides a balloon catheter comprising: a catheter shaft extending from a proximal end to a distal end, the catheter shaft having a drug injection port; a perforated balloon mounted to the catheter shaft and coupled to the drug injection port; the perforated balloon having a plurality of apertures for allowing an injected drug to flow out of the second balloon for delivery to a patient; wherein the plurality of apertures are disturbed in a non-uniform arrangement.

[0007] A third aspect of the present disclosure is a method of using the balloon catheter of the first or second aspects. The method comprises: inserting a distal end of the catheter into a blood vessel of a patient; injecting a fluid drug into the second balloon (or the perforated balloon) and allowing the drug to flow out through the apertures in the second balloon to treat a treatment site of the blood vessel of the patient.

[0008] A fourth aspect of the present disclosure is a balloon catheter comprising: a catheter shaft extending from a proximal end to a distal end, the catheter shaft having an inflation port and a drug injection port;a first balloon mounted to the catheter shaft, the first balloon being coupled to the inflation port;a second balloon mounted to the catheter shaft, the second balloon surrounding the first balloon and being coupled to the drug injection port;a space between the second balloon and the first balloon defining an annular lumen for receiving a drug injected through the drug injection port;wherein the second balloon has a plurality of apertures for allowing the drug to flow out of the second balloon to a treatment site on a patient; andwherein the plurality of apertures having a non-uniform arrangement, the balloon catheter further comprising:(i) a nanoparticulate polymer with a mean diameter of about 1 nm to about 50 nm and formed from a plasma comprising at least one monomer selected from: an alkene, an alkyne, a cycloalkene, a cycloalkyne, and a mixture thereof; or an aggregate comprising two or more of the nanoparticulate polymers, wherein the aggregate has a mean diameter of about 5 nm to about 500 nm; and(ii) a second species.

[0009] In one embodiment of the fourth aspect:the nanoparticulate polymer or aggregate; andthe second species,are disposed on or in at least a portion of the first balloon, the second balloon, or both.

[0010] In a fifth aspect of the present disclosure is a balloon catheter comprising: a catheter shaft extending from a proximal end to a distal end, the catheter shaft having a drug injection port;a perforated balloon mounted to the catheter shaft and coupled to the drug injection port;the perforated balloon having a plurality of apertures for allowing an injected drug to flow out of the second balloon for delivery to a patient;wherein the plurality of apertures are disturbed in a non-uniform arrangement, the balloon catheter further comprising:(i) a nanoparticulate polymer with a mean diameter of about 1 nm to about 50 nm and formed from a plasma comprising at least one monomer selected from: an alkene, an alkyne, a cycloalkene, a cycloalkyne, and a mixture thereof; or an aggregate comprising two or more of the nanoparticulate polymers, wherein the aggregate has a mean diameter of about 5 nm to about 500 nm; and(ii) a second species.

[0011] In one embodiment of the fifth aspect:the nanoparticulate polymer or aggregate; andthe second species,are disposed on or in at least a portion of the perforated balloon.

[0012] In a sixth aspect of the present disclosure is a kit comprising:a balloon catheter of the first or second aspect; anda container comprising a nanoparticulate polymer with a mean diameter of about 1 nm to about 50 nm and formed from a plasma comprising at least one monomer selected from: an alkene, an alkyne, a cycloalkene, a cycloalkyne, and a mixture thereof; or an aggregate comprising two or more of the nanoparticulate polymers, wherein the aggregate has a mean diameter of about 5 nm to about 500 nm.

[0013] In one embodiment of the sixth aspect, the kit further comprises a container comprising at least one second species.

[0014] Also disclosed herein is a kit comprising:a balloon catheter according to the first or second aspect; anda container comprising:(i) a nanoparticulate polymer with a mean diameter of about 1 nm to about 50 nm and formed from a plasma comprising at least one monomer selected from: an alkene, an alkyne, a cycloalkene, a cycloalkyne, and a mixture thereof; or an aggregate comprising two or more of thenanoparticulate polymers, wherein the aggregate has a mean diameter of about 5 nm to about 500 nm; and(ii) at least one second species.

[0015] In certain embodiments, the nanoparticulate polymer or aggregate is employed in two complementary modalities: (i) as a surface functionalization on at least a portion of the first balloon, second balloon (perforated balloon), and / or catheter components to immobilize a second species and enhance tissue retention at the treatment site; and / or (ii) as a dispersed component of the fluid drug injected into the catheter and delivered through the non-uniformly arranged apertures of the second balloon (or perforated balloon). Either modality may be used alone or in combination in a single procedure. In some embodiments only one of the modalities is provided.

[0016] In certain embodiments, the nanoparticulate polymer or aggregate is applied to a substrate, such as a balloon, catheter, or combination thereof, by immersing the substrate in a solution or suspension containing the nanoparticulate polymer or aggregate, with optional agitation and subsequent washing. This process may be carried out without any prior modification or functionalization of the substrate surfaces.

[0017] Further aspects and features of the present disclosure are provided in the following description and the appended claims.Brief Description of Drawings

[0018] Examples of the present disclosure will now be described, by way of nonlimiting example only, with reference to the accompanying drawings, in which:

[0019] Fig. 1 A shows an example of a balloon catheter according to the present disclosure.

[0020] Fig. IB shows the balloon catheter of Fig. 1A from another side.

[0021] Fig. 1C shows a cross section of a catheter shaft and tubes therein according to one example.

[0022] Fig. 2A shows an example of a first balloon inside a second balloon according to an example of the present disclosure;

[0023] Fig. 2B shows a cross section of the first balloon and second balloon according to one example;

[0024] Fig. 3 A is a schematic diagram showing flow of a drug out of the second balloon of the balloon catheter, according to one example;

[0025] Fig. 3B shows an example of a non-uniform arrangement of apertures on the second balloon;

[0026] Fig. 3C shows another example of a non-uniform arrangement of apertures on the second balloon;

[0027] Fig. 3D shows another example of a non-uniform arrangement of apertures on the second balloon;

[0028] Fig. 4A shows an example of fluid flow out of three sections of the second balloon;

[0029] Fig. 4B shows another example of a non-uniform arrangement of apertures on the second balloon; and

[0030] Fig. 5 show an example of a method of using a balloon catheter according to the present disclosure;Description of Embodiments

[0031] Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. The terms "includes" means includes but not limited to, the term "including" means including but not limited to. The term "based on" means based at least in part on. The term "number" means any natural number equal to or greater than one. The terms "a" and "an" are intended to denote at least one of a particular element.

[0032] The present application proposes a balloon catheter having a perforated balloon with a plurality of apertures for allowing a drug injected into the balloon to flow out of the plurality of apertures to treat the blood vessel walls.

[0033] Fig. 1 A and Fig. IB are schematic diagrams illustrating an example balloon catheter 100 according to the present disclosure. The balloon catheter 100 comprises a catheter shaft 110 extending from a proximal end 112 to a distal end 114. The catheter shaft 110 has an inflation port 122 and a drug injection port 130. A first balloon 140 is mounted to the catheter shaft 110 and a second balloon 150 is mounted to the catheter shaft in a position such that the second balloon 150 surrounds the first balloon 140.

[0034] The first balloon 140 is coupled to the inflation port 122 and may be referred to as an inflation balloon or an inner balloon. In this context “coupled to” means is in fluid communication with, so the first balloon may be radially inflated by injection of an inflation fluid (such as air, pressurised gas or water) via the inflation port. The second ballon 150 is coupled to the drug injection port 130 and may be referred to as a drug delivery ballon or an outer balloon. The second balloon 150 is perforated and has a plurality of apertures 152 for delivering a drug to a patient. The first and second balloons are shown in more detail in Fig. 2.

[0035] The distal end 114 of the catheter shaft may be tapered to a narrow tip. In some examples, the proximal end of the catheter shaft may comprise a manifold 120, which comprises the inflation port 122 and an aspiration port 124. The aspiration port 124 provides the option to remove excess fluid (e.g. drug solution) by aspiration (sucking) through the aspiration port. In the illustrated example, the inflation port 122 is a side port, while the aspiration port 124 is co-axial with the catheter shaft 110. The drug injection port 130 may communicate with the catheter shaft via a three-way valve, such as a three-way stop cock 132. The three-way valve may have a first opening coupled to the inflation port, a second opening coupled to the drug injection port and a third opening coupled to the catheter shaft on the distal side of the three way valve. The three way valve may be movable between a first position allowing fluid to flow from the injection port 122 to distal portion of the catheter shaft, a second position allowing fluid to flow from the drug injection port 130 to the distal portion of the catheter shaft and a third position allowing fluid to flow from the injection port 122 (or the aspiration port 124) to the drug injection port 130 or vice versa.

[0036] The catheter shaft 110 may be fairly long for example 30-45 cm and so only the proximal and distal portions are shown in Fig. 1 A and Fig. IB, while the middle section is indicated by the broken lines.

[0037] Fig. 2A shows the first balloon 140 and the second balloon 150 in greater detail. The first balloon 1540 is an inflation balloon and configured to receive an inflation fluid from the inflation port via the catheter shaft.

[0038] For example, the inflation fluid may be received at the proximal end 142 of the first balloon and the distal end 144 of the first balloon 140 may be sealed. In other examples the inflation fluid may delivered and / or aspirated at an intermediate location between the proximal and distal ends 142, 144 and both ends may be sealed. The first balloon 140 expands radially when the inflation fluid is delivered from the inflation port.

[0039] The first balloon 140 is contained inside the second balloon 150. Thus, when the first balloon inflates and expands radially this may cause the second ballon 150 to expand radially. The first balloon 140 may be inflated in order urge the second balloon 150 against the inner surfaces of an artery or blood vessel into which the catheter has been inserted. For instance, the catheter may be positioned so that the first balloon and second balloon are at a treatment site, such as the location of a plaque or stenosis and the first and second balloon may then be expanded by injecting the inflation fluid via the inflation port. In this way the second balloon may be brought close to or into contact with a treatment site or the walls of the blood vessel, which makes treatment by a drug released from the second balloon more effective.

[0040] The first and second balloon may be made from the same material or different materials. The first and second ballons are drug eluting ballons which are designed to inflate to contact the inner surfaces of the blood vessel so as to deliver the drug to the blood vessel walls. The balloon material for drug eluting ballons should be relatively compliant so as to conform well to the blood vessel walls. This is contrast to balloons which are intended to expand the blood vessel or artery and are relatively stiffer.Therefore the first and second balloons may be more compliant (as measured in change in balloon diameter per atmosphere of inflation pressure) compared to balloons which are intended to dilate the blood vessel. The first and second balloons may for example be made from Nylon, PET, HDPE, polyurethanes, PVC or silicone. In some examples, the catheter may have a separate balloon (not shown) which may be inflated to expand the blood vessel before or after the first and second balloon have delivered the drug to the blood vessel walls.

[0041] Referring to Fig. 2B, as the first balloon 140 and second balloon 150 are separate, a space 146 between the first balloon 140 and the second balloon 150 defines an annular lumen between an outer surface of the first ballon and an inner surface of the second balloon. This annular space 142 may receive a drug injected through the drug injection port 130. In some examples the first balloon 140 and second balloon 150 may initially be in contact with each other, but then separate to define the annular space 146 when the drug is injected.

[0042] In the context of this application, the term “drug” means any fluid comprising a medically effective agent that may be injected through the drug injection port. In some examples, the drug may be an anti -proliferative medication to help prevent restenosis. In some examples, the drug may be a drug to reduce inflammation, enhance endothelial growth or inhibit thrombosis in addition to or instead of preventing restenosis. The injected drug may further comprise an excipient to aid in drug transfer. In some examples, the term ‘drug’ encompasses a fluid comprising a nanoparticulate polymer or aggregate as described herein, optionally conjugated to one or more second species (e.g., pharmaceutical drugs, imaging agents, diagnostic markers), formulated as a dispersion or suspension suitable for delivery through the balloon apertures.

[0043] The second balloon 150 is a perforated balloon and comprises a plurality of apertures 152 through which the injected drug may flow out of the annular space 146 and onto the treatment site. The apertures thus allow the drug to flow out of the second balloon 150 to a treatment site on a patient. Fig. 3 A is a cross sectional view showing a portion of the catheter shaft 110 and the inflated first and second balloons 140, 150 inside a blood vessel 300. The arrows 310 show the drug being ejected through the apertures 152 in the second balloon and onto the walls of the blood vessel 300.

[0044] As shown in Fig. 2A, the second balloon 150 may be sealed at a distal end of the second balloon by an aspiration port 160. The aspiration port 160 may be openable to eject excess drug from the second balloon. For example, the aspiration port may be opened after a desired quantity of drug has been released through the apertures 152.

[0045] The ports may be coupled to the balloons by one or more tubes in the catheter shaft. As shown in Fig. 1C, the inflation port 122 may be coupled to the first balloon 140 by a first tube 180 within the catheter shaft 110, wherein the tube 180 defines an inflation lumen 182 for inflating the first balloon. The space between the second balloon and the first balloon may be coupled to the drug injection port by a second tube 190 within the catheter shaft which defines a drug delivery lumen 192 for delivering a drug to the second balloon. The catheter shaft 110 may further comprise or enclose a third tube 170 defining a guidewire lumen 172 for receiving a guidewire. The third tube170 may extend through the first and second balloons 140, 150 as shown in Figs. 2A and 2B.

[0046] The plurality of apertures 152 of the second balloon 150 have a non-uniform arrangement. By non-uniform arrangement it is meant that the distribution of the apertures and / or the size of the apertures varies along the length of the second balloon.

[0047] The non-uniform arrangement of the plurality of apertures may be such as to promote a desired distribution of the drug outflow along the length of the second balloon. For example the non-uniform arrangement may configured to provide a relatively even outflow of the drug along the length of the second balloon.

[0048] By relatively even outflow it is meant that when a main body of the balloon is split into three nominal sections of substantially even length, a standard deviation in the volume of drug effused by each section is no more than 11% of the total volume of drug effused. In some examples the arrangement may be such that he standard deviation is 10% or less, 8% or less, 6% or less or 5% or less than the total volume effused by the balloon. In some examples the non-uniform arrangement may be such that a standard deviation in egress rate (measured in ml / minute) per 5mm length section of the balloon is 11% or less, 10% or less, 8% or less, 6% or less, or 5% or less of the effusion rate by the balloon as a whole.

[0049] In contrast if the apertures are uniformly distributed and of the same size, this may result in greater egress of the drug at the proximal end of the second balloon compared to the distal end. The non-uniform arrangement of apertures may help to even out the egress to achieve a more even effusion along the length of the balloon. In this way the whole target area can be treated more effectively.

[0050] Figs. 3B to 3D show various examples of non-uniform arrangement of apertures. In these Figures the left side is the proximal end of the balloon and the right side is the distal end of the balloon. The main body of the balloon is indicated by reference numeral 150B and may have a substantially (e.g. within 20%) constantradius. On the proximal side and distal side of the main body there are respective tapered sections 150A and 150C which gradually reduce in radius to join with the catheter shaft 110.

[0051] In Fig. 3B, the second balloon 150 has a helical arrangement of apertures 152A, 152B. The helical pitch may vary along the length of the balloon. In the illustrated example, a first section 154A of the main body towards the proximal end of the balloon has apertures 152A with a first helical pitch (e.g. 5mm), while a second section 154B of the main body towards the distal end of the balloon has apertures 152B with a second helical pitch (e.g. 2.5mm), which is less than the first helical pitch. As a result there is a greater density of apertures (number of apertures per unit length) in the second section 154B than in the first section 154A.

[0052] While Fig 3B shows just two sections it is possible to have 3 or more sections, at least some of which have different helical pitches. Generally stated the apertures may have a helical arrangement and the helical pitch may vary along the length of the balloon. When the helical pitch varies, the density of apertures (number of apertures per unit length) will also vary along the length of the balloon. As the number of apertures per unit length varies, the total aperture area per unit length will also vary, in the case that the apertures have the same diameter (or area). The outflow from each section is influenced by the total aperture area of the section in question.

[0053] For a given longitudinal position (in the direction proximal to distal), a section with a greater total aperture area will have a greater outflow. However, as the outflow will generally be greater near the point of injection of the fluid drug into the balloon (usually injection is at the proximal end), the outflow has a tendency to gradually reduce at locations further away from the point of injection. Thus, by varying the total aperture area it is possible to counteract this tendency and provide a more even effusion along the length of the balloon.

[0054] Fig. 3C shows another example of a non-uniform arrangement of apertures. In this example, the apertures are arranged in a series of longitudinally spaced circularrings around the balloon. For example, each ring may comprise 6 apertures spaced around 360 degrees of the balloon circumference. The apertures in each ring may be evenly spaced.

[0055] Each ring may be equally longitudinally spaced from the adjacent rings. The main body of the balloon may be split into sections, with each section having the same number of rings. In the example of Fig. 3C the many body of the balloon is split into a proximal section 254, a middle section 254B and a distal section 254C, with each section having the same number of rings (e.g. 6 rings). The density of apertures (number of apertures per unit length) in each section is thus equal. However, the apertures in each section may have different sizes (i.e. different diameters and therefore different areas). In the illustrated example, the apertures 252C in the third section 254C are larger (e.g. diameter of 25pm), than the apertures 252B in the second section 254B (e.g. diameter of 20pm), and the apertures in the second section are larger than the apertures 252A in the first section 254A (e.g. diameter of 15pm).

[0056] As the distribution of the apertures is the same, but the size of the apertures is different, the total aperture area in each section is different. In the illustrated example the total aperture area in the third section 254C will be larger than the total aperture area in the second section 254B, which in turn is larger than the total aperture area in the first section 254A.

[0057] In other examples, the aperture density in each section could be varied by varying the number of rings per section (e.g. varying the spacing between adjacent rings in the longitudinal direction).

[0058] Fig. 3D shows an example of a non-uniform arrangement of apertures in which the apertures are arranged in a plurality of rings, similar to Fig. 3C. The size of the apertures may be the same. However, the number of apertures 352 A per ring in a first section 354A towards the proximal end is fewer (e.g. 6 apertures around the 360 degrees) compared to the number of apertures 352B per ring in a second section 354B towards the distal end (e.g. 12 apertures around the 360 degrees). The aperture density,or number of apertures per unit length, is thus greater in the second section 354B than the first section 354A. As the sections are the same length, the total aperture area is greater in the second section 354B than in the first section 354 A. The aperture area density (which is the aperture area per unit longitudinal length) is also greater in the second section than the first section.

[0059] It will be appreciated that Figs. 3B to 3D are just examples and other non-uniform arrangements of apertures are possible. In general terms, some non-limiting examples of ways in which the aperture area density may be varied along the length of the balloon are by varying a helical pitch of the apertures (if the apertures have a helical arrangement), varying a longitudinal spacing of the apertures (i.e. varying the longitudinal separation between adjacent apertures), varying a number of apertures around a circumference of the balloon (e.g. varying the number of apertures in a ring, where there are a plurality of spaced apart rings of apertures), varying a size of the apertures (e.g. varying the aperture diameter) or any combination of these approaches.

[0060] The second balloon may be split into a plurality of longitudinal sections, which may have the same or different lengths. The arrangement of apertures may be such that the standard deviation of effusion volume by the sections is not more than 11% of the total effusion volume, or not more than 10%, 8%, 6% or 5% in some examples. Each section may have a different arrangement of apertures compared to the adjacent section or sections. In some examples the second balloon may be split into three sections. In some examples the middle section may be not more than 50% of the length of the main body of the balloon. In some examples the three sections may be of equal length.

[0061] In some examples a total aperture area per unit length (aperture density) varies along the length of the second balloon. For example, the total aperture per unit length may vary between the different sections or parts of the second balloon. In some examples the total aperture area per unit length increases in the distal direction over at least a portion of the length of the second balloon. In some examples a total aperture area per unit length of the second balloon is greater at a distal end of the second balloonthan at a proximal end of the second balloon. In some examples, the total aperture area per unit length may be greater in a middle section than the distal and proximal sections.

[0062] In some examples the non-uniform arrangement may comprises apertures of a plurality of different sizes. In some examples the apertures may have different sizes (e.g. different diameters) in different sections of the balloon. In some examples the apertures may increase in size in the distal direction over at least a portion of the length of the second balloon. In some examples the aperture size is greater at a distal end of the second balloon than at a proximal end of the second balloon. In some examples, the aperture size may be greater in a middle section than the distal and proximal sections.

[0063] In some examples, the apertures have a diameter of 0.5mm or less. In some examples the apertures have a diameter of 0.25mm or less. In some examples the aperture have a diameter of 0.125mm. In some examples the drug comprises a fluid including drug nanoparticles having a diameter of 500nm in solution.

[0064] In some examples a longitudinal separation between adjacent apertures varies along the length of the second balloon. For example, longitudinal separation between adjacent apertures may vary between the different sections or parts of the second balloon. In some examples the longitudinal separation between adjacent apertures decreases in the distal direction over at least a portion of the length of the second balloon. In some examples a longitudinal separation between adjacent apertures of the second balloon is greater at a proximal end of the second balloon than at a distal end of the second balloon. In some examples, the longitudinal separation between adjacent apertures may be greater in the distal and proximal sections compared to the middle section.

[0065] In some examples a number of apertures around a circumference of the second balloon varies along the length of the second balloon. For example, the a number of apertures around a circumference may vary between the different sections of the second balloon. In some examples the a number of apertures around a circumference increases in the distal direction over at least a portion of the length of the second balloon. Insome examples a number of apertures around a circumference of the second balloon is greater at a distal end of the second balloon than at a proximal end of the second balloon. In some examples, a number of apertures around a circumference may be greater in a middle section than the distal and proximal sections.

[0066] Fig. 4A shows an example of the second balloon 400 in which the main body of the balloon of length L comprises a proximal section 454A, a middle section 454B and a distal section 454C. As shown by arrow 410, a volume X of fluid drug is injected into the second balloon. The arrangement of apertures (not shown) is such that the volume of drug effused (flowing out from) each of the proximal, middle and distal sections 454A, 454B, 454C is approximately the same, i.e. X / 3.

[0067] While in Fig. 4A each of the sections 454A, 454B, 454C has the same length, in other examples they may have different lengths. In some examples the middle section may have a length of not more than 50% of the total length of the main body (e.g. with 25% length for the proximal and distal sections). In this case, more fluid may flow from the section with the longer length but the volume effused per unit length may be approximately the same for each section.

[0068] In order to achieve a relatively even outflow between the sections, the arrangement of aperture may be such that at least one of the proximal section, middle section and distal section has a different total aperture area density compared to at least one of the other two sections. In some examples the middle section has a greater aperture area density (aperture area per unit length) compared to the proximal and distal sections. Where the sections have the same lengths, the middle section may have a greater total aperture area than the proximal section and the distal section.

[0069] Fig. 4B shows an example non-uniform distribution of apertures in which the middle section 454B has a greater aperture area density than the proximal section 454A and distal section 454C. The apertures are arranged in longitudinally spaced apart rings around the circumference of the balloon. The aperture rings in distal and proximal sections 454A, 454C have a smaller number of apertures around the circumference (e.g.6 apertures for each ring), compared to the aperture rings in the middle section 454B (e.g. 12 apertures for each ring). Therefore the aperture area density in the middle section is greater than the aperture area density in the proximal or distal sections.

[0070] It will be understood that variations on the above approach are possible. For instance, while in Fig. 4B each of the sections 454A, 454B, 454C has the same length, in other examples they may have different lengths. Further, while the aperture area density in Fig. 4B is varied by varying the number of apertures around the circumference, in other examples the aperture area density could be varied by varying the aperture size, varying a helical pitch of the apertures, varying a longitudinal spacing of the apertures, varying a number of apertures per unit length of the section etc or any combination thereof.

[0071] While the above examples have both a drug dispending balloon and an inflation balloon inside the drug dispensing balloon, in other examples there may be a drug dispensing balloon without an inflation balloon inside. For example, the catheter may have a single drug dispensing ballon or multiple drug dispensing balloons, without a separate inflation balloon.

[0072] According to one example, there is a balloon catheter comprising a catheter shaft extending from a proximal end to a distal end, the catheter shaft having a drug injection port, and a perforated balloon mounted to the catheter shaft and coupled to the drug injection port. The perforated balloon is a drug dispensing balloon having a plurality of apertures for allowing an injected drug to flow out of the second balloon for delivery to a patient. The plurality of apertures may have a non-uniform arrangement. The non-uniform arrangement may be in accordance with any of the examples discussed above. The non-uniform arrangement may be arranged to promote a desired distribution of the drug along the length of the second balloon. For instance a relatively even outflow between different sections of the second balloon.

[0073] Another example, has the features mentioned above and in addition a separate inflation balloon within the perforated balloon, the inflation balloon being coupled toan inflation port of the catheter shaft and inflatable to push the perforated balloon into contact with a blood vessel wall of the patient, a space between the perforated balloon and the inflation balloon defining an annular lumen for receiving a drug injected into the catheter shaft via the drug injection port.

[0074] Fig. 5 shows a method 500 of using any of the balloon catheters described herein.

[0075] At block 410 a distal end of the catheter is inserted into a blood vessel of a patient.

[0076] At block 520 a fluid drug is injected into the second balloon (or the perforated balloon in the case of a single balloon catheter).

[0077] At block 530 the fluid drug flows out through the apertures of the second balloon (or perforated balloon) to treat a treatment site of the blood vessel of the patient.

[0078] In some examples, the method may comprise inflating the first balloon (an inflation balloon) to push the second balloon (a perforated or drug dispensing balloon) into contact with walls of the blood vessel of the patient at the treatment site and then injecting the fluid drug into the second balloon (or the perforated balloon).

[0079] In some examples, the fluid drug may be delivered without nanoparticles. In other examples nanoparticles may be used to assist delivery of the drug to the treatment site. In certain embodiments, a nanoparticulate polymer or aggregate is applied to a substrate, such as a balloon, catheter, or combination thereof, by simply immersing the substrate in a solution or suspension containing the nanoparticulate polymer or aggregate. The substrate may be agitated in the solution, for example overnight, and subsequently washed to remove unbound material. Examples of agitation may include stirring and / or sonication for a period of timer. In other examples the injected fluid drug may comprise a nanoparticulate polymer or aggregate(optionally bearing one or more second species), thereby delivering nanoparticulate carriers through the apertures to the treatment site. In some examples, at least a portion of the balloon or catheter surfaces may be pre-coated with a nanoparticulate polymer or aggregate (optionally bearing one or more second species) prior to insertion.

[0080] A nanoparticulate material, as described herein, may be applied in any suitable concentration. For example, the concentration of the nanoparticulate polymer or aggregate (optionally bearing one or more second species), may range from IxlO9-IxlO11nanoparticulate polymer or aggregate or conjugate / mL. Suitably, the concentration of the nanoparticulate polymer or aggregate (optionally bearing one or more second species), may be about IxlO9, about lx 1010or about IxlO11per mL.

[0081] The attachment of the nanoparticulate polymer or aggregate (optionally bearing one or more second species), to a substrate, such as a balloon, catheter, or combination thereof, may be undertaken at an appropriate temperature and / or pH. For example at a temperature that would not denature of affect the chemical, physical and / or biological properties of the nanoparticulate polymer, aggregate and / or one or more second species. Exemplary temperatures include (in °C) about or at least about: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or in a range of any two of these values. Exemplary pH values includes about, or at least about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or in a range of any two of these values. The period of time that the nanoparticulate polymer or aggregate (optionally bearing one or more second species), is exposed to the substrate, such as a balloon, catheter, or combination thereof, to facilitate binding, may be dependent on a number of factors, including, but not limited to: the specific substrate, concentration of nanoparticulate polymer or aggregate and / or the type and / or number of one or more second species that may be optionally present. Exemplary period of time that may be used to facilitate binding may be a time period (in hours), of about or at least about: 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or in a range of any two of these values.Nanoparticles

[0082] Disclosed herein is a balloon catheter comprising:a catheter shaft extending from a proximal end to a distal end, the catheter shaft having an inflation port and a drug injection port;a first balloon mounted to the catheter shaft, the first balloon being coupled to the inflation port;a second balloon mounted to the catheter shaft, the second balloon surrounding the first balloon and being coupled to the drug injection port;a space between the second balloon and the first balloon defining an annular lumen for receiving a drug injected through the drug injection port;wherein the second balloon has a plurality of apertures for allowing the drug to flow out of the second balloon to a treatment site on a patient; andwherein the plurality of apertures having a non-uniform arrangement, the balloon catheter further comprising:(i) a nanoparticulate polymer with a mean diameter of about 1 nm to about 50 nm and formed from a plasma comprising at least one monomer selected from: an alkene, an alkyne, a cycloalkene, a cycloalkyne, and a mixture thereof; or an aggregate comprising two or more of the nanoparticulate polymers, wherein the aggregate has a mean diameter of about 5 nm to about 500 nm; and(ii) a second species.

[0083] In one embodiment:the nanoparticulate polymer or aggregate; andthe second species,are disposed on or in at least a portion of the first balloon, the second balloon, or both.

[0084] Also disclosed herein is a balloon catheter comprising:a catheter shaft extending from a proximal end to a distal end, the catheter shaft having a drug injection port;a perforated balloon mounted to the catheter shaft and coupled to the drug injection port;the perforated balloon having a plurality of apertures for allowing an injected drug to flow out of the second balloon for delivery to a patient;wherein the plurality of apertures are disturbed in a non-uniform arrangement, the balloon catheter further comprising:(i) a nanoparticulate polymer with a mean diameter of about 1 nm to about 50 nm and formed from a plasma comprising at least one monomer selected from: an alkene, an alkyne, a cycloalkene, a cycloalkyne, and a mixture thereof; or an aggregate comprising two or more of the nanoparticulate polymers, wherein the aggregate has a mean diameter of about 5 nm to about 500 nm; and(ii) a second species.

[0085] In one embodiment:the nanoparticulate polymer or aggregate; andthe second species,are disposed on or in at least a portion of the perforated balloon.

[0086] Also disclosed herein is a kit comprising:a balloon catheter as described herein; anda container comprising a nanoparticulate polymer with a mean diameter of about 1 nm to about 50 nm and formed from a plasma comprising at least one monomer selected from: an alkene, an alkyne, a cycloalkene, a cycloalkyne, and a mixture thereof; or an aggregate comprising two or more of the nanoparticulate polymers, wherein the aggregate has a mean diameter of about 5 nm to about 500 nm.

[0087] In one embodiment, the kit further comprises a container comprising at least one second species.

[0088] Also disclosed herein is a kit comprising:a balloon catheter as described herein; anda container comprising:(i) a nanoparticulate polymer with a mean diameter of about 1 nm to about 50 nm and formed from a plasma comprising at least one monomer selected from: an alkene, an alkyne, a cycloalkene, a cycloalkyne, and a mixture thereof; or an aggregate comprising two or more of the nanoparticulate polymers, wherein the aggregate has a mean diameter of about 5 nm to about 500 nm; and(ii) at least one second species.

[0089] The nanoparticles may be any nanoparticles described in WO2018 / 112543, (referred to as “nanoP3”, “NanoP3”, “nanoP3 material”, “NanoP3 material”, “NP3”, “PPN” or “nanoparticulate”) the entire content of which is incorporated herein by reference, in its entirety.

[0090] The nanoparticles disclosed herein may be produced by any means known in the art. Specific methods to produce such nanoparticles are described, for example, in WO2018 / 112543.

[0091] The nanoparticles disclosed herein can act as a class of versatile and multifunctional nanocarriers which may be readily functionalised. The nanoparticulate material can be conjugated to a large range of biomolecules and drugs through reaction with radicals embedded within the nanoparticulate material which diffuse to the surface of the nanoparticulate material and / or by reaction with moieties / functional groups formed on the surface of the nanoparticulate material, or conjugates thereof.

[0092] Accordingly, the nanoparticulate polymer or aggregate may be (a) applied to the balloon and / or catheter surface(s) before use, for example by dipping or immersing, thereby presenting the nanoparticulate polymer or aggregate at the tissue interface when the balloon or catheter surface is adjacent the treatment site (e.g. upon balloon apposition); and / or (b) suspended in the fluid drug introduced via the catheter, such that the nanoparticulate polymer or aggregate effuses through the apertures to the treatment site.. In certain embodiments, a nanoparticulate polymer or aggregate may applied to asubstrate, such as a balloon, catheter, or combination thereof, by simply immersing the substrate in a solution or suspension containing the nanoparticulate polymer or aggregate. The substrate may be agitated in the solution, for example overnight, and subsequently washed to remove unbound material.

[0093] As used herein, the term “nanoparticle” may be used interchangeably with “nanoparticulate polymer”, “nanoparticulate material”, “PPN” or “plasma polymerized nanoparticle”. Such terms refer to a nanoparticulate material having a size less than 100 micron unless otherwise specified or clear from the context in which it is used. For example, the nanoparticulate polymer may have a size of between about 1 to 50, 50 to 500, 100 to 500, 200 to 500, 5 to 200, 5 to 100, 5 to 50, 5 to 20, 20 to 100, 100 to 300 or 200 to 400 nm, e.g., about, or at least about 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 nm, or in a range of about 1 to about 50 nm, about 5 to about 400 nm, or about 5 to about 300 nm, or about 5 to about 200 nm, or about 5 to about 100 nm, or about 50 to about 100 nm, or about 100 to about 500 nm, or about 150 to about 500 nm, or about 180 nm to about 500 nm, or about 100 to about 400 nm, or about 150 to about 400 nm, or about 180 to about 400 nm, or about 100 to about 300 nm, or about 150 to 300 nm, or about 180 to 300 nm, or about 100 to about 200 nm, or about 150 to about 200 nm, or about 180 to about 200 nm, or about 150 to about 250 nm, or about 180 to about 250 nm, or about 200 to about 400 nm, or about 200 nm to about 300 nm, or a mixture thereof. Suitably, the nanoparticulate polymer is about 200 nm, or the nanoparticulate polymer is between about 1 to about 50 nm, or between about 50 to about 100 nm. It will be appreciated that the sizes described herein refer to diameters or average diameters of the nanoparticulate material.

[0094] The terms “nanoparticulate polymer” or “plasma polymerized nanoparticle” encompass both “nanoparticulate polymers” and “aggregates” as defined herein unless otherwise specified or clear from the context in which it is used. Thus, for example, the sizes described above apply equally to the nanoparticles or aggregates of nanoparticles. Suitably, the nanoparticulate polymer comprises a plasma polymer. The plasma polymer may be formed by the condensation of fragments in a plasma, said materialbeing capable of covalently coupling one or more compounds, for example one or more agents, including organic or organometallic species.

[0095] As used herein, the term “polymer” refers to a chemical compound or mixture of compounds consisting of repeating structural units that may be heterogeneous and / or arranged into a disordered structure, created through a process of polymerization.Suitable polymers useful in this disclosure are described throughout. Suitably, the polymer is a plasma polymer in which the repeating units are assembled into a relatively disordered structure.

[0096] A nanoparticle, nanoparticulate polymer, PPN, plasma polymerized nanoparticle, and / or polymer, as described herein, may comprise or consist of a polymer as shown in Formula (I):Formula (I)

[0097] wherein R1-R9 are independently selected from: H, OH, carbonyl (=0), amine, imine or nitrile, or molecular groups which bind with other structures of Formula I, each molecular group independently selected from (C1-10) alkylene-, (C1-5) alkylene-, (Ce-io) cycloalkylen-(Ci-io) alkylene-, or (Ce-io) cycloalkylen-(Ci-s) alkylene-, and wherein the alkylene groups can be saturated or have one or more carbon-carbon double bonds, wherein the cycloalkylene groups may have one or more carbon-carbon double bonds, and wherein one or more carbon atoms of the alkylene and cycloalkylene chains can be substituted by a -O- bridge or by -OH.

[0098] As used herein, the term "alkylene" refers to a straight or branched chain divalent saturated hydrocarbon radical having, for example, from one to ten carbon atoms, which may be optionally substituted as herein further described (e.g. with one ormore of OH, carbonyl (=0), amine, imine or nitrile), with multiple degrees of substitution being allowed. Examples of "alkylene" as used herein include, but are not limited to, optionally substituted, methylene, ethylene, n-propylene, 1 -methylethylene, 2- methylethylene, dimethylmethylene, n-butylene, 1-methyl-n-propylene, and 2-methy 1 -n-propy 1 ene .

[0099] The number of carbon atoms in an alkylene group is represented by the phrase "Cx-y alkylene," which refers to an alkylene group, as herein defined, containing from x to y, inclusive, carbon atoms. Similar terminology will apply for other terms and ranges as well. Thus, Ci-salkylene represents an alkylene chain having from 1 to 5 carbons atoms, and, for example, includes, but is not limited to, methylene, ethylene, n-propylene, 1 -methylethylene, 2-methylethylene, 5 dimethylmethylene, n-butylene, 1-methyl-n-propylene, and 2-methyl-n-propylene.

[0100] Herein, "cycloalkylen" denotes a divalent saturated carbocyclic ring having, for example 6 to 10 carbon atoms. One or more cycloalkylen groups may be optionally substituted as herein further described (e.g. with one or more of OH, carbonyl (=0), amine, imine or nitrile). The number of carbon atoms in a cycloalkylen group will be represented by the phrase "Cx-y cycloalkylen," which refers to a cycloalkyl group, as herein defined, containing from x to y, inclusive, carbon atoms. Similar terminology will apply for other terms and ranges as well. Thus, Ce-io cycloalkylen represents a cycloalkylen group having from 6 to 10 carbons as described above

[0101] In one embodiment at least one of Ri, R2, R3, R4, R5, Re, R7, Rs, R9, or a mixture thereof, is H, OH, carbonyl (=0), amine, imine or nitrile. In another embodiment a plurality, for example least 2, 3, 4 or 5, of Ri, R2, R3, R4, Rs, Re, R7, Rs, R9, or a mixture thereof, is H, OH, carbonyl (=0), amine, imine or nitrile.

[0102] In one embodiment at least one of Ri, R2, R3, R4, Rs, Re, R7, Rs, R9, or a mixture thereof, is (C1-10) alkylene-, (C1-5) alkylene-, (Ce-io) cycloalkylen-(Ci-io) alkylene-, or (Ce-io) cycloalkylen-(Ci-s) alkylene-. In another embodiment a plurality, for example least 2, 3, 4 or 5, of Ri, R2, R3, R4, Rs, Re, R7, Rs, R9,, or a mixture thereof,is (Ci-io) alkylene-, (C1-5) alkylene-, (Ce-io) cycloalkylen-(Ci-io) alkylene-, or (Ce-io) cycloalkylen-(Ci-s) alkylene-.

[0103] In one embodiment at least one of Ri, R2, R3, R4, R5, Re, R7, Rs, R9, or a mixture thereof, is (Cl-10) alkylene- or (Cl -5) alkylene-, optionally wherein the one or more alkylene groups are saturated or have one or more carbon-carbon double bonds and / or wherein one or more carbon atoms of the one or more alkylene groups are substituted by a -O- bridge or by -OH. In another embodiment a plurality, for example least 2, 3, 4 or 5, of Ri, R2, R3, R4, Rs, Re, R7, Rs, R9, or a mixture thereof, is (Cl-10) alkylene- or (Cl -5) alkylene-, optionally wherein the one or more alkylene groups are saturated or have one or more carbon-carbon double bonds and / or wherein one or more carbon atoms of the one or more alkylene groups are substituted by a -O- bridge or by -OH.

[0104] In one embodiment at least one of Ri, R2, R3, R4, Rs, Re, R7, Rs, R9,, or a mixture thereof, is (ce-io) cycloalkylen-(Ci-io) alkylene- or (Ce-io) cycloalkylen-(Ci-s) alkylene-, optionally wherein the one or more alkylene groups are saturated or have one or more carbon-carbon double bonds and / or wherein one or more carbon atoms of the one or more alkylene groups are substituted by a -O- bridge or by -OH. In another embodiment a plurality, for example least 2, 3, 4 or 5, of Ri, R2, R3, R4, Rs, Re, R7, Rs, R9, or a mixture thereof, is (Ce-io) cycloalkylen-(Ci-io) alkylene- or (Ce-io) cycloalkylen-(Ci-s) alkylene-, optionally wherein the one or more alkylene groups are saturated or have one or more carbon-carbon double bonds and / or wherein one or more carbon atoms of the one or more alkylene groups are substituted by a -O- bridge or by -OH.

[0105] As used herein, the term “plasma polymer” is a polymer derived from a plasma containing one or more monomers.

[0106] As used herein, the term "nanoparticulate polymer" refers to a polymer formed with monomers defined herein, wherein the nanoparticulate polymer has a particle size in the range of about 1 nm to about 50 nm. For example, the nanoparticulate polymerhas a particle size of about or at least about (in nm): 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50. Suitably, a nanoparticulate polymer is formed by the condensation of fragments in a plasma, said material being capable of covalently coupling one or more compounds including organic or organometallic species.

[0107] As used herein, the term “aggregate” refers to a particle comprising a plurality of nanoparticulate polymers and having a size in a range of about 5 nm to about 100 pm, such as a size in a range of about 5 nm to about 500 nm, unless otherwise specified or clear from the context in which it is used. For example, the aggregate may have a size of about, or at least about (in nm): 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500.Monomers

[0108] The nanoparticulate polymers described herein are derived from one or more monomers. As used herein, the term “monomer”, unless stated otherwise, refers to a monomeric compound that can be reacted to form a polymer by means of one or more reactive functional groups that may be created by fragmentation and reaction processes in a plasma. Suitably, the one or more monomers are used in a gaseous form for forming the nanoparticulate polymer.

[0109] A monomer may be a hydrocarbon. As used herein, the term “hydrocarbon” refers to monomers consisting of hydrogen and carbon atoms only. Examples of hydrocarbons include alkenes, alkynes, cycloalkenes and cycloalkynes.

[0110] Examples of suitable alkene monomers include, but are not limited to ethylene, propene, 1 -butene, 1 -pentene, 1 -hexene, 1 -heptene, 1 -octene, 1 -nonene, 1-decene, isomers thereof, or a mixture thereof.

[0111] Examples of suitable alkyne monomers include, but are not limited to ethyne (acetylene), propyne, 1 -butyne, 1 -pentyne, 1 -hexyne, 1 -heptyne, 1 -octyne, 1 -nonyne 1-decyn, isomers thereof, or a mixture thereof.

[0112] Examples of suitable cycloalkene monomers include, but are not limited to cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, 1,5-cyclooctadiene, isomers thereof, or a mixture thereof.

[0113] Examples of suitable cycloalkyne monomers include, but are not limited to cycloheptyne, cyclooctyne, cyclononyne, isomers thereof, or a mixture thereof.

[0114] Suitably, an alkene is used as a monomer. The alkene may be the only monomer utilised in the formation of nanoparticulate polymer, or it may be used in the presence of at least one other monomer to form a copolymer, for example another alkene and / or an alkyne, cycloalkene or cycloalkyne.

[0115] Suitably, an alkyne is used as a monomer. The alkyne may be the only monomer utilised in the formation of nanoparticulate polymer, or it may be used in the presence of at least one other monomer to form a copolymer, for example another alkyne and / or an alkene, cycloalkene or cycloalkyne.

[0116] Further suitably, acetylene is used as a monomer, either on its own or in the presence of at least one other monomer.

[0117] Suitably, acetylene is used as a monomer in combination with at least one other monomer, for example at least one other monomer which is an alkene, alkyne, cycloalkenes or cycloalkyne.

[0118] Suitably, a cycloalkene is used as a monomer. The cycloalkene may be the only monomer utilised in the formation of nanoparticulate polymer, or it may be used in the presence of at least one other monomer to form a copolymer, for example another cycloalkene and / or an alkene, alkyne or cycloalkyne.

[0119] Suitably, a cycloalkyne is used as a monomer. The cycloalkyne may be the only monomer utilised in the formation of nanoparticulate polymer, or it may be usedin the presence of at least one other monomer to form a copolymer, for example another cycloalkyne and / or an alkene, alkyne or cycloalkene.

[0120] Other monomers that may be used for forming the nanoparticulate polymer include perfluorocarbons, ethers, esters, amines, alcohols or carboxylic acids.

[0121] Examples of suitable perfluorocarbons include, but are not limited to, perfluoroallyl benzene.

[0122] Examples of suitable ethers include, but are not limited to, di ethylene glycol vinyl ether, diethylene glycol divinyl ether, diethylene glycol monoallyl ether, or a mixture thereof.

[0123] Examples of suitable amines include, but are not limited to: allylamine, cyclopropylamine, poly (vinyl amine), or a mixture thereof.

[0124] Examples of suitable alcohols include, but are not limited to, poly (vinyl alcohol), allyl alcohol, ethanol, or a mixture thereof.

[0125] Examples of suitable carboxylic acids include, but are not limited to, acrylic acid.Nanoparticulate polymer

[0126] The nanoparticulate polymer may be a homopolymer or a copolymer.

[0127] Suitably, the nanoparticulate polymer may be derived from a plasma comprising one or more monomers as described herein, which are initially present in a gaseous form. One or more gases, for example one or more inert gases, may be present For example one or more of helium, neon and / or argon may optionally be present with the one or more monomers.

[0128] Nanoparticulate polymers may be formed in the presence of a gas from group 15, 16 or 17 of the periodic table, such as nitrogen. Fragments of this gas may be imported into the nanoparticulate polymer. For example, the presence of nitrogen may result in the presence of amine, imine or nitrile groups, or a mixture thereof in a nanoparticulate polymer. Suitably, the nanoparticulate polymer disclosed herein may comprise nitrogen.

[0129] Nitrogen has been found to be suitable not only as a carrier but also as a reactive non-polymerisable gas. This means that nitrogen may also be incorporated in the nanoparticulate polymer, imparting particular physico-chemical properties to the resulting functionalised nanoparticulate polymer. Furthermore, nitrogen is also thought to enable different modes of nanoparticle formation that otherwise would not be possible if nitrogen was not used. It is considered that the inclusion of other gases, such as those in the same group of nitrogen, will also provide an extra degree of freedom in modulating nanoparticle formation mechanisms and physical -chemi cal properties.

[0130] Suitably, the nanoparticulate polymer is derived from a plasma. As used herein, the term “plasma” generally refers to a (partially) ionized gas-like mass comprising a mixture of ions, electrons, neutral species and radiation. The plasmas referred to herein comprise at least one monomer. Optionally, the nanoparticulate polymer is formed in the presence of a gas, for example nitrogen, wherein fragments of the gas are incorporated into the nanoparticulate polymer.

[0131] The nanoparticulate polymer may have a nitrogen: carb on elemental ratio of about 0.01 : 1 to about 2:3. For example, the nanoparticulate polymer may have a nitrogen: carb on elemental ratio of about 0.05 to about 1, or about 0.1 to about 1, or about 0.15 to about 1, or about 0.2 to about 1, or about 0.25 to about 1, or about 0.3 to about 1, or about 0.35 to about 1, or about 0.4 to about 1, or about 0.45 to about 1, or about 0.5 to about 1, or about 0.55 to about 1, or about 0.6 to about 1, or about 0.65 to about 1. Alternatively, the nanoparticulate polymer may have a nitrogen: carb on elemental ratio of about 0.1 to about 1:2. In one example, the nanoparticulate polymermay have a nitrogen: carb on elemental ratio of about 0.35 to about 0.5 or about 0.35 to about 1. In another example, the nanoparticulate polymer may have a nitrogemcarbon elemental ratio of about 0.38.

[0132] The nanoparticulate polymers described herein preferably comprise at least one binding site capable of binding one or more compounds, for example an organic or an organometallic compound, or a second species as defined herein.

[0133] Suitably, the nanoparticulate polymers described herein comprises at least a binding site capable of binding one or more compounds, wherein the binding site comprises unpaired electrons which are capable of binding an organic or an organometallic compound, or a second species as defined herein.

[0134] The nanoparticulate polymer may comprise unpaired electrons in the polymer. These unpaired electrons may be on or near the surface of the nanoparticles. The unpaired electrons may be at a depth of about 40 nm or less within particles of the nanoparticulate polymer, or within about 30, 20 or 10 nm of the surface, or may be between about 10 and about 40nm from the surface or between about 10 and 30, 20 and 40 or 20 and 30 nm from the surface, or about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35 or 40 nm from the surface. They may be at a variety of depths from about 0 to about 40 nm. In some instances, they may be at depths of greater than 40 nm. Unpaired electrons may be dispersed throughout the volume of one or more nanoparticulate polymers and / or aggregates. This may render the polymer capable of reacting with a second species, such as an organic or organometallic species, so as to covalently couple said species to the nanoparticulate polymer and form a conjugate.

[0135] Suitably, the present disclosure may provide a nanoparticulate polymer, particles or aggregates thereof having a mean diameter of about 5nm to about 500 nm, said nanoparticulate polymer comprising an organic plasma polymer and said nanoparticulate polymer comprising unpaired electrons, thereby being capable of covalently coupling with an organic or organometallic species.

[0136] Suitably, the nanoparticulate polymer may comprise at least one functional moiety which is capable of chemically or physically coupling a second species.

[0137] The nanoparticulate polymer may have a mean diameter of about 1 nm to less than about 1000 nm. For example, the nanoparticulate polymer may have a mean diameter of from about 5 nm to about 500 nm, or about 5 to 500, 50 to 500, 100 to 500, 200 to 500, 5 to 200, 5 to 100, 5 to 50, 5 to 20, 20 to 100, 100 to 300 or 200 to 400 nm, e.g., about, or at least about, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 nm, or in a range of about 5 to about 400 nm, or about 5 to about 300 nm, or about 5 to about 200 nm, or about 5 to about 100 nm, or about 100 to about 500 nm, or about 100 to about 400 nm, or about 100 to about 300 nm, or about 100 to about 200 nm, or about 200 to about 400 nm, or about 200 nm to about 300 nm, or a mixture thereof.

[0138] The size of the nanoparticulate polymer may be measured by scanning electron microscopy, transmission electron microscopy, low angle laser light scattering, photon correlation spectroscopy, differential mobility analysis, or some other suitable technique. The particles of the nanoparticulate polymer may have a narrow size distribution or a broad size distribution. The standard deviation of the particle size distribution may be between about 1 % and about 500% of the mean particle size, or between about 1 and 200, 1 and 100, 1 and 50, 1 and 20, 1 and 10, 1 and 5, 1 and 2, 10 and 500, 20 and 500, 50 and 500, 100 and 500, 200 and 500, 10 and 100, 10 and 50 or 50 and 100%, e.g., about 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500%. In some instances, they may be approximately monodispersed, i.e., all particles may be approximately the same size (e.g., within about 10%, or about 5%, or about 2% of the same diameter).

[0139] The nanoparticulate polymer may comprise an organic plasma polymer.Plasma polymers are characterised by a heterogeneous, dense, highly crosslinked network. They may be amorphous. This plasma polymer may be generated by the reaction (e.g., ionisation and fragmentation), of active species generated in the plasma from the organic gas and other reactive gases in a gas mixture or by reactive species inthe plasma / gas mixture resulting from the ionization and fragmentation of gases in the gas mixture.

[0140] The nanoparticulate polymer may be characterised via a number of methods including, but not limited to: electron paramagnetic resonance (EPR) spectroscopy, infrared spectroscopy (such as Fourier transform infrared spectroscopy), Raman spectroscopy, UV-VIS spectroscopy, elemental analysis (e.g., X-ray photoelectron spectroscopy), soft X-ray spectroscopy, determination of a zeta potential, nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, gel permeation chromatography, scanning electron microscopy (SEM), transmission electron microscopy (TEM), low angle laser light scattering, photon correlation spectroscopy, differential mobility analysis, elastic recoil detection analysis (ERDA), or neutron scattering.

[0141] The nanoparticulate polymer may be characterised by one or more of the following features:• a broad electron paramagnetic resonance peak centred in a range of about 3470G to about 3520G, and / or corresponding to a g-factor in a range of about 2.001 to about 2.005;• a spin density measured by electron paramagnetic resonance within about 0 hours to about 2 hours post-synthesis in the range of about 1019 to about 1015 spins / cm3;• a spin density in the range of about 1017 to about 1015 spins / cm3 measured by electron paramagnetic resonance within about 0 hours to about 240 hours post synthesis.• one or more absorbance bands in an infrared spectrum centred:■ in a range of about 3680 - about 2700 cm'1;■ in a range of about 1800 - about 1200 cm'1;■ in a range of about 2330 - about 2020 cm'1;■ in a range of about 1200 - about 1010 cm'1; and / or■ in a range of about 1010 - about 700 cm'1;• one or more absorbance bands in an infrared spectrum centred:■ in a range of about 3600 - 3100 cm'1; and / or■ in a range of about 3100 - 2700 cm'1;• a zeta potential in a range of from about -100 mV to about +100 mV;• a zeta potential in a range of from about -80 mV to about +80 mV measured in a solution within a pH range of about 2 to about 10; or• a nitrogen: carb on elemental ratio of about 0.1:1 to about 2:3.

[0142] Thus, the nanoparticulate polymer disclosed herein may have any one or more of the above features, in any combination.

[0143] Suitably, the nanoparticulate polymer may be characterised using EPR spectroscopy. The nanoparticulate polymer or aggregate may show a broad electron paramagnetic resonance peak centred in a range of about 3470G to about 3520G, and / or corresponding to a g-factor in a range of about 2.001 to about 2.005.

[0144] Suitably, the nanoparticulate polymer may have a spin density measured by EPR spectroscopy within about 0 hours to about 2 hours post-synthesis in the range of about 1019 to about 1015 spins / cm3. The measurement may be made: about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, or about 120 minutes, post-synthesis.

[0145] Suitably, the nanoparticulate polymer may have a spin density in the range of about 1017 to about 1015 spins / cm3 measured by electron paramagnetic resonance within about 0 hours to about 240 hours post-synthesis. The measurement may be made: about 0.5, about 1, about 2, about 4, about 5, about 6, about 8, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150 hours, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, or about 240 hours, post-synthesis.

[0146] Suitably, the nanoparticulate polymer may be characterised using infrared spectroscopy (such as Fourier transform infrared spectroscopy). For example, the nanoparticulate polymer may show one or more absorbance bands in an infrared spectrum centred:• in a range of about 3680 - about 2700 cm'1;• in a range of about 1800 - about 1200 cm'1;• in a range of about 2330 - about 2020 cm'1;• in a range of about 1200 - about 1010 cm'1;• in a range of about 1010 - about 700 cm'1;• in a range of about 3600 - 3100 cm'1;• in a range of about 3100 - 2700 cm'1; and / ora mixture thereof.

[0147] Suitably, the nanoparticulate polymer may be characterised using the zeta potential of the nanoparticulate polymer or aggregate. For example, the nanoparticulate polymer may possess a zeta potential in a range from about -100 mV to about +100 mV. For example, the zeta potential may be in a range from about -50 mV to about 60 mV.

[0148] Further suitably, the nanoparticulate polymer may have a zeta potential in a range of from about -80 mV to about +80 mV, when measured in a solution within a pH range of about 2 to about 10.

[0149] The nanoparticulate polymer may have a rough cauliflower like surface morphology. This may be due to their formation by aggregation of the nanoparticulate polymers. Thus, the nanoparticulate polymer may be aggregates of the nanoparticulate polymers. The nanoparticulate polymer may be spherical, or generally spherical. The nanoparticulate polymers may have a diameter of about 1 to about 50 nm, or about 5 to 10, 5 to 10, 10 to 50, 20 to 50 or 10 to 30 nm, e.g., about, or at least about, 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nm. Aggregates (and the associated nanoparticulate polymers) may have embedded highly reactive radicals that diminish in quantity overtime. The nanoparticulate polymers may also have embedded long-lived and stable radicals in delocalised orbitals of carbon clusters.

[0150] The stable radicals (secondary radicals) may result from reactions involving highly reactive radicals (primary radicals). The nanoparticulate polymers may have a surface that is hydrophilic. The surface may therefore allow ready dispersion of the nanoparticulate polymers in water. It may allow retention of bioactivity of surface immobilised bioactive molecules. The hydrophilic surface may be a result of oxidation of radicals during formation or after formation by exposure of the surface to air.Following conjugation with one or more second species, the nanoparticulate polymer conjugate may be hydrophilic or hydrophobic. Alternatively, the nanoparticulate polymer conjugate may display amphiphilic properties.

[0151] Depending on the monomers used or the conditions applied during the polymerisation, the nanoparticulate polymer may be crosslinked. The term "crosslinked" herein refers to a polymer composition containing intramolecular and / or intermolecular bonds. These crosslinking bonds may be covalent or non-covalent in nature. Non-covalent bonding includes hydrogen bonding, electrostatic bonding, and ionic bonding.

[0152] One potential advantage obtained from crosslinking is the stability of the resulting nanoparticulate polymer and potentially a conjugate formed from such a material. For example, crosslinking can reduce the solubility of the nanoparticulate polymer (or a resulting conjugate) in comparison to similar compositions which are not crosslinked. In addition, the crosslinked nature of the nanoparticulate (or a conjugate formed thereof), may increase the chemical resistance of the nanoparticulate polymer or resulting conjugate.Conjugates and second species

[0153] The conjugation of a nanoparticulate polymer to a second species can be performed by any means known in the art, for example, as demonstrated in WO 2018 / 112543, the entire content of which is incorporated herein by reference in itsentirety. In particular, page 66 line 15 to page 71 line 7 of WO 2018 / 112543 describes suitable methods for conjugating a second species to the nanoparticulate polymer.

[0154] As used herein, the term “conjugate” refers to molecules formed by the attachment of one or more compounds to a nanoparticulate polymer or an aggregate comprising nanoparticulate polymers. The “one or more compounds” may be a second species as defined herein. The attachment may be via a covalent bond or an electrostatic interaction.

[0155] In one embodiment, when applied to a material, substrate, article and / or tissue, the conjugation of one or more second species does not impair at least one of the chemical, biological and / or physical properties of the material, substrate, article, and / or tissue. Physical properties include, but is not limited to: density conductivity, hardness, ductility, colour, elasticity, strength, such as tensile strength, load, corrosion resistance, thermal expansion, and / or wettability of the material, substrate, article and / or tissue.

[0156] As used herein a "second species" is a compound that can be physically adsorbed on or chemically bound to a nanoparticulate polymer (i.e., a nanoparticulate polymer or aggregate thereof), to form a conjugate. When the second species carries a surface charge, the binding of a charged second species to nanoparticulate polymer may be modulated by changing the pH of the reaction conditions during the conjugation process. The pH of the solution can modulate the charge of nanoparticulate polymer through protonation or de-protonation of surface functional groups, such as amines and carboxylic acid groups. For example, the binding of positively-charged conjugates to nanoparticulate polymers may be improved by increasing the pH of the solution containing the nanoparticulate polymers and the second species. At highly alkaline media, nanoparticulate polymers become negatively charged via deprotonation carboxylic surface groups, which also stabilizes the nanoparticles due to the repulsion between negatively charged particles. Alternatively, the binding of negatively-charged conjugates to nanoparticulate polymers may be improved by decreasing the pH of the solution containing the nanoparticulate polymers and the second species. As demonstrated herein, many second species can be conjugated to the nanoparticulatepolymers described herein without changing the pH of the reaction conditions, irrespective of any surface charge on the second species.

[0157] Also disclosed herein is the use of a nanoparticulate polymer, in the formation of a conjugate. The conjugate may comprise only a single second species.Alternatively, the conjugate may comprise two or more different second species, for example two, three or four second species.

[0158] The nanoparticulate polymer of the present disclosure not only allows immobilisation of a broad range of molecules but the attached species maintains its functionality and activity after immobilisation. This feature has been demonstrated with more than one type of biomolecule attached to the nanoparticulate polymer at the same time.

[0159] The nanoparticulate polymer and / or aggregates thereof may be capable of reacting with more than one type of second species. Different types of molecules and permutations within those different molecules may be reacted and immobilised at the same time or sequentially in or on the nanoparticulate polymer. The coupled species may maintain their uncoupled activity, e.g., bioactivity and functionality, after immobilisation on the nanoparticulate polymer and the resulting conjugate.

[0160] The nanoparticulate polymers are generally capable of directly coupling, for example by covalent coupling or ionic coupling, to a second species, such as an organic or an organometallic species. When the nanoparticle polymer or aggregate is a plasma polymer, the coupling process is generally rapid and capable of proceeding under mild conditions. The coupling may be by means of unpaired electrons in the polymer structure (i.e., radical sites) or by means of functional groups generated on the nanoparticulate polymer, or incorporated onto the resulting conjugate via the addition of an appropriate second species or by reaction with air (or another gas), or some other fluid to which the nanoparticulate polymer is exposed. For example, the use of nitrogen during a plasma polymerisations may yield one or more amine, imine and / or nitrile groups.

[0161] The nanoparticulate polymer may include monomer units which comprise functional moieties which are capable of chemically coupling a second species. The conjugation of one or more second species with the nanoparticulate polymer may introduce functional groups on or in the resulting conjugate, which can be used for further chemical reactions or used as binding sites for processes such as biochemical / biological processes taking place in in vitro or in vivo conditions.

[0162] Herein, functional moieties (or "functional groups"), refers to a group of atoms present on the monomer, nanoparticulate polymer, or conjugate comprising a nanoparticulate polymer, which can react with other complementary functional groups, for example, other functional groups present on a second species. Functional groups include but are not limited to the following moieties: carboxylic acid (-(C=O)OH), carbonyl, primary or secondary amine (-NH2, -NH-), nitric oxide, maleimide, thiol (-SH), sulfonic acid (-(O=S=O)OH), carbonate, carbamate (-O(C=O)N<), hydroxy (-OH), aldehyde (-(C=O)H), ketone (-(C=O)-), hydrazine (>N-N<), isocyanate, isothiocyanate, phosphoric acid (-O(P=O)OHOH), phosphonic acid (-O(P=O)OHH), haloacetyl, alkyl halide, acryloyl, aryl fluoride, hydroxylamine, disulfide, vinyl sulfone, vinyl ketone, diazoalkane, oxirane, and aziridine, or a mixture thereof.

[0163] The second species to which the nanoparticulate material can be conjugated may be an inorganic element or compound, or organometallic compound, which may act as image enhancing contrast agent, for example, in medical imaging techniques. The nanoparticulate polymer may be conjugated to (or ‘loaded’ with or ‘doped’ with) a magnetic resonance imaging (MRI) contrast agent such as iron oxide or gadolinium compounds. Examples of imaging enhancing contrast agents include: fluorescent dyes (e.g., Alexa 680, indocyanine green, and Cy5.5); isotopes and radionuclides, such as, but not limited to:11C,13N,15O,18F,32P,51Mn,52mMn,52Fe,55Co,62Cu,64Cu,67Cu,67Ga,68Ga,72As,73Se,75Br,76Br,82mRb,83Sr,86Y,90Y,89Zr,94mTc,94Tc,99mTc,110In,116mIn,120I,123I,124I,125I,131I,154Gd,155Gd,156Gd,157Gd,158Gd,177Lu,186Re,188Re, and / or223Ra; paramagnetic ions, such as chromium (III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II), copper (II), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), vanadium (II), terbium (III), dysprosium (III), holmium (III) orerbium (III); metals, such as lanthanum (III), gold (III), lead (II), and bismuth (III); oxides of chromium (III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II), copper (II), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), vanadium (II), terbium (III), dysprosium (III), holmium (III) or erbium (III); metals, such as lanthanum (III), gold (III), lead (II), and bismuth (III), including iron oxide and gadolinium oxide; ultrasound-contrast enhancing agents, such as liposomes; and radiopaque agents, such as barium, gallium, and thallium compounds. The imaging enhancing contrast agents may be incorporated directly onto the nanoparticulate polymer, or indirectly by using an intermediary functional group, such as chelators.

[0164] Thus, the second species may be an imaging agent. Additional examples of imaging agents include, but are not limited to: luciferase; fluorescently labelled dyes and antibodies; contrast agents (including: iopamidol, iohexol and ioxilan); barium sulfate; MRI contrast agents (for example: gadolinium, iron oxide and manganese based imaging agents); Indocyanine green (ICG; sodium 4-[2-[(lE,3E,5E,7Z)-7-[l,l-dimethyl-3-(4-sulfonatobutyl)benzo[e]indol-2ylidene]hepta-l,3,5-trienyl]-l,l-dimethylbenzo[e]indol-3-ium-3-yl]butane-l-sulfonate; CAS number 3599-32-4); and mixtures thereof.

[0165] The second species may be a cleavable linking molecule. Examples of a cleavable linking molecule such as a pH-sensitive linker, may be found in Leriche et al., "Cleavable linkers in chemical biology" Bioorganic & Medicinal Chemistry, 20, 571-582, 2012, the contents of which are included by reference. Exemplary groups of linkers and compounds include, but are not limited to pH cleavable, photocleavable (for example cleavable via laser or infrared light), laser cleavable, heat cleavable, and protease cleavable (including via the action of blood proteases like kallekrein and thrombin) linkers and compounds.Biologically active agent

[0166] The second species may be a biologically active agent (also referred to herein as a biologically active molecule). As used herein, the term “biologically active agent” refers to any agent that has a biological and / or pharmacological activity in vitro or invivo. The biologically active agent may be a peptide, polypeptide, nucleic acid, small molecule drug, or any other pharmacologically active agent.

[0167] Examples of biologically active agents include, but are not limited to pharmaceutical drugs, diagnostic drugs and reagents; haematological drugs; cardiovascular drugs; sympathomimetic drugs; cholinomimetic drugs; adrenergic antagonists and adrenergic; neuron blocking drugs; anti-muscarinic and antispasmodic drugs; hormones and hormone antagonists; general anaesthetics; local anaesthetics; antiepileptic drugs; analgesic, antipyretic, and anti-inflammatory drugs; histamine and antihistaminic drugs; central nervous system stimulants; antineoplastic drugs; immunoactive drugs; parasiticides; immunising agents and allergenic extracts; anti-infectives; enzymes; nutrients and associated substances, or a mixture thereof.

[0168] Examples of pharmaceutical drugs include, but are not limited to anticancer drugs (such as: doxorubicin, paclitaxel, vincristine, cyclophosphamide and topotecan); anti-HIV retrovirals (e.g., abacavir (Ziagen), efavirenz / emtriacitabine / tenofovir disoproxil fumarate (Atripla), lamivudine / zidovudine (Combivir), emtriacitabine / rilpivirine / tenofovir disoproxil fumarate (Complera), emtricitabine (Emtriva), lamivudine (Epivir), abacavir / lamivudine (Epzicom), zidovudine (Retrovir)); agents modulating cell replication / proliferation: target of rapamycin (TOR) inhibitors (including sirolimus, everolimus and ABT-578); paclitaxel and antineoplastic agents (including alkylating agents, e.g., cyclophosphamide, mechlorethamine, chlorambucil, melphalan, carmustine, lomustine, ifosfamide, procarbazine, dacarbazine, temozolomide, altretamine, cisplatin, carboplatin and oxaliplatin); antitumor antibiotics (bleomycin, actinomycin D, mithramycin, mitomycin C, etoposide, teniposide, amsacrine, topotecan, irinotecan, doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone and mitoxantrone); antimetabolites (including: deoxycoformycin, 6-mercaptopurine, 6-thioguanine, azathioprine, 2-chlorodeoxyadenosine, hydroxyurea, methotrexate, 5-fluorouracil, capecitabine, cytosine arabinoside, azacytidine, gemcitabine, fludarabine phosphate and aspariginase); antimitotic agents (including: vincristine, vinblastine, vinorelbine, docetaxel, estramustine); molecularly targeted agents (including: imatinib, tretinoin,bexarotene, bevacizumab, gemtuzumab ogomicin and denileukin diftitox); antiinflammatory drugs; anti-calcification drugs; anti-thrombotic drugs; corticosteroids; estrogens; androgens; progestogens and adrenal androgens; antibiotics, analgesics; opoids, or a mixture thereof.Contacting the catheter with the nanoparticulate polymers

[0169] The nanoparticulate polymers described herein may be applied on or in a suitable material or article. The nanoparticular polymers may be contacted with any: catheter, balloon, first balloon, second balloon, perforated balloon, or combination thereof, disclosed herein. Thus, the present disclosure provides a method of contacting any: catheter, balloon, first balloon, second balloon, perforated balloon, or combination thereof with the nanoparticulate polymers disclosed herein. As used herein, the terms “contact” and “contacting” refer to the application of the nanoparticulate polymer or aggregate or conjugate to one or more surfaces of any of: a catheter, balloon, first balloon, second balloon, perforated balloon, or combination thereof, under conditions suitable to allow the nanoparticulate polymer or aggregate or conjugate to attach to the surface of the: catheter, balloon, first balloon, second balloon, perforated balloon, or combination thereof.

[0170] One particular advantage resulting from the properties of the nanoparticulate material disclosed herein is that the contacting may comprise simply dipping the catheter, balloon, first balloon, second balloon, perforated balloon, or combination thereof in a solution or suspension of the nanoparticulate polymer or aggregate or conjugate disclosed herein.

[0171] Thus, the nanoparticulate polymers may be provided in solution, dispersion or suspension. The nanoparticulate polymer or aggregate or conjugate may be lyophilised, and subsequently dispersed or resuspended in a solution in order to facilitate attachment to the catheter; balloon, first balloon, second balloon, perforated balloon, or combination thereof.

[0172] The solution or suspension may comprise nuclease free water or any other suitable liquid that does not interfere with the binding properties of the nanoparticulate material, for example one or more inert organic solvents.

[0173] The nanoparticulate material may be applied in any suitable concentration. For example, the concentration of the nanoparticulate polymer or aggregate or conjugate may range from lxlO9-lxlOnnanoparticulate polymer or aggregate or conjugate / mL. Suitably, the concentration of the nanoparticulate polymer or aggregate or conjugate may be about IxlO9, about lx IO10or about IxlO11.

[0174] The attachment of nanoparticulate polymers to at least a portion of a surface of the catheter, balloon, first balloon, second balloon, perforated balloon, or combination thereof, may be confirmed by any means known in the art, for example, by scanning electron microscopy.

[0175] The method of preparing the catheter, balloon, first balloon, second balloon, perforated balloon, or combination thereof may also comprise contacting the nanoparticulate polymer with one or more biologically active agents. Such biologically active agents may be any one or more disclosed herein. When there is more than one biologically active agent, the nanoparticulate polymer may be contacted with the biologically active agents simultaneously or sequentially. The attachment of the second species to the nanoparticulate material may be performed before the nanoparticulate material is applied to the catheter, balloon, first balloon, second balloon, perforated balloon, or combination thereof, or after the nanoparticulate material is applied to the catheter, balloon, first balloon, second balloon, perforated balloon, or combination thereof. Either option has been demonstrated as being suitable to achieve effective attachment of the second species to the catheter, balloon, first balloon, second balloon, perforated balloon, or combination thereof, such that the second species is able to exert its own physiological effect.

[0176] Again, the process of attaching the second species to the nanoparticulate material can be performed simply by combining a solution or suspension of the secondspecies with a solution or suspension of the nanoparticulate material. When facilitating attachment of the second species to the catheter, balloon, first balloon, second balloon, perforated balloon, or combination thereof, via the nanoparticulate material, simple contacting steps can be performed. Thus, in one example, the catheter, balloon, first balloon, second balloon, perforated balloon, or combination thereof can be submerged in a solution or suspension comprising the nanoparticulate polymer or aggregate or conjugate, and subsequently submerged in a solution or suspension comprising the second species. A wash step may optionally be performed between the two submerging steps. Alternatively, the catheter, balloon, first balloon, second balloon, perforated balloon, or combination thereof can be submerged in a solution or suspension comprising the nanoparticulate polymer or aggregate or conjugate and the second species. The catheter, balloon, first balloon, second balloon, perforated balloon, or combination thereof disclosed herein may advantageously retain its functional properties after being contacted with the nanoparticulate polymer or aggregate or conjugate and / or the second species.

[0177] The nanoparticulate polymers that contact the catheter, balloon, first balloon, second balloon, perforated balloon, or combination thereof may be exposed to various environments and conditions, for example, various pH environments, temperatures and / or chemical / biological compounds or entities. Thus, suitably, the nanoparticular polymers on the catheter, balloon, first balloon, second balloon, perforated balloon, or combination thereof may maintain attachment under high peristaltic flow.

[0178] EXAMPLES

[0179] A variety of perforated balloons having the structure shown in Fig. 4B were tested by injecting approximately 9mL of fluid through a 0.018” needle and measuring the fluid outflow through the proximal, middle and distal sections. Each tested balloon had a main body with proximal, middle and distal sections of equal length and each section had apertures arranged in a plurality of longitudinally spaced circumferential rings. The longitudinal spacing of the rings was the same for each tested balloon, but balloons with different numbers of apertures in the rings of each section were tested.

[0180] In a first set of experiments shown in Table 1, the apertures had a diameter of 0.5mm and the flow rate of the injected fluid was 75 ml / min.Balloon No. Number of aperturesper ring Volume of fluic effusedProx Mid Dist Prox Mid Dist SUM SD SD / SUM 1 4 4 4 1.9 2.4 4.9 9.2 1.61 18% 2 12 12 12 0 3 6 9 3.00 33% 3 4 8 12 0.2 2.9 5.9 9 2.85 32% 4 12 8 4 2.9 5.1 1 9 2.05 23%5 4 12 40.3 6 2.5 8.8 2.87 33% Table 1

[0181] The first three columns show the number of apertures per ring in the proximal (Prox), middle (mid) and distal (Dist) sections respectively. The fourth to sixth columns show the volume of fluid effused through the apertures of each section. The seventh column (SUM) shows the total volume of fluid effused by the balloon in mL. The eight column (SD) shows the standard deviation in mL in the volume effused by the different sections. The final column (SD / SUM) shows the standard deviation as a percentage of the volume effused. As can be seen, the 2ndand 3rdballoons, marked in bold text, had a particularly uneven distribution of fluid flow between the three sections. Generally the results for this group were poor with the conclusion that a aperture diameter of 0.5mm was sub-optimal.

[0182] In a second set of experiments shown in Table 2, the apertures had a diameter of 0.25mm and the flow rate of the injected fluid was 20 ml / min.Balloon Number ofNo. apertures per ring Vo ume ol?fluic effusedProx Mid Dist Prox Mid Dist SUM SD SD / SUM 1 4 4 4 3.6 4.1 1.5 9.2 1.38 15% 2 12 12 12 4.2 1.9 2.8 8.9 1.16 13% 3 4 8 12 1.7 3.8 3.6 9.1 1.16 13% 4 12 8 4 15 23 13 93 2.19 24% 5 4 8 4 2.4 3.9 2.6 8.9 0.81 9% 6 4 12 4 2.1 6 0.8 8.9 2.71 30%7 8 12 82.9 3.6 2.6 9.1 0.51 6% Table 2

[0183] The columns in Table 2 have the same parameters as Table 1. It can be seen that the results are better than for the first group of balloons, with the conclusion that 0.25mm aperture diameter is better than 0.5mm aperture diameter. Furthermore, while balloon 4 which is underlined gave poor results, balloons 5 and 5 marked in bold text gave good results. Balloon 5 had a pattern of 4, 8, 4 for number of apertures per ring in the proximal, middle and distal sections respectively, while balloon 5 had a pattern or 8, 12, 8. This indicates that an arrangement with greater aperture area density in the middle section provides superior results in terms of more balanced outflow between the sections. This was surprising as intuitively one would expect a greater aperture area density in the distal section (i.e. linearly increasing aperture area density from proximal to distal) to work well. However, it can be seen that while balloon 4 had this arrangement, it was outperformed by balloons 5 and 7 which have a greater aperture area density in the middle section. It is posited that this is due to the complicated fluid dynamics at play.

[0184] In a third set of experiments shown in Table 3, the apertures had a diameter of 0.125mm and the flow rate of the injected fluid was 15 ml / min.Balloon Number of aperturesNo. per ring Volume of luid e FusedProx Mid Di st Prox Mid Di st SUM SD SD / SUM 1 4 4 4 3.8 3.9 1.4 9.1 1.42 16% 2 12 12 12 (H> 12 V7 82 2.65 32% 3 4 8 12 1 2.7 5.4 9.1 2.22 24% 4 4 8 4 2.2 4.1 2.7 9 0.98 11% 5 4 12 4 1 3.7 4.5 9.2 1.83 20%6 8 12 82.9 3.6 2.7 9.2 0.47 5% Table 3

[0185] The columns in Table 3 have the same parameters as Table 1. It can be seen that the results are better than for the first group of balloons, with the conclusion that 0.125mm aperture diameter is better than 0.5mm aperture diameter. Furthermore, while balloon 2 which is underlined gave poor results, balloons 4 and 6 marked in bold text gave good results. Balloon 4 had a pattern of 4, 8, 4 for number of apertures per ring in the proximal, middle and distal sections respectively, while balloon 6 had a pattern or 8, 12, 8. This indicates that an arrangement with greater aperture area density in the middle section provides superior results in terms of more balanced outflow between the sections.

[0186] Meanwhile it is noted that balloon 5 which has a pattern of 4, 12, 4 did not give as good results as ballons 4 and 6. This suggests that the middle section may have as much as double the aperture area density as the proximal / distal sections, but results are not as good where the middle section has triple the aperture area density of the sections on either side. Accordingly, it is suggested that the middle section have an aperture area density up to 2 times greater than the proximal and distal sections, and in some examples up to 2 times greater.

[0187] All of the features of the various example apparatus disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the blocks of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or blocks are mutually exclusive.

[0188] It will be appreciated by persons skilled in the art that numerous variations and / or modifications may be made to the above-described embodiments, without departing from the broad general scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Claims

CLAIMS:

1. A balloon catheter comprising:a catheter shaft extending from a proximal end to a distal end, the catheter shaft having an inflation port and a drug injection port;a first balloon mounted to the catheter shaft, the first balloon being coupled to the inflation port;a second balloon mounted to the catheter shaft, the second balloon surrounding the first balloon and being coupled to the drug injection port;a space between the second balloon and the first balloon defining an annular lumen for receiving a drug injected through the drug injection port;wherein the second balloon has a plurality of apertures for allowing the drug to flow out of the second balloon to a treatment site on a patient; andwherein the plurality of apertures having a non-uniform arrangement.

2. The balloon catheter of claim 1 wherein the non-uniform arrangement of the plurality of apertures is arranged to promote a relatively even outflow of the drug along the length of the second balloon.

3. The balloon catheter of any of the above claims, wherein a total aperture area per unit length increases in the distal direction over at least a portion of the length of the second balloon.

4. The balloon catheter of any of the above claims, wherein a total aperture area per unit length of the second balloon is greater at a distal end of the second balloon than at a proximal end of the second balloon.

5. The balloon catheter of any of the above claims, wherein the second balloon comprises a proximal section, a middle section and a distal section, and wherein at least one of the proximal section, middle section and distal section has a different aperture area per unit length compared to at least one of the other two sections.

6. The balloon catheter of claim 5, wherein the middle section has a greater aperture area per unit length than the proximal section and the distal section.

7. The balloon catheter of any of the above claims wherein the density of apertures varies along the length of the balloon catheter.

8. The balloon catheter of any of the above claims wherein the number of apertures per unit length varies in different parts of the second balloon.

9. The balloon catheter of any of the above claims wherein the non-uniform arrangement comprises apertures of a plurality of different sizes.

10. The balloon catheter of any of the above claims wherein a longitudinal separation between adjacent apertures varies along the length of the second balloon.

11. The balloon catheter of any of the above claims wherein a number of apertures around a circumference of the second balloon varies along the length of the second balloon.

12. The balloon catheter of any of the above claims wherein the inflation port is coupled to the first balloon by a tube within the catheter shaft which defines an inflation lumen for inflating the first balloon.

13. The balloon catheter of any of the above claims wherein the space between the second balloon and the first balloon is coupled to the drug injection port by a tube within the catheter shaft which defines a drug delivery lumen for delivering a drug to the second balloon.

14. The balloon catheter of any of the above claims wherein the first balloon is sealed at a distal end of the first balloon.

15. The balloon catheter of any of the above claims wherein the second balloons is sealed at a distal end of the second balloon by an aspiration port, the aspiration port being openable to eject excess drug from the second balloon.

16. The balloon catheter of any of the above claims wherein the catheter shaft comprises a tube defining a guidewire lumen.

17. A balloon catheter comprising:a catheter shaft extending from a proximal end to a distal end, the catheter shaft having a drug injection port;a perforated balloon mounted to the catheter shaft and coupled to the drug injection port;the perforated balloon having a plurality of apertures for allowing an injected drug to flow out of the second balloon for delivery to a patient;wherein the plurality of apertures are disturbed in a non-uniform arrangement.

18. The balloon catheter of claim 17 where the non-uniform arrangement is arranged to promote a desired distribution of the drug along the length of the second balloon.

19. The balloon catheter of claim 17 or 18 further comprising a separate inflation balloon within the perforated balloon, the inflation balloon being coupled to an inflation port of the catheter shaft and inflatable to push the perforated balloon into contact with a blood vessel wall of the patient, a space between the perforated balloon and the inflation balloon defining an annular lumen for receiving a drug injected into the catheter shaft via the drug injection port.

20. The balloon catheter of any one of claims 1 to 19 further comprising a nanoparticulate polymer with a mean diameter of about 1 nm to about 50 nm and formed from a plasma comprising at least one monomer selected from: an alkene, an alkyne, a cycloalkene, a cycloalkyne, and a mixture thereof; or an aggregate comprising two or more of the nanoparticulate polymers, wherein the aggregate has a mean diameter of about 5 nm to about 500 nm.

21. The balloon catheter of claim 20, further comprising at least one second species.

22. The balloon catheter of claim 20 wherein the nanoparticulate polymer or aggregate are disposed on or in at least a portion of:the first balloon, the second balloon, or both; orthe perforated balloon.

23. The balloon catheter of claim 21 wherein:the nanoparticulate polymer or aggregate; andthe at least one second species,are disposed on or in at least a portion of:the first balloon, the second balloon, or both; orthe perforated balloon.

24. The balloon catheter of any one of claims 21 or 23, wherein the second species is carried by the nanoparticulate polymer or aggregate disposed on or in at least one of the first balloon and the second balloon, and wherein the catheter is configured to deliver a fluid drug comprising additional nanoparticulate polymer or aggregate through the apertures of the second balloon.

25. The balloon catheter of any one of claims 20 to 24 wherein the nanoparticulate polymer or aggregate is disposed adjacent to or lining at least a portion of the apertures of the second balloon.

26. A method of using the balloon catheter of any of claims 1 to 25, the method comprising:inserting a distal end of the catheter into a blood vessel of a patient; injecting a fluid drug into the second balloon (or the perforated balloon) and allowing the drug to flow out through the apertures in the second balloon to treat a treatment site of the blood vessel of the patient.

27. The method of claim 26 comprising inflating the first balloon (or the inflation balloon) to push the second balloon (or the perforated balloon) into contact with walls of the blood vessel of the patient at the treatment site and then injecting the fluid drug into the second balloon (or the perforated balloon).

28. A method of using the balloon catheter of any one of claims 20 to 25, the method comprising:inserting a distal end of the catheter into a blood vessel of a patient; injecting a fluid drug into the second balloon (or the perforated balloon) and allowing the drug to flow out through the apertures in the second balloon to treat a treatment site of the blood vessel of the patient.

29. The method of claim 28 comprising inflating the first balloon (or the inflation balloon) to push the second balloon (or the perforated balloon) into contact with walls of the blood vessel of the patient at the treatment site and then injecting the fluid drug into the second balloon (or the perforated balloon).

30. The method of any one of claims 26 to 29, wherein the injected fluid drug comprises the nanoparticulate polymer or aggregate of claim 20.

31. The method of claim 30 wherein the nanoparticulate polymer or aggregate is conjugated to a second species prior to injection32. The method of claim 30 or 31, wherein the nanoparticulate polymer or aggregate has a mean diameter of about 1 nm to about 50 nm or is an aggregate having a mean diameter of about 5 nm to about 500 nm, and wherein the perforated balloon has apertures of about 0.125 mm to about 0.25 mm.

33. A kit compri sing :a balloon catheter according to any one of claims 1 to 19; anda container comprising a nanoparticulate polymer with a mean diameter of about 1 nm to about 50 nm and formed from a plasma comprising at least one monomer selected from: an alkene, an alkyne, a cycloalkene, a cycloalkyne, and a mixture thereof; or an aggregate comprising two or more of the nanoparticulate polymers, wherein the aggregate has a mean diameter of about 5 nm to about 500 nm.

34. The kit of claim 33 further comprising a container comprising at least one second species.

35. A kit compri sing :a balloon catheter according to any one of claims 1 to 19; anda container comprising:(i) a nanoparticulate polymer with a mean diameter of about 1 nm to about 50 nm and formed from a plasma comprising at least one monomer selected from: an alkene, an alkyne, a cycloalkene, a cycloalkyne, and a mixture thereof; or an aggregate comprising two or more of the nanoparticulate polymers, wherein the aggregate has a mean diameter of about 5 nm to about 500 nm; and(ii) at least one second species.

36. The kit of claim 35 wherein:(i) the nanoparticulate polymer or aggregate is provided in a lyophilized or suspension form for (a) contacting the balloon to form a surface coating and / or (b) admixture into a fluid drug for infusion through the balloon apertures; and(ii) instructions for either or both of (a) and (b) are provided.

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