CN114010915B

CN114010915B - Medicine elution saccule

Info

Publication number: CN114010915B
Application number: CN202111072113.9A
Authority: CN
Inventors: 骆静南; 王红蕾
Original assignee: Shanghai Pulse Medical Technology Co ltd
Current assignee: Shanghai Pulse Medical Technology Co ltd
Priority date: 2016-11-17
Filing date: 2017-11-06
Publication date: 2024-07-30
Anticipated expiration: 2037-11-06
Also published as: CN114010915A; WO2018093329A1; CN109414571A; CN109414571B

Abstract

The present invention is directed to providing a drug eluting balloon and balloon catheter wherein the drug coating is protected and/or coated onto the elastic membrane by one or more sleeves, rather than directly onto the balloon.

Description

Medicine elution saccule

Technical Field

The present invention contemplates various drug eluting balloons that may be implanted within the body lumen of a human body to deposit a pharmaceutical composition at a site in need of treatment.

Technical Field

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

Coronary heart disease/peripheral arterial disease is a common disease of blood circulation, and plaque formed in arteries restricts blood flow to various parts of the body. Typical treatment modalities today are: coronary artery bypass grafting, stent implantation, and balloon angioplasty. After stent implantation and balloon angioplasty for several months, some cases of narrowing of the vessel wall at the site of intervention occur in the patient, known as restenosis. Having recognized the problems associated with stenosis and restenosis, there has been development of drug eluting stents to combat the condition. The drug eluting stent is designed to release one or more drugs over a period of time sufficient to inhibit the hyperproliferation of cells (thereby resulting in stenosis/restenosis). However, the use of drug eluting stents may pose a risk of chronic irritation of chronically implanted devices causing inflammation. Thus, even though the permanently implanted device is capable of being resorbed over time, a device that is capable of delivering a therapeutic composition to a treatment site and that is completely removable from an intervention site is preferred over a permanently implanted device.

In recent years, the concept of Drug Eluting Balloons (DEB) or Drug Coated Balloons (DCB) has been introduced, DEB being used as an angioplasty balloon for Percutaneous Transluminal Angioplasty (PTA) and percutaneous coronary arterial transluminal angioplasty (PTCA). The surface of the drug eluting balloon is coated with an active agent. In practice, DEB transfers the active agent to the vessel wall when the balloon is inflated and pressed against the vessel wall at the site of action. The use of DEB generally requires:

(1) An uncoated balloon catheter is inserted into the body cavity for pre-dilation to provide an unobstructed path for subsequent coated drug-coated balloon catheters, which prevents drug loss during DEB delivery. The uncoated balloon catheter is then removed;

(2) The coated saccule catheter is inserted into the pre-dilated blood vessel through the guiding sheath/guiding catheter/sleeve to reach the medium-in position;

(3) The coated balloon catheter is positioned at an interventional site (e.g., a lesion site in a blood vessel);

(4) Expanding the balloon to a predetermined size to radially press against the hardened plaque of the lesion to alter the vessel wall structure;

(5) The balloon is depressurized and retracted through the introducer sheath/guide catheter/sheath.

Although DEB has promise, there are many problems that need to be addressed, including DEB itself and the problems associated with DEB use. These problems are discussed below.

(1) DEB is the application of one or more drugs directly to the outer surface of a balloon, with the coated surface typically exposed to circulating blood (or other body fluids) during use. Because of this, during the procedure of delivering DEB to a stenotic or occluded lesion, the drug on the balloon surface may become severely compromised and may be lost more near the site of intervention, as well as during intraluminal delivery of different diameters and curvatures. Furthermore, even before the balloon catheter reaches the lesion, the percentage of drug loss is often already high when the balloon catheter is passed through an introducer sheath/guide catheter or tortuous vessels. Thus, the amount of drug lost varies from case to case and is often not controllable, resulting in unpredictability of the procedure. This unpredictability results in different therapeutic effects of DEB on a patient-by-patient basis, and thus inconsistent clinical treatment results. If a large amount of drug is lost during the passage of the catheter through the lumen of the patient, a large amount of drug coated particles or fragments may fall off the balloon surface into the patient's blood stream. This may cause blockage of the body lumen, for example: distal embolism of capillary.

(2) Currently, all manufacturers of DEBs apply drug coatings directly on balloon surfaces. Traditional balloon materials are hydrophobic and inelastic PET, pebax and nylon. Due to the hydrophobicity of the drug (e.g., paclitaxel), the interaction forces between the balloon surface and the drug are typically very large. Thus, it may be difficult to transfer drug particles on the balloon surface to the lesion after inflation and expansion of the insertion site. Thus, to achieve low loss and high transfer effects of the drug, the following two types of techniques are applied to DEB: (a) Small molecule additives are used to improve the release of the drug from the balloon surface; or (b) treating the balloon surface to be hydrophilic by mechanical or chemical means. Both of these approaches attempt to attenuate the interfacial interactions between the drug and the balloon surface to improve drug transfer rates. However, this will also reduce the adhesion of the drug to the balloon surface during transport, possibly resulting in increased drug loss during delivery. Since drug adhesion and drug release are contradictory, the drugs currently on the market cannot balance between efficient drug transfer (in the site of action) and low rate of loss (en route to the treatment site). At present, none of the drug coating techniques developed by either method (a) or method (b) above can achieve maximum drug transfer while minimizing drug loss.

(3) Most DEB catheters require pre-dilation of the site of action prior to use. Pre-dilation is accomplished by a standard balloon angioplasty prior to the application of the DEB, which ensures that a clear delivery path is provided for the DEB. But this also increases the cost and time required to execute the program.

Thus, there remains a need for DEB that ameliorates one or more of the problems described above.

Disclosure of Invention

Aspects and embodiments of the invention are discussed below.

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

A balloon having a proximal end and a distal end;

a first elastic membrane surrounding at least a portion of the balloon, or the first elastic membrane may be configured such that the first elastic membrane surrounds at least a portion of the balloon;

a drug coating applied to a second surface of the first elastic membrane;

Wherein when the first elastic membrane surrounds at least a portion of the balloon, the side of the first elastic membrane facing the balloon is a first surface of the first elastic membrane, the side facing away from the balloon is a second surface of the first elastic membrane, and the first elastic membrane can expand to at least 1.1 times its original size when the balloon is inflated.

In an embodiment of the first aspect of the invention:

(a) The drug delivery device may be a catheter balloon for a balloon catheter, or a balloon catheter;

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

(c) After the balloon is inflated, the first elastic membrane may expand to 1.1 to 20 times (e.g., 1.5 times, such as 2 to 5 times) its original size.

(D) Wherein the first elastic membrane expands in a radial direction;

(e) The first elastic membrane may be made of a material comprising silicone, thermoplastic elastomer or a mixture of both, optionally wherein the material further comprises a scaffold material for limiting longitudinal expansion of the first elastic membrane.

(F) The first elastic film may be a continuous film, or a web, or a film having a plurality of holes;

(g) The first elastic membrane may surround the entire balloon and be bonded to the balloon at the proximal and distal ends of the balloon, respectively, or near the proximal and distal ends of the balloon, respectively. Optionally, the device further comprises a third sleeve surrounding the first elastic membrane and the balloon, the third sleeve and the balloon being relatively movable such that the first elastic membrane and the balloon are exposed from the third sleeve such that upon inflation of the balloon, the first elastic membrane can expand to 1.1 times its original size (optionally, the third sleeve comprises a non-elastic polymeric material);

(h) The device may further comprise a first sleeve having a first surface facing the balloon and a second surface facing away from the balloon, wherein the first elastic membrane forms at least a portion of the first sleeve, the first sleeve and the balloon being movable relative to each other to expose the balloon from the first sleeve. Optionally, the device further comprises a second sleeve surrounding the first sleeve, the second sleeve being relatively movable with respect to the first sleeve such that the first elastic membrane forming part of the first sleeve is exposed from the second sleeve such that upon inflation of the balloon, the first elastic membrane can expand to at least 1.1 times its original size. Optionally, the second sleeve comprises a non-elastic polymeric material;

(i) The device may further comprise a first sleeve movable relative to the balloon, the first sleeve covering at least a portion of the balloon when in a first position and the balloon being exposed from the first sleeve when in a second position, the first elastic membrane having a first end, a second end and an intermediate portion, wherein the first end of the first elastic membrane is connected to the first sleeve, the second end of the first elastic membrane is connected to the distal end of the balloon, and the intermediate portion of the first elastic membrane extends along the first surface of the first sleeve when the first sleeve is in the first position. Optionally, wherein when the first sleeve is in the first position, the intermediate portion of the first elastic membrane is folded and stretched along the first surface of the first sleeve;

(j) The drug coating comprises one or more of the following group: antiproliferative agents, immunosuppressive agents, anti-angiogenic agents, anti-inflammatory agents and antithrombotic agents [ e.g.: the drug may be selected from one or more of the following group: paclitaxel, rapamycin, everolimus, zotarolimus, temsirolimus (umirolimus), tacrolimus and pimecrolimus (e.g., the drug may be selected from one or more of the following group: paclitaxel, rapamycin, zotarolimus, temsirolimus (umirolimus), e.g., paclitaxel and rapamycin), wherein, optionally:

(I) The drug coating further comprises an excipient selected from one or more of the following groups: tartaric acid, sugar and sugar alcohol [ e.g. the pharmaceutically acceptable carrier is further selected from one or more of the following groups: fructose, glucose, sucrose, lactose, maltose, erythritol, threitol, arabitol, ribitol, mannitol, galactitol, fucitol, iditol, inositol, heptatol (volemitol), isomalt, maltitol, lactitol, maltotriotol, maltotetraitol, or xylitol, tartaric acid, and sorbitol (e.g., one or more selected from the group consisting of fructose, glucose, sucrose, mannitol, or sorbitol, or xylitol and tartaric acid); and

The drug coating of (II) further comprising an adhesion balancing layer or primer layer directly attached to the second surface of the first elastic film, the adhesion balancing layer or primer layer comprising a hydrophilic polymer and/or a hydrophilic compound, wherein optionally the hydrophilic compound is selected from one or more of the following groups: sugar, sugar alcohol and polyethylene glycol [ e.g.: the hydrophilic compound has a molecular weight of less than 1,000 daltons and is selected from one or more of the following groups: fructose, glucose, sucrose, lactose, maltose, erythritol, threitol, arabitol, ribitol, mannitol, galactitol, fucitol, iditol, inositol, heptatol (volemitol), isomalt, maltitol, lactitol, maltotriose, maltotetraitol, xylitol, sorbitol, and polyethylene glycol (e.g., one or more selected from the group consisting of fructose, glucose, sucrose, xylitol, mannitol, and sorbitol).

A second aspect of the invention relates to the use of a medicament selected from one or more of the following groups: antiproliferative agents, immunosuppressants, anti-angiogenic agents, anti-inflammatory agents and anti-thrombotic agents [ e.g.: the drug may be selected from one or more of the following groups: paclitaxel, rapamycin, everolimus, zotarolimus, temsirolimus (umirolimus), tacrolimus and pimecrolimus (e.g., the drug may be selected from one or more of the group consisting of paclitaxel, rapamycin, zotarolimus, temsirolimus (umirolimus), e.g., paclitaxel and rapamycin) for the preparation of a drug delivery device for the treatment of a disease or disorder caused by stenosis or blockage of a body lumen (e.g., an artery or vein) that may be obtained in any technically reasonable combination according to the first aspect of the present invention and embodiments thereof.

Drawings

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

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

Fig. 1 (b) illustrates a balloon that may be adapted for use with the present invention, which may be further attached to or integral with a balloon catheter shaft.

Fig. 2 (a) is a schematic diagram of a drug delivery system of design 1.

Fig. 2 (b) is a schematic diagram of the drug delivery system of design 2.

Fig. 2 (c) is a schematic diagram of the drug delivery system of design 3.

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

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

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

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

Fig. 4 is a side view of a hypotube with a longitudinal slot therethrough.

Fig. 5 is a top view of a hypotube with a longitudinal slot therethrough.

Fig. 6 is a cross-sectional side view of a port for irrigation.

Fig. 7 is a cross-sectional elevation view of a tip.

Fig. 8 illustrates a guidewire port at the proximal end of the balloon.

Fig. 9A illustrates a top view of a wire access port of an outer sleeve in accordance with an embodiment of the present invention.

Fig. 9B illustrates a cross-sectional view of a guidewire port of an outer cannula in an embodiment of the present invention.

Fig. 9C illustrates a top view of a wire access port of an outer sleeve in accordance with an embodiment of the present invention.

Fig. 9D illustrates a cross-sectional view of a guidewire port of an outer cannula in an embodiment of the present invention.

Fig. 10A is a side view of an example drug delivery system (design 2) for PTA, wherein the elastic membrane surrounding the balloon is attached near the proximal and distal ends of the balloon.

Fig. 10B is a side view of an example drug delivery system (design 2) for PTA, wherein the elastic membrane surrounding the balloon is attached to a cannula.

Fig. 10C is a side view of an example of a drug delivery system (design 2) for PTA, wherein the elastic membrane is folded and attached to a balloon and a cannula.

Fig. 11A is a side view of an example of a drug delivery system (design 3) for PTA, wherein the elastic membrane surrounding the balloon is attached near the proximal and distal ends of the balloon, and an outer sleeve surrounds the balloon and elastic membrane.

Fig. 11B is a side view of an example drug delivery system (design 3) for PTA, wherein the elastic membrane surrounding the balloon is connected to a middle sleeve, and an outer sleeve encloses the balloon and elastic membrane.

Fig. 11C is a side view of the outer sleeve, middle sleeve and movement mechanism of the catheter shaft of the drug delivery system.

Fig. 11D is a side view of an example of a drug delivery system (design 3) for PTA/PTCA, the drug delivery system consisting of: the PTA/PTCA is comprised of a sleeve comprised of an inner sleeve and an outer sleeve, the inner sleeve being coupled to the polymer film.

FIG. 12 is a graph showing the comparison of the drug loss amounts of the balloons of the devices A to D described in example 1.

FIG. 13 is a graph showing the comparison of the drug adhesion of silicon tubes of devices C and D described in example 2.

Detailed Description

Fig. 1 (a) illustrates a balloon suitable for use in the present invention, and fig. 1 (b) illustrates a balloon catheter shaft attached to or integral with the balloon catheter shaft. As shown in fig. 1 (a), the balloon 1 comprises a balloon body 2 made of a suitable material, as discussed in more detail below: two balloon shafts 3,4 are located at the balloon ends 5,6. As shown in fig. 1 (b), one balloon shaft 3 may be connected to a balloon catheter 7, while the other balloon shaft 4 may contain a tip 8 of the balloon catheter.

As used herein, "proximal" refers to the end furthest from the tip 8, and "distal" refers to the end closest to the tip 8.

Reference herein to "end" may refer to a portion of the balloon, including two tapered portions immediately following the balloon shaft, respectively. The "working portion" of the balloon may refer to a non-tapered portion intermediate the two tapered portions of the balloon.

For purposes of illustration and not limitation, fig. 2 (a) refers to fig. 2 (c) illustrating the basic concept of an embodiment of the disclosed drug delivery system.

As shown in fig. 2 (a), the drug delivery system 10 may include a balloon 11 having a drug 20 coated on an outer surface 12 of the balloon 11. The outer sleeve 30 is located outside the balloon 11. The outer sleeve 30 protects the drug coated on the balloon surface and minimizes the amount of drug loss during transport of the drug delivery system. We call the subsystem design 1.

The balloon of design 1 for use in therapy or surgery may comprise the steps of:

(1) Optionally, pre-expanding an uncoated balloon catheter into the body cavity to provide an unobstructed passageway for a subsequently coated drug-coated balloon catheter;

(2) Inserting a drug delivery system of design 1;

(3) Placing a distal region of the coated drug-coated balloon delivery system at the lesion, the outer sleeve being retractable in a proximal direction to expose the DEB or the distal region of the coated drug-coated balloon delivery system to the lesion, and the balloon catheter reaching the lesion in advance, the DEB being exposed;

(4) The balloon is expanded to a predetermined size, radially compressing the diseased atherosclerotic plaque to alter the vessel wall structure;

(5) Depressurizing the balloon;

(6) The drug-coated balloon delivery system may be retracted directly. The outer sleeve may be pushed forward or the balloon catheter may be retracted back into the outer sleeve prior to retraction of the drug coated balloon delivery system.

It should be understood that other methods may be employed within the scope of the surgeon's/surgeon's authority to achieve the desired surgical or therapeutic effect. It should also be appreciated that the above-described methods may be used to treat any disease or condition that may be applicable to the treatment of narrowing or obstruction of a body lumen such as, but not limited to, blood vessels (e.g., arteries, capillaries, and veins).

In use of the system, the drug coating on the balloon surface of design 1 is protected by an external cannula, which is passed through the catheter cannula or lumen before the drug delivery system reaches the treatment site. The drug coated on the drug delivery system passes through body lumens of different diameters, different curvatures and different lengths before reaching the treatment site without significant drug loss. The drug coating is exposed to only body fluids or tissues in step (3). The loss of drug during this process can be well controlled because it depends on the friction between the drug coating and the inner surface of the outer sleeve. With a lubricious lining of the outer cannula, drug losses caused by the outer cannula when retracted are minimized.

As shown in fig. 2 (b), the drug delivery system 10 may include a balloon 11 covered with an elastic membrane 40. The outer surface 41 of the elastic membrane 40 is coated with the drug coating 20. The mechanical force generated by the expansion of the elastic membrane 40, and the intermolecular forces between the elastic membrane 40 and the drug coating 20, significantly increase the drug transfer rate, and the drug delivery system is design 2.

The elastic membrane 40 surrounds the balloon so that when the balloon is inflated, the elastic membrane is subjected to pressure from the balloon. Since the therapeutic coating on the surface of the elastic membrane is a rigid material, the pressure applied by the balloon after the expansion weakens the adhesion of the drug coating to the elastic membrane. Thus, when the drug coating is in contact with the treatment site, the treatment coating readily breaks away from the elastic membrane and adheres to the treated tissue.

As shown in fig. 2 (c), the drug delivery system 10 may include a balloon 11 covered with an elastic membrane 40. The outer surface 41 of the elastic membrane 40 is coated with the medicament 20. An outer sleeve 30 is positioned on top of the elastic membrane for protecting the balloon and the elastic membrane. The outer sleeve 30 may protect the drug coating and minimize the amount of drug lost during transport of the drug delivery system. The mechanical force generated by the expansion of the elastic membrane 40 and the intermolecular force between the elastic membrane 40 and the drug coating 20 significantly improve the drug transfer rate, and in this embodiment, the drug loss in the transportation of the drug delivery system and the drug transfer efficiency can be well controlled. The drug delivery system is design 3.

The general features of designs 1 through 3 are discussed below. It is to be understood that such features may be universally applicable unless otherwise indicated.

The use of "including" and "comprising" herein is intended to include all of the mentioned components, but allow for the addition of other components. It should be understood that "comprising," including, "and" also including "are made up of … …," "made up of … …," as a subset of "including," "containing," and "made up of … …" mean being limited to the components mentioned or their components including some other components. For the avoidance of doubt, the explicit "comprising," "including," or "comprising" may be replaced by the word "consisting of … …" or variants thereof.

In aspects and embodiments of the invention, the balloon may be a catheter balloon for a balloon catheter, or the balloon catheter may be, for example, as shown in fig. 1. The material of the balloon may be compliant, semi-compliant or non-compliant. As used herein, "compliant material" refers to a material that allows the balloon to expand and stretch to several times its original size as pressure increases. The balloon may be made of silicone, latex, thermoplastic elastomer material (TEP), and the like. As used herein, "semi-compliant material" and "non-compliant material" refer to a material for a balloon that can maintain the size and shape of the balloon, even when the air pressure inside the balloon exceeds the desired air pressure. When the balloon is made of the semi-compliant or non-compliant material, the balloon may be thin-walled and have a relatively high tensile strength and a relatively low elongation. The material from which the balloon is made is, for example: polyethylene terephthalate (PET), polyamide [ e.g.: polyether block amide (Pebax ^TM) and nylon 12 or Du Lidu (DURETHAN ^TM) or CRISTAMID ^TM), polyurethane, polyethylene (PE) [ for example: marlex ^TM high density polyethylene, marlex ^TM low density polyethylene, and linear low density polyethylene (e.g., REXELL ^TM), polypropylene (PP), polyetherimide (PEI), polytetrafluoroethylene (PTFE), tetrafluoroethylene-ethylene (ETFE), fluorinated Ethylene Propylene (FEP), polyoxymethylene (POM), polybutylene terephthalate (PBT), polyvinyl chloride (PVC), polyether block amides (PEBA, e.g., available from Pebax ^TM), polyethylether ketone (PEEK), polyimide (PI), polyphenylene Sulfide (PPs), polyphenylene oxide (PPO), polyethylene naphthalate (PEN), polysulfone amide, perfluoro (propyl vinyl ether) (PFA), or combinations or mixtures thereof.

When the outer sleeve 30 is present and in design, the outer sleeve 30 covers the balloon and moves relatively. As described herein, the outer sleeve may be moved in a proximal direction or the balloon may be moved in a distal direction to expose the coating. The outer sleeve may be moved a distance equal to or greater than the length of the dilation balloon relative to the balloon catheter. The outer sleeve may be a single layer tube or a multi-layer tube. For example, the single layer tube may be selected from the following materials, but is not limited to: polyethylene (PE), pebax, polyurethane (PU) and nylon. The multilayer tube may be selected from, but is not limited to: double and triple tube. For example, a double tube having an outer layer and an inner layer, or a triple tube having an outer layer, an intermediate layer and an inner layer. For a two-layer structure, the inner layer may be attached to the outer layer, or the outer layer may form the inner layer. The outer layer material of the outer sleeve may be selected from: PE, pebax, polyurethane and nylon. The inner layer material may be selected from: polytetrafluoroethylene (PTFE), fluorinated Ethylene Propylene (FEP), perfluoroalkoxy polymer material (PFA), PE, pebax, polyurethane, and nylon. Preferably, the inner and outer sleeves of the catheter balloon may be of a lubricious material, which may increase the smoothness of sliding of the two. Preferred materials for the inner layer may be selected from, but are not limited to, PTFE, PFA, FEP or HDPE. The three-layer tube may include an outer layer, an intermediate layer, and an inner layer. The three-layer tube may be a braided tube having high torque, high pushability, handleability and bending resistance. The intermediate layer may be a braided wire layer. The material of the braided wire may be 304 stainless steel, 316 stainless steel, polyester, nylon, and nitinol. The density of the braided wire may be 10 to 250 picks per inch and the size of the braided wire may be: the round wire is 0.0005"-0.004", and the flat wire is 0.0005 ". Times.0.003" to 0.002 ". Times.0.007". The intermediate layer may also be formed of one or two wires, such as yarn and stainless steel material. Or the intermediate layer may be a coil structure. The material for the outer layer may be selected from, but is not limited to, PE, pebax, PU and nylon. The material for the inner layer may be selected from PTFE, FEP, PFA, PE, pebax, polyurethane and nylon. Preferably, the inner and outer sleeves of the catheter balloon may be of a lubricious material, which may increase the smoothness of sliding of the two. Preferred materials for the inner layer may be selected from, but are not limited to, PTFE, PFA, FEP or HDPE. Different portions of the outer sleeve may be constructed of different materials. For example, the outer sleeve may be a braided tube connected to a double layer tube. The double-layer tube may be the same as the outer diameter of the braided tube, but may have an inner diameter greater than the inner diameter of the braided tube, as compared to the braided tube.

The drug coating may be selected from one or more of the following group: antiproliferative agents, immunosuppressants, anti-angiogenic inhibitors, anti-inflammatory agents and antithrombotic agents (e.g., the drug may be selected from one or more of the group consisting of paclitaxel, rapamycin, everolimus, zotarolimus, tem Mi Remo st (umirolimus), tacrolimus and pimecrolimus (e.g., the drug may be selected from one or more of the group consisting of paclitaxel, rapamycin, zotarolimus, temsirolimus (umirolimus), such as paclitaxel and rapamycin)).

The drug coating may further comprise an excipient, which may be selected from one or more of the following groups: tartaric acid, sugar, and sugar alcohols (e.g., fructose, glucose, sucrose, lactose, maltose, erythritol, threitol, arabitol, ribitol, mannitol, galactitol, fucitol (fucitol), iditol, inositol, dulcitol, isomalt, maltitol, lactitol, maltotriose, maltotetraol, or, more specifically, xylitol, tartaric acid, and sorbitol (e.g., the excipient may be selected from one or more of the following groups: fructose, glucose, sucrose, mannitol, or, more specifically, sorbitol, or, more specifically, xylitol and tartaric acid)).

The drug coating may further comprise an adhesion balancing layer or primer layer directly attached to the balloon, the adhesion balancing layer or primer layer comprising a hydrophilic polymer and/or a hydrophilic compound, optionally, wherein the hydrophilic compound is selected from one or more of sugar, sugar alcohol and polyethylene glycol (e.g., the hydrophilic compound has a molecular mass of 1000 daltons and may be selected from one or more of fructose, glucose, sucrose, lactose, maltose, erythritol, threitol, arabitol, ribitol, mannitol, galactitol, fucitol (fucitol), iditol, inositol, dulcitol, isomalt, maltitol, lactitol, maltotriose, maltotetraitol, xylitol, tartaric acid and sorbitol (e.g., the hydrophilic compound is selected from one or more of fructose, glucose, sucrose, xylitol, mannitol and sorbitol)). The adhesion balancing layer may be adhered to the drug layer using any suitable method, such as, but not limited to: spray coating, dipping or dip coating, etc.

It will be appreciated that the drug coating may be made by coating the substrate surface (e.g., the elastic film or balloon surface) with a mixture of the drug and optionally excipients, which may include a solvent that makes the coating useful. The manner in which the coating is applied includes, but is not limited to: spray coating, dipping or dip coating, etc.

When present, the elastic membrane 40 has an inner surface and an outer surface, wherein the inner surface is adjacent to or in contact with the balloon. The outer surface may be coated directly with a drug coating, or with an adhesion balancing layer applied to the bottom of the outer surface and a drug coating applied to the top of the outer surface, the drug being as described above.

When present, the elastic membrane 40 may stretch and stretch as the pressure within the balloon increases as the balloon expands. The elastic membrane may cover the balloon in a number of ways. For example, the elastic membrane may cover the balloon as an elastic membrane tube like a tube sleeve. The elastic membrane tube may have a proximal end and a distal end, wherein both ends of the elastic membrane tube may be respectively connected to respective ends of the balloon, or to respective balloon shafts. Alternatively, the elastic membrane may be connected to the sleeve as an elastic tube, such as in fig. 10B, which is relatively movable with respect to the balloon.

In all embodiments and aspects of the present invention, the elastic membrane 40 is in the form of an elastic tube, and the elastic membrane 40 can radially expand when the balloon is expanded. In addition, the elastic tube may be made of a polymeric film, which may optionally further comprise a stent. The stent may minimize the extent of longitudinal expansion of the elastic membrane such that the elastic membrane is primarily radially expanded. The material of the stent may be selected from, but is not limited to, 304 stainless steel, 316 stainless steel, nylon, PET, polyamide, and nitinol, wherein the material is aligned such that the extent of longitudinal expansion of the elastic membrane is minimized without affecting the extent of radial expansion.

The elastic membrane 40 may be made of materials including, but not limited to: silicone elastomers, thermoplastic vulcanizates (TPV), thermoplastic polyester elastomers (COPE), polyether copolyamides (PEBA), thermoplastic Polyurethanes (TPU), polyolefin Thermoplastic Elastomers (TEO), styrene-ethylene-butylene-styrene block copolymers (SEBS). The elastic membrane 40 may also be made of biocompatible materials including, but not limited to: polyolefin copolymers and polyethylene, poly (lactide-co-caprolactone), poly (DL-lactide-co-caprolactone) (DL-PLCL), poly (L-lactide-co-caprolactone) (PLLCL), polycaprolactone (PCL), polyglycolide (PGA), poly (L-lactic acid) (PLLA), poly (glycolide-co-caprolactone) (PGCL) copolymers, poly (D, L-lactic acid), poly (L-lactide-co-D, L-lactide) (PLDLLA), poly (L-lactide-co-glycolide) (PLGA), poly (D-lactide) (PDLA), poly (trimethylene carbonate) (PTMC), poly (lactic acid-trimethylene carbonate) (PLTMC), poly (ethylene glycol carbonate), polydioxanone (PDO), poly (4-hydroxybutyrate) (PHB), polyhydroxyalkanoates (PHA), polyphosphazenes, polybutylene succinate (PBS), copolymers thereof, poly (ethyl-phosphazene), poly (caprolactone-co-hydroxybutyrate), poly (trimethylene carbonate).

The elastic film may have a thickness of 0.001 to 2 millimeters (e.g., 0.05mm to 1 mm).

Specific embodiments of designs 1 through 3 will now be discussed with reference to fig. 3 through 11.

Embodiments of design 1 may include:

A balloon catheter shaft having an inflation lumen, both the inflation lumen and the balloon catheter shaft having proximal and distal ends;

A balloon having a proximal end, a distal end, and a working portion disposed between the proximal and distal ends, wherein the proximal end of the balloon is connected to and in fluid communication with the distal end of the inflation lumen, wherein the balloon forms a cylindrical shape along the working portion when in use or inflated;

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

A drug coating on a surface of the balloon facing the first sleeve, wherein the first sleeve is disposed in a first position such that the balloon is fully covered and the first sleeve is movable relative to the balloon to a second position such that the balloon is fully exposed.

A first embodiment of design 1 is provided in fig. 3 (a), illustrating the device as a drug delivery system for percutaneous transluminal angioplasty. The drug delivery system 100 includes a catheter shaft 110 having a proximal end (proximal to the handle 140) and a distal end (proximal to the tip 155). In this embodiment, the catheter shaft includes a guidewire lumen 120 and an expansion-expanding lumen 130. The guidewire lumen 120 extends to a guidewire port 141 at the proximal side of the handle 140. A guidewire may be introduced through guidewire port 141.

As shown in fig. 3 (a), at the proximal end of the dilation balloon 130, a Y-joint 173 is formed by branching the guidewire lumen 120, and the dilation balloon 130 may be further connected to the hypotube 160. Both hypotube 160 and dilation lumen 130 may be in fluid communication with the interior of expandable dilation balloon 150. Fluid is introduced into the fluid cavity through a female luer adapter 142 or other feature located at the proximal end of the handle 140. The inflation lumen 130 may provide inflation medium for inflation balloon 150 under positive air pressure conditions, and may retract inflation medium for inflation balloon 150 under negative air pressure conditions, with the entire working length of balloon 150 (i.e., the portion of the balloon in contact with the body cavity during operation) remaining cylindrical and of constant length during use or inflation of balloon 150. The tip 155 is connected to the distal end of the expandable balloon 150.

The outer deployment sleeve 180 may cover the entire catheter shaft except for the tip 155. A slotted hypotube 171 may be connected to the proximal end of an outer deployment sleeve 180. Figure 4 shows a slotted hypotube having a distal end 174 and a proximal end 173. As shown in fig. 4, the slotted hypotube also includes a longitudinal slot 177, the slot 177 being one extending partially from the distal end 174 toward the proximal end 173, as shown in fig. 4. The longitudinal slots allow the Y-shaped tabs to move longitudinally relative to each other along the longitudinal slots 177. The Y-joint may include a second hypotube (not shown) that extends through the handle to the Y-joint. The second hypotube may provide a housing within the handle for expanding the dilation lumen 160. The second branch of the Y-connector may comprise a guidewire lumen. Figure 4 also illustrates that the slotted hypotube structure may further include at least one or more cuts or slits 175 to increase the flexibility of the hypotube toward its distal end. The strain relief 185 may be located at the distal end of the handle 140. The strain relief 185 has a channel that receives the slotted hypotube 171 so that the slotted hypotube 171 can move relative to the strain relief. The strain relief provides adequate stress distribution during use of the delivery system, yet avoids unnecessary buckling of the slotted hypotube 171.

Fig. 3 (a) shows a triangular clamping shell 172 located in the handle 140. The triangular clamping housing 172 has a Y-shaped junction with one branch for the guidewire lumen and the other branch for the slotted hypotube 171 and the second hypotube, and the branches are connected to the outer deployment sleeve 180 and the inner dilating catheter lumen 130, respectively. The use of a triangular clamping shell 172 may facilitate relative independent movement of the catheter shaft 110 and the outer deployment sleeve 180. The handle 140 may also include an actuation member 145, the actuation member 145 being configured in a longitudinal position relative to the deployment sleeve 180. For example, when the distal region of the drug delivery system reaches the treatment site, the clinician may move actuation member 145 rearward to retract the proximal end of outer deployment sleeve 180, thereby exposing balloon 150 to the treatment site. After balloon 150 is deflated, and before the drug delivery system is retracted from the body, the clinician may move actuating member 145 forward so that outer deployment sleeve 180 may cover balloon 150.

The outer deployment sleeve may be provided with a substantially constant outer diameter and inner diameter. Alternatively, the outer deployment sleeve may define a first inner diameter at its proximal end and a second, different inner diameter at its distal end. The first inner diameter may be smaller than the second inner diameter and vice versa. By adjusting the inner diameter of the outer sleeve and the outer diameter of the (unexpanded expanded) balloon, the friction generated between balloon 150 and outer sleeve 180 may be reduced, which may reduce drug loss as outer sleeve 180 moves rearward. Alternatively or additionally, the inner diameter of the outer sleeve may be coated with a second material as a balloon cover. The second material may be made of a well known material that reduces friction, such as PTFE or other lubricating materials mentioned herein.

As shown in FIG. 3 (a), the outer sleeve 180 may further include a radiopaque marker band 156 on its distal end, the marker band 156 being used to enable a clinician to precisely locate the catheter position within the patient. It should be understood that the use of radiopaque marker bands is generally applicable to all aspects and embodiments of the invention described herein.

It is necessary to evacuate the gas inside the outer cannula before the drug delivery system is inserted into the blood vessel. Typically, the clinician injects water into the proximal end of the outer cannula and flows water out of the distal end of the outer cannula to complete the evacuation of the gas. This is to prevent the formation of air bubbles in the blood vessel of the subject during implantation. In the drug delivery system 100, there may be at least one port 183 located on the outer deployment sleeve, as shown in fig. 6. In this configuration, the drug delivery system may flush the drug delivery system (e.g., expel air bubbles trapped inside the outer sleeve 180) by pouring fluid into the catheter tubing via port 183. Water may be flushed out from the distal and proximal ends of outer sleeve 180. At the proximal end of outer sleeve 180, fluid may be flushed out through slotted hypotube 171. At the distal end of the outer sleeve 180, fluid may be flushed out through a flat surface or channel 156 on the tip 155 (see fig. 7), which may allow fluid to flow out of the sleeve through the gap between the catheter shaft 110 and the outer deployment sleeve 180.

An alternative embodiment of a drug delivery system 200 for percutaneous transluminal angioplasty according to the general principles of design 1 is provided in fig. 3 (b). This embodiment includes a catheter shaft 210 having a proximal portion and a distal portion, which in this embodiment includes a guidewire lumen 220 that extends through the entire inner tubular member. The proximal end of the handle 230 may be provided with an adapter or manifold 240. Adapter 240 may be a Y-luer connector in which one branch (e.g., proximal to adapter 242) is connected to guidewire lumen 220 and the other branch (e.g., proximal to adapter 241) is connected to dilation lumen 250.

As shown in fig. 3 (b), catheter shaft 210 has an expanding dilation lumen 250 and a guidewire lumen 220. The dilation lumen 250 surrounds the guidewire lumen 220 and further forms a Y-joint at the proximal end of the dilation lumen, the Y-joint being located at the end of the handle 230. Hypotube 265 may surround a proximal portion of dilation lumen 250. Only the dilation lumen 250 is in fluid communication with the lumen of the expandable dilation balloon 260. Fluid is introduced into the fluid chamber through luer adapter 241 or similar port at the proximal end of handle 230. The dilation lumen 250 may provide a dilation medium at positive pressure and the dilation medium may be withdrawn from the expandable dilation balloon 260 at negative pressure. The guidewire lumen 220 is connected to the adapter 242 by a Y-joint. Tip 255 is coupled to the distal end of expandable dilation balloon 260.

The outer deployment sleeve 280 covers the entire catheter shaft except for the tip 255. A flexible hypotube 271 (having one slit 275 at its distal end) is attached to the proximal end of the outer deployment cannula. This design can increase the flexibility of the metallic hypotube and enhance the pushability and crossability of the overall system. The relative movement between the outer sleeve and the catheter shaft is achieved by movement of hypotube 265 and second hypotube 271. The strain relief device 285 may be located between the handle 230 and the hypotube 271, which functions in a similar manner as the strain relief device 185 described above with respect to the device disclosed in fig. 3 (a). The handle 230 may include an actuating member 235, the actuating member 235 being configured to shift the longitudinal position of the catheter shaft member relative to the deployment sleeve 280. For example, when the distal region of the drug delivery system reaches the treatment site, the clinician may move actuating member 235 rearward to retract the proximal end of outer deployment sleeve 280, thereby exposing balloon 2620 to the treatment site. After balloon 260 is deflated, and prior to retraction of drug delivery system 200 from the body, the clinician may move actuating member 235 forward so that outer deployment sleeve 280 may cover balloon 260.

The outer deployment sleeve 280 has a similar construction and functions in a similar manner as that shown in the drug delivery system 100.

An alternative embodiment of a drug delivery system 300 for percutaneous transluminal angioplasty according to the general principles of design 1 is provided in fig. 3 (c). This embodiment includes a catheter shaft 310 having a proximal portion and a distal portion, and an outer sleeve 380, in this embodiment, the catheter shaft includes an expanding inflation lumen 350 and a guidewire lumen 320, as shown in fig. 3 (c), extending from the distal end of the balloon through balloon 360 to a guidewire outlet 321 at the proximal end of the balloon, as shown in fig. 8. The guidewire 322 may be introduced into the guidewire lumen through the outlet 321. The dilation lumen 350 surrounds the guidewire lumen 320 and further extends from the outlet 321.

As shown in fig. 3 (c), the hypotube surrounds the distended distention lumen 350 at its proximal end. Only the inflation lumen 350 is in fluid communication with the inner lumen of the expandable lumen 360. Fluid is introduced into the fluid cavity through luer adapter 340 or similar port at the proximal end of handle 330. The inflation lumen 350 may provide an inflation medium at positive air pressure and the inflation medium may be withdrawn from the inflatable balloon 360 at negative air pressure. Tip 355 is coupled to the distal end of expandable balloon 360.

The outer deployment sleeve 380 covers the entire catheter shaft except for the tip 355. Having a hypotube 371 with a slit similar in structure to that used in the system 200 of fig. 3 (b), the hypotube 371 is attached to the proximal end of an externally deployed cannula. The strain relief device 385 may be located between the handle 330 and the hypotube 371, which functions in a similar manner as previously described. The outer sleeve may have an opening 381 in its distal region to allow the guidewire 322 to extend further from the outlet port 321, as shown in fig. 9A-D. The opening may be a slot (fig. 9A and 9B) or a circle (fig. 9C and 9D). An adapter may be provided at the proximal end of handle 330. The adapter may be a luer connector 340 that connects (or connectable) to the expansion lumen 350. The handle 330 may include an actuation member 335, the actuation member 335 configured in a longitudinal position relative to the deployment cannula 380. The guidewire 322 may move with the catheter shaft along a slot 381 in the outer sleeve 380.

For both PTA and PTCA, a polymeric film may be added to a balloon catheter having a first end, a second end and a middle portion. The preferred material from which the polymer film is made is a non-elastic polymer, but elastic polymers can still be used. The first end is connected to the outer sleeve and the second end is connected to the proximal end of the balloon, while the intermediate portion may or may not be folded and extends along the inner surface of the sleeve when the sleeve is retracted. The handle operates in a similar manner to PTA and PTCA. Fig. 3 (d) is a diagram of the application of such a polymer film to a drug-based delivery device 100. The first end 161 of the polymer membrane is connected to the outer sleeve 180 and the second end 163 of the membrane is connected to the proximal end of the balloon. When the outer sleeve 180 is retracted, the middle portion of the polymer film will extend along the inner surface of the sleeve. By using this design, there is little likelihood of introducing air bubbles in the blood system. It should be understood that such polymer films may be generally applicable to other aspects and embodiments of the present invention where one or more cannulae are present.

Materials used in catheter shafts, including guidewire lumens, dilation balloons, and tips that may be made of any suitable material, including but not limited to: polymeric materials, for example: nylon, polyurethane, PEEK, PTFE, PVDF, PEBAX, PE. The outer deployment sleeve may be constructed of a suitable single layer of material. For example, suitable materials may include, but are not limited to, polymeric materials such as nylon, polyurethane, PEEK, PTFE, PVDF, PEBAX, PE or bilayer and trilayer materials selected from nylon, polyurethane, PEEK, PTFE, PVDF, PEBAX, PE. In addition, unless specifically stated otherwise, these materials are generally applicable to similar components in other aspects and embodiments of the present invention.

The hypotube or slotted hypotube may be made of a material comprising metal or plastic. Metals from which hypotubes are made include, but are not limited to, stainless steel including 302, 304v,316l or nitinol. The plastic from which the hypotube is made includes, but is not limited to, a polymeric material such as nylon, polyurethane, PEEK, PTFE, PVDF, PEBAX, or PE. As shown in fig. 5, the slot 177 may be located in a longitudinal direction on one side of the hypotube, which facilitates movement of the hypotube coupled to the inner catheter shaft. As shown in fig. 5, the slot 177 may be located in a longitudinal direction on one side of the hypotube, which facilitates movement of the hypotube coupled to the inner catheter shaft. The slot is wide enough to allow the hypotube to move with the guidewire lumen. The slotted hypotube may also include one or more cuts or slits to improve the flexibility of the hypotube. These features may be applied generally to all aspects and embodiments of the present invention.

In the embodiments discussed herein, the expandable balloon may be designed as a collapsible structure and covered by a deployment cannula tube. When used at a treatment site, the outer deployment sleeve is retracted to a length at least equal to the total length of the expandable balloon and the tip to allow for balloon deployment.

It should be appreciated that when using the device of design 1 as described herein, the drug coating remains in the patient's body cavity and the drug is consumed. Thus, the device is suitable for use with drugs according to the design of design 1 as a reference example, and the invention is therefore not limited to the specific embodiments discussed herein.

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

a balloon having a proximal end and a distal end;

A first elastic membrane configured to encase at least a portion of the balloon;

a drug coated on the second surface;

When the first elastic film is arranged to at least wrap a part of the balloon, the surface of the first elastic film, which is contacted with the balloon, is a first surface, the surface of the first elastic film, which is opposite to the balloon, is a second surface, and the first elastic film can be stretched to 1.1 times of the original size of the first elastic film.

As used herein, "configured to" may refer to a component securing configuration that stretches the first elasticity to the desired effect, as shown in fig. 10A below. Alternatively, "set to" may also refer to movement of a component from a first spatial arrangement to a second spatial arrangement, wherein either the first spatial arrangement (see fig. 10B) or the second spatial arrangement (see fig. 11B) may expand the first elastic membrane, while other spatial arrangements may not achieve this effect. It should be understood that "disposable" means that the device is movable in the above-described spatial arrangements and that the device is usable in both the first spatial arrangement and the second spatial arrangement.

It will be appreciated that the device may be a catheter balloon of a balloon catheter, or a balloon catheter. The material of the balloon may be compliant, semi-compliant or non-compliant. In particular embodiments of designs 2 and 3, the balloon material may be semi-compliant or non-compliant.

After balloon inflation, the elastic membrane may be stretched to a diameter 1.1 to 20 times (e.g., 1.5 to 10 times, such as 2 to 5 times) its original diameter.

Without wishing to be bound by theory, the drug coating on the elastic membrane is stretched as the elastic membrane expands, under the mechanical pressure resulting therefrom, causing the drug coating to rupture. Mechanical disruption of the drug coating may assist in transferring the drug to the desired site of action. In addition, the elastic membrane may be selected to have a suitable balance of chemical properties (e.g., hydrophilicity and hydrophobicity) such that the intermolecular interactions between the elastic membrane and the drug coating are sufficiently strong to prevent excessive detachment of the drug, yet to ensure that the intermolecular interactions between the elastic membrane and the drug coating are not so strong as to not interfere with the efficiency of drug transfer to the site of action (e.g., when otherwise subjected to mechanical pressure from balloon expansion).

An embodiment of the present invention relating to a drug delivery system designed according to the principles of design 2 is shown in fig. 10A. Drug delivery device 400 includes a catheter shaft 410 having a proximal portion and a distal portion. In this embodiment, the catheter shaft includes a guidewire lumen 420 and an expansion lumen 430. The catheter shaft 410 is connected at its distal end to a balloon 450. The elastic membrane 440 covers the balloon 450 and is coupled to the proximal and distal ends of the balloon shaft 455, and the drug coating 460 is located on the surface of the elastic membrane 440.

The elastic membrane herein may refer to the elastic membrane being directly coupled to the proximal end of the balloon, the proximal end of the balloon shaft, or the catheter shaft when the elastic membrane herein covers the balloon, and may refer to the elastic membrane being directly coupled to the tapered portion of the distal end of the balloon, the proximal balloon shaft, or the tip of the catheter shaft when the elastic membrane is coupled to the distal end of the balloon. It should be understood that these attachment/bonding points may be generally applicable when the elastic membrane is described as being in direct contact with the balloon unless otherwise indicated. Methods of attaching the elastic membrane to the balloon include, but are not limited to, attaching the elastic membrane to the balloon

One possible method of using a balloon for treatment or surgery according to the present invention designed according to the principles of design 2 is shown in fig. 10A, wherein the combination of the elastic membrane and the balloon may comprise the steps of:

(2) The coated balloon catheter is inserted into the pre-dilated vessel through the guiding sheath/guiding catheter/sleeve to reach the intervention site;

Another embodiment of the present invention relating to a drug delivery system designed according to the principles of design 2 is shown in fig. 10A. Drug delivery device 500 includes a catheter shaft 510 having a proximal portion and a distal portion. In this embodiment, catheter shaft 510 includes a guidewire lumen 520 and an expansion lumen 530. Elastic membrane 540 surrounds balloon 550. The proximal end of the elastic membrane is connected to the sleeve 545. The sleeve 545 may be moved relative to the catheter shaft 510 to allow relative movement of the elastic membrane 540 and the balloon 550. The drug coating 560 is located on the surface of the elastic membrane 540. The assembled structure of the device is similar to drug delivery systems 100 and 200. The drug delivery system 500 may be applied regardless of the handle design. Fig. 10B shows a design similar to drug delivery system 100.

One possible method of using a balloon for treatment or surgery according to the present invention designed according to the principles of design 2 is shown in fig. 10B, wherein the elastic membrane forms part of a cannula on the balloon, which may include the steps of:

(1) The drug-coated balloon delivery system according to design 2, wherein the elastic membrane forms a sleeve over at least a portion of the balloon and advances into the treatment site;

(2) Advancing the balloon without the sleeve for pre-dilation to ensure a clear passageway;

(3) Releasing the pressure of the balloon;

(4) Retracting the balloon into the cannula, the balloon entering the lesion site together with the cannula, or the cannula may have covered the balloon when reaching the lesion site (the cannula covering the balloon is an elastic membrane);

(5) Expanding the balloon to a predetermined size, radially pressing against the atherosclerotic plaque at the lesion to alter the vessel wall structure, thereby expanding the elastic membrane and transferring the drug from the membrane to the lesion site;

(6) The drug-coated balloon delivery system may be directly withdrawn.

Another embodiment of the present invention relating to a drug delivery system designed according to the principles of design 2 is shown in fig. 10C. In this embodiment, the elastic membrane 540 may have a first end 511, a second end 512, and an intermediate portion 513, wherein the first end 511 is connected to the sleeve 545, the second end 512 is connected to the distal end 551 of the balloon, and the intermediate portion 513 may extend along the inner surface of the sheath when the sleeve 545 is covering the balloon (it will be appreciated that the intermediate portion may be folded along the inner surface of the sleeve when the sleeve is covering the balloon). When the cannula 545 is retracted, the therapeutic coating 560 is exposed. The above method is applicable to the present embodiment.

In the case where the elastic membrane is attached to the cannula, the pre-dilation step of the balloon catheter may be omitted. The relative movement between the cannula and the balloon catheter enables the balloon catheter to be used for pre-dilation and drug delivery. It should be appreciated that pre-dilation is an optional step and its use depends on the choice of clinician and the clinical condition of the patient.

It should be understood that other methods within the scope of physician/surgeon authority may be used as well using design 2 mentioned herein and other derivations methods that may achieve the desired effect of the procedure or treatment. It should also be appreciated that the above-described methods may be applicable to the treatment of any disease or condition that results in a stenosis or obstruction of a body lumen, such as, but not limited to, blood vessels (e.g., arteries, capillaries, and veins).

It will be appreciated that when using the device of design 2 as described herein, the device is consumed because the drug coating remains in the body cavity of the patient. Thus, the device may be adapted for use with the medicament of the medicament delivery device prepared according to the principles of design 2 described above, such as, but not limited to, the specific embodiments discussed above.

An embodiment of the present invention relating to a drug delivery system designed according to the principles of design 3 is shown in fig. 11A. Drug delivery device 600 includes a catheter shaft 610 having a proximal portion and a distal portion, which in this embodiment includes a guidewire lumen 620 and an expansion lumen 630. Coupled to balloon 650 at the distal end of dilation lumen 630. The elastic membrane 640 surrounds the balloon 650. As shown in fig. 11A, the elastic membrane may be bonded to the proximal and distal ends of the balloon shaft 655, or to the balloon body or catheter shaft. The elastic membrane may be wrapped around the balloon as a sleeve, or may be further folded with the balloon. The drug coating 660 is located on the surface of the elastic membrane 640. The outer sleeve 680 covers the entire catheter shaft. The outer cannula 680 may be moved rearward by a clinician to proximally withdraw the cannula. The outer sleeve 680 may be moved forward by a clinician's operation to retract the proximal end of the catheter shaft into the sleeve.

One possible method of using a balloon for treatment or surgery according to the present invention designed according to the principles of design 3 is shown in fig. 11A, wherein the combination of the elastic membrane and the balloon may comprise the steps of:

(1) Inserting an uncoated balloon catheter into the body cavity for pre-dilation to provide an unobstructed passageway for a subsequent coated drug-coated balloon catheter;

(2) Combining the elastic membrane with a balloon and introducing a drug delivery system according to design 3;

(3) The distal region of the drug delivery system is advanced and positioned at the lesion site, and the outer deployment sleeve is retracted in the proximal direction exposing the drug coating on the elastic membrane; or the distal end region of the drug delivery system is advanced and positioned at the lesion site, and then the balloon catheter is advanced and positioned at the lesion site, thereby exposing the drug coating;

(4) Expanding the balloon to a predetermined size, radially pressing against the atherosclerotic plaque at the lesion to alter the vessel wall structure, thereby expanding the elastic membrane and transferring the drug from the membrane to the lesion site;

(5) Releasing the pressure of the saccule to recover the elastic membrane and leave the medicament on the treatment point;

(6) The drug delivery system is retracted and the balloon is either covered with neither a cannula nor an elastic membrane, or is subsequently covered.

In this procedure, the drug on the elastic membrane requires protection by the external cannula because the drug delivery system needs to traverse the tortuous blood vessel before reaching the treatment site. The drug coating in the drug delivery system can pass through body lumens of different diameters, different curvatures and different lengths without any loss of drug. Since the drug coating is exposed to body fluids or tissues only in step (3), the loss of drug in the process can be well controlled. By reducing friction between the drug coating and the inner surface of the outer sleeve. This control effect can be further enhanced. For example, a lubricious layer may be added to the inner surface of the outer sleeve to minimize drug loss by the balloon as it moves out of the outer sleeve.

Another embodiment of the present invention relating to a drug delivery system designed according to the principles of design 3 is shown in fig. 11B. Drug delivery system 700 includes a catheter shaft 710 having a proximal portion and a distal portion. In this embodiment, the catheter shaft 710 includes a guidewire lumen 720 and an expansion lumen 730. Elastic membrane 740 is positioned over balloon 750. The proximal end of the elastic membrane is connected to an intermediate sleeve 745. The middle sleeve 745 may move relative to the catheter shaft 710, which results in relative movement of the elastic membrane 740 and balloon 750.

The drug coating 760 is located on the surface of the elastic membrane 740. The outer sleeve 780 covers the intermediate sleeve and is movable relative to the catheter shaft 710 and the intermediate sleeve 745. When drug delivery is required to pass through a guide catheter or a curved blood vessel before reaching the lesion site, the drug coating 760 on the surface of the balloon 750 is protected by the outer cannula 780. The drug coating in the drug delivery system can thus pass through vessels of different diameters, different tortuosity and different lengths without any loss of drug on its way to the lesion site. When the outer sleeve 780 is retracted, the drug coating is exposed only to body fluids and/or tissue. So that the loss of drug during retraction can be well controlled as long as the friction between the drug coating 760 and the inner surface of the outer cannula is controlled. The use of a lubricating material in the inner liner of the outer sleeve minimizes drug loss during shrinkage. In addition, the drug delivery effect to the site of action is significantly enhanced by using mechanical forces generated by the expansion of the elastic membrane and intermolecular interactions between the elastic membrane 740 and the drug coating 760.

Fig. 11C shows a hub element 711 (hub) connected to the catheter shaft 710, which hub element 711 can be pulled back and forth to allow movement relative to the middle and outer sleeves 745, 780. The outer sleeve 780 is coupled to the slider 712 such that the slider 712 can move the outer sleeve 780 relative to the intermediate sleeve 745 and the catheter shaft 710. The elastic membrane 740 is connected at the distal end to the intermediate sheath 745, in this embodiment the handle body is not movable. It should be appreciated that other suitable configurations may be devised.

One possible method of the present invention for treatment or surgery using a balloon designed according to the principles of design 3 is shown in fig. 11B and 11C, wherein the combination of the elastic membrane and balloon may comprise the steps of:

(1) Advancing the balloon delivery system coated with the drug to the lesion site, and then advancing the balloon catheter under the protection of the outer sleeve and the inner sleeve to pre-expand, thereby ensuring a clear passage for delivering the drug, or advancing the balloon catheter to the lesion site before the sleeve for ensuring a clear passage;

(2) Releasing pressure of the balloon catheter;

(3) The balloon may be retracted into an intermediate sleeve containing the elastic membrane and advanced with the balloon catheter to the lesion, or both the outer sleeve and the intermediate sleeve may be advanced to cover the balloon, the outer sleeve may be retracted and expose the elastic membrane and balloon;

(4) The balloon expands to a predetermined size, radially compressing the diseased atherosclerotic plaque to alter the vessel wall structure, thereby expanding the elastic membrane and transferring the drug from the membrane to the diseased site;

(5) Releasing the pressure of the saccule, recovering the elastic membrane and leaving the medicine on the lesion site;

(6) The drug delivery system may be retracted directly, or the outer cannula may be pushed forward to cover the balloon, and the balloon and intermediate cannula of the intermediate cannula retracted into the outer cannula before the drug coated balloon delivery system is retracted.

In the above method, it should be understood that the apparatus shown in fig. 11B may be provided:

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

(b) A balloon covered with a sheath 745, the balloon and intermediate sheath being in an advanced position relative to the outer sheath 780; or (b)

(C) The balloon is covered by a middle sleeve 745 and an outer sleeve 780.

In the case where the elastic membrane is connected to the intermediate sleeve, the balloon catheter for pre-dilation may be omitted. The relative movement between the intermediate sleeve and the balloon catheter enables the balloon catheter to be used for pre-dilation and drug delivery.

Yet another alternative embodiment of a drug delivery system according to the principles of design 3 is shown in fig. 11D. Drug delivery system 800 includes a balloon catheter (e.g., PTCA catheter 810 or PTA catheter 815) and a sleeve 820. The sleeve consists of an inner sleeve 821 and an outer sleeve 822. The inner sleeve 821 has a resilient membrane 825 at its distal end that can cover at least a portion of the balloon 870. The drug coating 860 is on the surface of the elastic membrane 825. Outer sleeve 822 surrounds inner sleeve 821 and thereby encloses the balloon. Inner sleeve 821 and outer sleeve 822 may be movable together or may be movable relative to each other. The cannula 820 and the PTCA balloon catheter 810 or PTA balloon catheter 815 may be introduced separately.

It will be appreciated that when using the device of design 3 as described herein, the device is consumed because the drug coating remains in the patient's cavity. Thus, the device may be adapted for use of a drug as defined in the manufacture of a drug delivery device according to the concept of design 3 as a reference example, and the invention is therefore not limited to the specific embodiments discussed herein.

Detailed Description

Example 1

The test article was coated with the same drug coating formulation and the same coating method.

Test article

Device a is a drug delivery device similar to that prepared in fig. 3 (a).

Device B is a drug delivery device prepared similarly to fig. 10 (c).

Device C is a drug delivery device similar to that prepared in fig. 10 (a).

Device D is a typical balloon catheter.

Method of

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

The following adaptations were made:

The wall of the model vessel uses a silicon tube.

No imaging of the model vessel wall is required, so the balloon is not treated with fluorescent material.

Drug content was extracted with ACN and analyzed at 227nm with an ultraviolet spectrophotometer.

The balloon was under pressure of 12 ATM.

In addition, residual drug on the balloon was also analyzed, deducing the loss of drug during balloon introduction and delivery.

Results

As shown in fig. 12, device a with an outer sleeve has significantly reduced drug loss compared to typical balloon catheters D. The device C with elastic membrane also has significantly reduced drug loss compared to the typical balloon catheter D device. The device B with the elastic membrane and the outer sleeve has a more remarkable effect of reducing the loss of the drug than the typical balloon catheter D. Device B also has lower drug loss than a and C.

Example 2

Test article

Device C is a drug delivery device similar to that prepared in fig. 10 (a).

Device D is a typical balloon catheter.

Method of

The following adaptations were made:

The wall of the model vessel uses a silicon tube.

Shortening the transport path.

No imaging of the model vessel wall was performed, so the balloon was not treated with fluorescent material.

Drug content was extracted in ACN and analyzed at 227nm using UV spectrometer.

The balloon was under pressure of 12 ATM.

Results

As shown in fig. 13, device C with an elastic membrane, silicon tubing significantly adheres more drug than typical balloon catheter D devices. The results shown in fig. 2 clearly demonstrate that the device design described above significantly improves the drug transfer efficiency at the site of action.

Claims

1. A drug delivery device, comprising:

A balloon having a proximal end and a distal end;

a drug coating applied to a second surface of the first elastic membrane;

Wherein when the first elastic membrane surrounds at least a portion of the balloon, the side of the first elastic membrane facing the balloon is a first surface of the first elastic membrane, the side facing away from the balloon is a second surface of the first elastic membrane, and the first elastic membrane can expand to at least 1.1 times its original size when the balloon is inflated;

the device further comprises a first sleeve movable relative to the balloon, the first sleeve covering at least a portion of the balloon when in a first position, the balloon being exposed from the first sleeve when in a second position,

The first elastic film has a first end, a second end and a middle portion,

Wherein a first end of the first elastic membrane is connected to the first sleeve and a second end of the first elastic membrane is connected to the distal end of the balloon, and wherein an intermediate portion of the first elastic membrane extends along the first surface of the first sleeve when the first sleeve is in the first position.

2. The drug delivery device of claim 1, wherein the balloon is constructed of a compliant material, a semi-compliant material, or a non-compliant material.

3. The drug delivery device of claim 1, wherein the first elastic membrane expands to 1.1 to 20 times its original size after the balloon is inflated.

4. The drug delivery device of claim 1, wherein the first elastic membrane expands in a radial direction.

5. The drug delivery device of claim 1, wherein (a) the material from which the first elastic membrane is made comprises a silicone, a thermoplastic elastomer, or a mixture of both; and/or

(B) The first elastic film is a continuous film, or a web, or a film having a plurality of apertures.

6. The drug delivery device of claim 5, wherein the material from which the first elastic membrane is made further comprises a scaffold material for limiting longitudinal expansion of the first elastic membrane.

7. The drug delivery device of claim 1, wherein the first elastic membrane surrounds the balloon and is bonded to the balloon at a proximal end and a distal end of the balloon, or is bonded to the balloon near the proximal end and near the distal end of the balloon, respectively.

8. The drug delivery device of claim 1, further comprising a first sleeve, a side of the first sleeve facing the balloon being a first surface of the first sleeve and a side facing away from the balloon being a second surface of the first sleeve, wherein the first elastic membrane forms at least a portion of the first sleeve, the first sleeve and the balloon being relatively movable to expose the balloon from the first sleeve.

9. The drug delivery device of claim 8, further comprising a second sleeve surrounding the first sleeve, the second sleeve being movable relative to the first sleeve to expose the first elastic membrane from the second sleeve.

10. The drug delivery device of claim 1, wherein the intermediate portion is folded and extends along the first surface of the first sleeve when the first sleeve is in the first position.

11. The drug delivery device of claim 7, further comprising a third sleeve surrounding the first elastic membrane and the balloon, the third sleeve being movable relative to the balloon such that the first elastic membrane and the balloon are exposed from the third sleeve.

12. The drug delivery device of claim 9, wherein the second sleeve comprises a non-elastic polymeric material.

13. The drug delivery device of claim 11, wherein the third sleeve comprises a non-elastic polymeric material.

14. The drug delivery device of any one of claims 1 to 13, wherein the drug coating comprises one or more drugs from the group: antiproliferative agents, immunosuppressants, anti-angiogenic agents, anti-inflammatory agents and antithrombotic agents.

15. The drug delivery device of claim 14, wherein the drug is selected from one or more of the group consisting of: paclitaxel, rapamycin, everolimus, zotarolimus, temsirolimus (umirolimus), tacrolimus and pimecrolimus.

16. The drug delivery device of claim 14, wherein the drug coating further comprises: an excipient selected from one or more of the following: tartaric acid, sugar and sugar alcohols; and/or

The drug coating further comprises an adhesion balancing layer or primer layer directly attached to the balloon, the adhesion balancing layer or primer layer comprising a hydrophilic polymer and/or a hydrophilic compound, wherein the hydrophilic compound is selected from one or more of a sugar, a sugar alcohol and a polyethylene glycol.

17. The drug delivery device of claim 16, wherein the excipient is selected from one or more of the group consisting of: fructose, glucose, sucrose, lactose, maltose, erythritol, threitol, arabitol, ribitol, mannitol, galactitol, fucitol (fucitol), iditol, inositol, dulcitol, isomalt, maltitol, lactitol, maltotriose, maltotetraol;

The hydrophilic compound has a molecular mass of less than 1,000 daltons and is selected from one or more of the following groups: fructose, glucose, sucrose, lactose, maltose, erythritol, threitol, arabitol, ribitol, mannitol, galactitol, fucitol (fucitol), iditol, inositol, dulcitol, isomalt, maltitol, lactitol, maltotriose, maltotetraitol, xylitol, sorbitol, and polyethylene glycol.

18. The drug delivery device of claim 16, wherein the excipient is selected from one or more of the group consisting of: xylitol, tartaric acid and sorbitol;

19. Use of a medicament as defined in claim 14 for the preparation of a drug delivery device as defined in claims 1 to 18.