Drug delivery device and method of manufacturing medical device

Abstract

The invention relates to a drug delivery device and a method of manufacturing a medical device. The present invention provides a drug delivery device, the drug delivery device comprising: a matrix comprising a hydrophilic polyether block amide copolymer, the hydrophilic polyether block amide copolymer comprising PEG; a coating comprising a layer of therapeutic agent forming an outer surface of at least a portion of the drug delivery device, the layer of therapeutic agent contacting the hydrophilic surface of the matrix and comprising a particulate hydrophobic therapeutic agent and a cationic agent. Additional drug delivery devices and methods of making medical devices are also provided.

Description

[0001] This application is a continuation-in-part of the invention patent application entitled "Delivery of Hydrophobic Active Agents from Hydrophilic Polyether Block Amide Copolymer Surfaces" having an application date of December 15, 2017, and application number 2017800790755 (International Application Number PCT / US2017 / 066573), naming Surmodics, Inc., a U.S. national corporation, as the applicant for all designated countries, and Timothy M. Kloke, a U.S. citizen, as the inventor for all designated countries.

[0002] This invention patent application is being filed on December 15, 2017 as a PCT International Patent Application in the name of Surmodics, Inc., a U.S. national corporation, applicant for all designated countries, and Timothy M. Kloke, a U.S. citizen, inventor for all designated countries, and claims priority to U.S. Provisional Patent Application No. 62 / 436,694, filed December 20, 2016, and U.S. Patent Application No. 15 / 840,540, filed December 13, 2017, the contents of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0003] The present invention relates to devices and coatings for medical devices. More specifically, the present invention relates to devices and coatings for medical devices that include a hydrophilic polyether block amide copolymer and hydrophobic active agent particles disposed thereon. BACKGROUND

[0004] The human vascular system is prone to blockage due to plaque within the arteries. Partial and even complete blockage of the arteries by atheromatous plaque formation is a well-known and often occurring medical problem. Frequently, such blockages occur in the coronary arteries. Blockages can also occur secondarily after treatment at a particular site (restenosis - for example, restenosis caused by rapid division of smooth muscle cells). In addition, blockages can occur in the context of peripheral arteries.

[0005] Blockages can be treated using atherectomy devices that mechanically remove plaque; thermal or cryogenic lasers that vaporize plaque; stents that keep the artery open; and other devices and procedures designed to increase blood flow through the artery.

[0006] One common procedure for treating clogged arteries is percutaneous transluminal coronary angioplasty (PTCA), also known as balloon angioplasty. In this procedure, a catheter having an inflatable balloon at its distal end is introduced into a coronary artery, the deflated, collapsed balloon is placed at the site of stenosis, and then the balloon is inflated. Inflation of the balloon disrupts and destroys plaque attached to the artery wall and stretches the artery wall, which results in enlargement of the intraluminal passageway and increased blood flow. After such inflation, the balloon is deflated and the balloon catheter is removed. A similar procedure called percutaneous transluminal angioplasty (PTA) is used for arteries other than coronary arteries in the vascular system. In other related procedures, a small mesh tube called a stent is implanted at the site of stenosis to help maintain the opening of the coronary artery. In an atherectomy procedure, also known as percutaneous transluminal rotablation (PCRA), small, diamond-tipped drill-like devices are inserted into the affected artery by a catheterization procedure to remove fatty deposits or plaque. In a cutting balloon procedure, a balloon catheter having small blades is inflated to position the blades, score the plaque, and press fatty material into the artery wall. During one or more of these procedures, it can be desirable to deliver a therapeutic agent or drug to the area being treated to prevent restenosis, repair vascular dissections or small aneurysms, or provide other desired treatment.

[0007] Additionally, it can be desirable to deliver a therapeutic agent to other locations in a mammal, such as the skin, the neurovascular system, the nasal cavity, the oral cavity, the lungs, the mucosa, the sinuses, the gastrointestinal tract, or the perirenal vasculature. SUMMARY

[0008] Embodiments of the present invention include drug delivery coatings and devices including the drug delivery coatings. In one embodiment, a drug delivery coating is included. The drug delivery coatings include a base polymer layer comprising a hydrophilic polyether block amide copolymer and having a hydrophilic surface. The drug delivery coating can further include a therapeutic agent layer forming an outer surface of the drug delivery coating, the therapeutic agent layer contacting the hydrophilic surface of the base polymer layer and having a composition different from the base polymer layer. The therapeutic agent layer can comprise a particulate hydrophobic therapeutic agent and a cationic agent.

[0009] In one embodiment, a drug delivery device is included. The drug delivery device can include a matrix comprising a hydrophilic polyether block amide copolymer and having a hydrophilic surface. The drug delivery device can further include a therapeutic agent layer forming an outer surface of at least a portion of the drug delivery device, the therapeutic agent layer contacting the hydrophilic surface of the matrix. The therapeutic agent layer can comprise a particulate hydrophobic therapeutic agent and a cationic agent.

[0010] In one embodiment, a method of making a medical device is included. The method can include depositing a therapeutic agent layer onto at least a portion of the medical device, the medical device including a matrix comprising a hydrophilic polyether block amide copolymer. The therapeutic agent layer can contact a surface of the matrix. The therapeutic agent layer can include a particulate hydrophobic therapeutic agent and a cationic agent.

[0011] This Summary is a broad overview of some of the teachings of this application and is not intended to be exclusive or exhaustive. Further details can be had in the following detailed description and the appended claims. Other aspects will be apparent to persons skilled in the art upon reading and understanding the following detailed description and viewing the drawings that form a part of this detailed description. The scope of the present application is defined by the appended claims and their legal equivalents. BRIEF DESCRIPTION OF DRAWINGS

[0012] The present application can be more completely understood in consideration of the following detailed description in connection with the following drawings, in which: Figure 1 is a schematic cross-sectional view of a coating according to one embodiment herein.

[0013] Figure 2 is a schematic cross-sectional view of a coating according to one embodiment herein.

[0014] Figure 3 is a schematic cross-sectional view of a coating according to one embodiment herein.

[0015] Figure 4 is a schematic cross-sectional view of a coating according to one embodiment herein.

[0016] Figure 5 is a schematic view of a device according to one embodiment herein.

[0017] Figure 6 is a schematic cross-sectional view of a coating according to different embodiments herein.

[0018] Figure 7 is a schematic cross-sectional view of a coating according to different embodiments herein.

[0019] Figure 8 is a schematic cross-sectional view of a coating according to different embodiments herein.

[0020] Figure 9 is a schematic cross-sectional view of a coating according to different embodiments herein.

[0021] While the application is susceptible to various modifications and alternative forms, specific embodiments thereof have been shown by way of example and are herein described in detail. It should be understood, however, that the application is not to be limited to the particular embodiments described. Rather, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the application. DETAILED DESCRIPTION

[0022] The embodiments of the application described herein are not intended to be exhaustive or to be limited to the precise form disclosed in the following detailed description. Rather, the intention is to convey the spirit and scope thereof. Accordingly, we intend in the following detailed description that changes be made in form and content, also.

[0023] All publications and patents mentioned herein are incorporated by reference. The disclosures of publications and patents in this document are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate the publications and / or patents by virtue of prior application or anticipation.

[0024] As noted above, it can be desirable to deliver a therapeutic agent or drug to a region undergoing treatment in connection with a procedure, such as percutaneous transluminal coronary angioplasty (PTCA), percutaneous transluminal angioplasty (PTA), and the like, to prevent restenosis, repair a vascular dissection or small aneurysm, or provide other desired treatment. One approach for accomplishing this is to deliver a therapeutic agent (or active agent) to a desired tissue site using a drug delivery device, such as a drug eluting balloon catheter or a balloon catheter containing a drug.

[0025] Drug delivery coatings for certain medical applications desirably exhibit different characteristics. By way of example, in the context of a drug eluting balloon catheter or a balloon catheter containing a drug, the coating should maintain structural integrity during steps associated with the manufacture of the balloon catheter device, including crimping, folding, and curing (e.g., heat treatment). In addition, it is desirable for the coating to maintain structural integrity (limited loss of active agent) during passage through the vasculature via a catheter and / or guide wire. Furthermore, it is desirable for the coating to maximize active agent uptake into the tissue of the vessel wall and reduce the amount of active agent that is washed into the blood flowing through the treatment site of the vasculature when the balloon is inflated at the desired site to transfer a quantity of active agent from the balloon to the vessel wall.

[0026] Embodiments herein can be useful for enhancing one or more desirable properties of a drug delivery coating, such as those desirable in the context of drug eluting balloon catheters, balloon catheters containing drugs, and similar devices. In various embodiments, a drug delivery device is provided that includes a substrate and coated therapeutic agent particles disposed on the substrate. The coated therapeutic agent particles can include particulate hydrophobic therapeutic agent and cationic agent disposed on the particulate hydrophobic therapeutic agent.

[0027] Referring now to Figure 1 , a schematic cross-sectional view (not to scale) of a coating according to one embodiment herein is provided. In this embodiment, coated therapeutic agent particles 104 are disposed on a substrate 102. Exemplary substrates are described in greater detail below. The coated therapeutic agent particles 104 can include a plurality of cationic agent 108 disposed on particulate hydrophobic therapeutic agent 106. The coated therapeutic agent particles 104 can be continuously coated with cationic agent 108. In other embodiments, the cationic agent 108 coating on the therapeutic agent particles 104 can be discontinuous. Additionally, the particulate hydrophobic agent 106 can be co-resident in the matrix with the cationic agent 108, where the cationic agent 108 does not coat the particulate hydrophobic agent 106. Various mixtures of the above embodiments can be found in a particular substrate 102. For example, but not by way of limitation, a coating on a substrate can include coated therapeutic agent particles 104 that are continuously coated with cationic agent 108 and particulate hydrophobic agent 106 in a matrix with cationic agent 108, where the cationic agent 108 does not coat the particulate hydrophobic agent 106. It will be appreciated that when actually applied, there will be many hydrophobic therapeutic agent microparticles within a given coating, and a single microparticle is shown in Figure 1 for ease of illustration purposes only. Exemplary cationic agents and hydrophobic therapeutic agents are described in greater detail below. The charge provided by the cationic agent 108 can be electrostatically attracted to negative charges and / or polar groups associated with the lipid bilayer 110 of a cell membrane and cellular components within the lipid bilayer 110.

[0028] In some embodiments, nucleic acids can also be included in the coatings herein. By way of example, nucleic acids, including but not limited to siRNA, can be associated with the cationic agent. Exemplary nucleic acids are described in greater detail below. Referring now to Figure 2, a schematic cross-sectional view (not to scale) of another embodiment herein is provided. In this embodiment, coated therapeutic particles 204 are disposed on a matrix 202. Coated therapeutic particles 204 can include a plurality of cationic agents 208 disposed on particulate hydrophobic therapeutic agents 206. Nucleic acids 212 can be associated with the cationic agents. The charge provided by cationic agents 208 can be electrostatically attracted to negative charges and / or polar groups associated with the lipid bilayer 210 of a cell membrane and cellular components within the lipid bilayer 210.

[0029] In some embodiments, an additive can be included in the coating herein along with coated therapeutic particles 304. Referring now to Figure 3 , a schematic cross-sectional view (not to scale) of another embodiment is provided. In this embodiment, coated therapeutic particles 304 are disposed on a matrix 302. An additive 314 can be disposed along with coated therapeutic particles 304. The amount of additive 314 can be greater than, less than, or equal to the amount of coated therapeutic particles 304. In some embodiments, additive 314 can form a matrix or layer in which coated therapeutic particles 304 are disposed. In various embodiments, the additive can be hydrophilic. Exemplary additive components are described in greater detail below. Coated therapeutic particles 304 can include a plurality of cationic agents 308 disposed on particulate hydrophobic therapeutic agents 306. The charge provided by cationic agents 308 can be electrostatically attracted to negative charges and / or polar groups associated with the lipid bilayer 310 of a cell membrane and cellular components within the lipid bilayer 310.

[0030] In some embodiments, a hydrophilic polymer layer can be disposed on the surface of the matrix, between the coated therapeutic particles and the surface of the matrix. Exemplary polymers for the hydrophilic polymer layer are described in greater detail below. Referring now to Figure 4 , a schematic cross-sectional view (not to scale) of another embodiment herein is provided. In this embodiment, coated therapeutic particles 404 are disposed on a hydrophilic polymer layer 416, which in turn is disposed on a matrix 402. Coated therapeutic particles 404 can include a plurality of cationic agents 408 disposed on particulate hydrophobic therapeutic agents 406. The charge provided by cationic agents 408 can be electrostatically attracted to negative charges and / or polar groups associated with the lipid bilayer 410 of a cell membrane and cellular components within the lipid bilayer 410.

[0031] Referring now to Figure 5A schematic diagram of an exemplary device according to one embodiment is shown. Device 500 may be, for example, an angioplasty balloon catheter, a drug-eluting balloon catheter, or a drug-containing balloon catheter. However, further examples of the exemplary device are described in more detail below. Device 500 includes a catheter shaft 502 and a manifold end 505. Device 500 also includes an inflatable balloon 504 configured around the catheter shaft 502. Figure 5 In the diagram, balloon 504 is shown in an inflated configuration. The catheter shaft 502 may include a channel for delivering fluid through or from balloon 504, such that balloon 504 can selectively move from a deflated configuration to an inflated configuration and back from an inflated configuration.

[0032] The manufacture of inflatable balloons is well known in the art, and any suitable process can be performed to provide the inflatable matrix portion of the insertable medical device as described herein. Catheter balloon constructions are described in various reference documents, such as U.S. Patent Nos. 4,490,421, 5,556,383, 6,210,364, 6,168,748, 6,328,710, and 6,482,348. A molding process is typically performed for balloon construction. In an exemplary molding process, an extruded polymer tube is radially and axially expanded in a mold having a balloon of the desired shape at a high temperature. Following the molding process, the balloon can be subjected to further treatment. For example, the molded balloon can be subjected to an additional heating step to reduce balloon contraction.

[0033] Return to reference Figure 5 The insertable medical device 500 may also have one or more non-expandable (or inelastic) portions. For example, in a balloon catheter, the catheter shaft 502 portion may be a non-expandable portion. The non-expandable portion may be partially or wholly assembled from a polymer. Polymers include those formed from synthetic polymers, including oligomers, homopolymers, and copolymers derived from addition polymerization or condensation polymerization.

[0034] Examples of suitable addition polymers include, but are not limited to, acrylic resins, such as those polymerized from: methyl acrylate, methyl methacrylate, hydroxyethyl methacrylate, hydroxyethyl acrylate, acrylic acid, methacrylic acid, glyceryl acrylate, glyceryl methacrylate, methacrylamide, and acrylamide; and vinyl resins, such as those polymerized from: ethylene, propylene, vinyl chloride, vinyl acetate, vinylpyrrolidone, vinylidene fluoride, and styrene. Examples of condensation polymers include, but are not limited to, polyamides, such as polycaprolactam, polylaurolactam, polyhexamethylene adipamide, and polyhexamethylene dodecanediamide, as well as polyurethanes, polycarbonates, polyamides, polysulfones, poly(ethylene terephthalate), polydimethylsiloxane, and polyetherketones. Non-expandable portions may also be partially or wholly assembled from metal.

[0035] Now refer to Figure 6 A schematic cross-sectional view (not to scale) of a drug delivery coating according to different embodiments herein is provided. In this embodiment, a particulate hydrophobic therapeutic agent 606 is disposed on a matrix 602. An exemplary matrix is ​​described in more detail below. A plurality of cationic agents 608 are also disposed on the matrix. The particulate hydrophobic therapeutic agent 606 and the cationic agent 608 may form a matrix. It should be understood that, in practical applications, more hydrophobic therapeutic agent particles may be present in a given matrix. Exemplary cationic agents and hydrophobic therapeutic agents are described in more detail below. The charge provided by the cationic agent 608 can be electrostatically attracted to negatively charged and / or polar groups associated with the lipid bilayer 610 of the cell membrane and to cellular components within the lipid bilayer 610.

[0036] Now refer to Figure 7 This document provides schematic cross-sectional views (not to scale) of drug delivery coatings according to different embodiments of the invention. In this embodiment, a particulate hydrophobic therapeutic agent 706 is disposed on a matrix 702. A plurality of cationic agents 708 are also disposed on the matrix. The particulate hydrophobic therapeutic agent 706 and the cationic agents 708 may form a matrix. The particulate hydrophobic therapeutic agent 706 and the cationic agents 708 may be associated with each other and, in some cases, may form coated therapeutic agent particles 704 disposed on the matrix 702. The coated therapeutic agent particles 704 may include a plurality of cationic agents 708 disposed on the particulate hydrophobic therapeutic agent 706. It should be understood that, in practical applications, a plurality of hydrophobic therapeutic agent particles may be present within a given coating, and Figure 7 The particles shown are for illustrative purposes only. The charge provided by the cationic agent 708 can be electrostatically attracted to the negatively charged and / or polar groups associated with the lipid bilayer 710 of the cell membrane and to the cellular components within the lipid bilayer 710.

[0037] In some embodiments, a hydrophilic polymer layer may be disposed on the surface of the matrix, between the therapeutic agent, cationic agent, and / or coated therapeutic agent particles and the surface of the matrix. Exemplary polymers for the hydrophilic polymer layer are described in more detail below. Referring now to... Figure 8 Schematic cross-sectional views (not to scale) of drug delivery coatings according to different embodiments herein are provided. A hydrophilic polymer layer 816 is disposed on a matrix 802. A particulate hydrophobic therapeutic agent 806 is disposed on the hydrophilic polymer layer 816. A plurality of cationic agents 808 may also be disposed on the hydrophilic polymer layer 816. The particulate hydrophobic therapeutic agent 806 and the cationic agent 808 may be associated with each other. The particulate hydrophobic therapeutic agent 806 and the cationic agent 808 may form a matrix. The charge provided by the cationic agent 808 can be electrostatically attracted to negatively charged and / or polar groups associated with the lipid bilayer 810 of the cell membrane and to cellular components within the lipid bilayer 810.

[0038] Now refer to Figure 9 Schematic cross-sectional views (not to scale) of drug delivery coatings according to different embodiments herein are provided. A hydrophilic polymer layer 916 is disposed on a matrix 902. Particulate hydrophobic therapeutic agents 906 may be disposed on the hydrophilic polymer layer 916. A plurality of cationic agents 908 may be disposed on the hydrophilic polymer layer 916. The particulate hydrophobic therapeutic agents 906 and cationic agents 908 may form a matrix. The particulate hydrophobic therapeutic agents 906 and cationic agents 908 may be associated with each other and, in some cases, may form coated therapeutic agent particles 904 disposed on the hydrophilic polymer layer 916. The coated therapeutic agent particles 904 may include a plurality of cationic agents 908 disposed on the particulate hydrophobic therapeutic agents 906. The charge provided by the cationic agents 908 may be electrostatically attracted to negatively charged and / or polar groups associated with the lipid bilayer 910 of the cell membrane and to cellular components within the lipid bilayer 910.

[0039] Cationic agent The cationic agents used in the embodiments herein may include compounds comprising a portion that is positively charged in aqueous solution at neutral pH, together with a portion that exhibits affinity (e.g., hydrophobic or amphiphilic properties) for hydrophobic surfaces and is therefore capable of interacting with hydrophobic surfactants. In some embodiments, the cationic agents used in the embodiments herein may include those having the general formula XY, where X is a group comprising a positively charged group in aqueous solution at neutral pH and Y is a group exhibiting hydrophobic properties. In some embodiments, the cationic agent may include a hydrophilic head and a hydrophobic tail, together with one or more positively charged groups typically in the region of the hydrophilic head.

[0040] The cationic agents disclosed herein may include salts of cationic agents in different pH ranges, such as, but not limited to, halide salts, sulfates, carbonates, nitrates, phosphates, acetates, and mixtures thereof.

[0041] Cationic agents may specifically include cationic lipids and reticulated neutral lipids having cationic groups (neutral lipids having cationic groups). Exemplary lipids may include, but are not limited to, 3β-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol hydrochloride (DC-cholesterol); 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP); dimethyl dioctadecylammonium (DDAB); ethyl 1,2-dioleoyl-sn-glycero-3-choline phosphate (EPC); 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA); 1,2-di-(9Z-octadecenyl)-3-dimethylammonium-propane (DODAP); 1,2-dilinoleyloxy-3-dimethylaminopropane (DLinDMA) and its derivatives. Other lipids may include, but are not limited to, 1,2-dioleoyl- sn -Glyceryl-3-phosphate ethanolamine (DOPE); cholesterol; 1,2-octacosanoyl- sn -Glyceryl-3-phosphate choline (DSPC); 1,2-distearate- sn 1,3-glycero-3-phosphoethanolamine (DSPE). Other cationic agents may include monoamino or polyamino alkanes, such as spermine and spermidine.

[0042] Cationic agents may specifically include cationic polymers. Cationic agents may also include polycationic cyclodextrins (e.g., but not limited to aminocyclodextrin and its derivatives), aminoglucans, histones, protamines, cationic human serum albumin, aminopolysaccharides (e.g., chitosan), peptides (e.g., poly-L-lysine, poly-L-ornithine, and poly(4-hydroxy-L-proline esters), and polyamines (e.g., polyethyleneimine (PEI; available from Sigma-Aldrich), polyallylamine, polypropyleneimine, polyamide-amine dendritic compounds (PAMAM; available from Sigma-Aldrich)), cationic polyoxazolines, and poly(β-amino esters). Cationic agents may also specifically include cationic lipids (e.g., described by KT Love in publication PNAS 107, 1864-1869 (2010)). Other exemplary cationic polymers include, but are not limited to, block copolymers such as PEG-PEI copolymers and PLGA-PEI copolymers. Other exemplary cationic agents include positively charged gelatin (e.g., alkali-treated gelatin) and amination-modified cucurbit[n]uril family (where n = 5, 6, 7, 8, 10).

[0043] In other embodiments disclosed herein, the cationic agent comprising a positively charged portion in an aqueous solution at neutral pH includes the following compounds (AI):

[0044] In addition, other cationic agents include those having a structure of general formula I: Formula I Table 1. Values ​​of variables x + z, y, and R for compound JR having formula I.

[0045]

[0046] Cationic agents (such as those listed above) can generally be prepared by reacting suitable hydrophobic epoxy compounds (e.g., oleylene epoxy compounds) with polyfunctional amines (e.g., propylenediamine). Details of the synthesis of the relevant cationic agents are described by KTLove in PNAS 107, 1864-1869 (2010) and by Ghonaim et al. in Pharma Res [Pharmaceutical Research] 27, 17-29 (2010).

[0047] It should be understood that polyamide derivatives of PEI (PEI-amides) can also be used as cationic agents. PEI-amides are typically prepared by reacting PEI with acids or acid derivatives (such as acyl chlorides) or esters to form different PEI-amides. For example, PEI can react with methyl oleate to form PEI-amides.

[0048] In other embodiments, the cationic agent may include portions used to condense nucleic acids (e.g., lipids, peptides, and other cationic polymers). In some cases, these cationic agents may be used to form liposomes and polyplexes.

[0049] Exemplary embodiments of cationic agents may also include, but are not limited to, cationic agent derivatives having photoreactivity. Photoreactive groups are described below. Such cationic agent derivatives include PEI polymer derivatives of benzophenone and PAMAM polymer derivatives of benzophenone.

[0050] In some embodiments, the molecular weight of the cationic agent can be about 1.2 kDa, 2.5 kDa, 10 kDa, 25 kDa, 250 kDa, or even 750 kDa in some cases. In still other embodiments, the molecular weight of the cationic agent can be in the range of 50-100 kDa, 70-100 kDa, 50-250 kDa, 25-100 kDa, 2.5-750 kDa, or even 2.5-2,000 kDa in some cases. Other embodiments include molecular weights greater than 1.2 kDa, 2.5 kDa, 10 kDa, 25 kDa, 250 kDa, or even greater than 750 kDa in some cases. Other embodiments may include cationic agents with a molecular weight of up to 2,000 kDa.

[0051] Low molecular weight cationic monomers or low molecular weight cationic oligomers can be combined with hydrophobic surfactants to produce reactive coatings. These reactive coatings can then be applied to a substrate and thermally polymerized or polymerized using UV radiation. Exemplary monomers include, but are not limited to, aziridine, vinylamine, allylamine, and oligomers from 80 g / mol to 1200 g / mol. Crosslinking agents (e.g., 1,2-dichloroethane, epichlorohydrin, 1,6-diisocyanate hexane) can be used to crosslink the oligomers.

[0052] Additive component In some embodiments disclosed herein, these additive components may be hydrophilic in nature. Exemplary hydrophilic polymers include, but are not limited to, PEG, PVP, and PVA.

[0053] Exemplary additive components may include sugars. Sugars may include monosaccharides, disaccharides, trisaccharides, oligosaccharides, and polysaccharides. Polysaccharides may be linear or branched. Exemplary sugars may include, but are not limited to, dextran, sucrose, maltose, mannose, trehalose, etc. Exemplary sugars may further include, but are not limited to, polysaccharides, including pentose and / or hexose subunits, specifically including dextran (such as glycogen and amylopectin); and dextrins, including maltodextrin, fructose, mannose, galactose, etc. Polysaccharides may also include gums, such as pullulan, arabinose, galactan, etc.

[0054] Sugars can also include derivatives of polysaccharides. It should be understood that polysaccharides include a variety of functional groups that can act as attachment sites or be chemically modified in other ways to alter the characteristics of the sugar. As an example only, it should be understood that the sugar backbone typically includes a considerable number of hydroxyl groups that can be utilized to derivatize the sugar.

[0055] Sugars may also include copolymers and / or trimers, which include sugars and / or sugar subunits and / or blocks.

[0056] The polysaccharides used with the embodiments herein can have different molecular weights. For example, the glycogen used with the embodiments herein can have a molecular weight greater than about 250,000. In some embodiments, the glycogen used with the embodiments herein can have a molecular weight between about 100,000 and 10,000,000 Daltons.

[0057] Dialysis filtration can be used to refine the molecular weight of polysaccharides. Ultrafiltration membranes with different pore sizes can be used for dialysis filtration of polysaccharides (such as maltodextrin). As an example, a dialysis filtration process can use one or more cartridges having molecular weight cutoff membranes in the range of about 1 K to about 500 K to provide polysaccharide formulations having the following average molecular weights: less than 500 kDa, about 100 kDa to about 500 kDa, about 5 kDa to about 30 kDa, about 30 kDa to about 100 kDa, about 10 kDa to about 30 kDa, or about 1 kDa to about 10 kDa.

[0058] It should be understood that polysaccharides (such as maltodextrin and amylose with different molecular weights) are commercially available from many different sources. For example, Glucidex™ 6 (average molecular weight about 95,000 Da) and Glucidex™ 2 (average molecular weight about 300,000 Da) are available from Roquette (France); and MALTRIN™ maltodextrin with different molecular weights (including those from about 12,000 Da to 15,000 Da) are available from GPC (Muscatine, Iowa). Examples of other hydrophobic polysaccharide derivatives are disclosed in U.S. Patent Publication 2007 / 0260054 (Chudzik), which is incorporated herein by reference.

[0059] Exemplary additive components may include amphiphilic compounds. Amphiphilic compounds include those having both relatively hydrophobic and relatively hydrophilic portions. Exemplary amphiphilic compounds may include, but are not limited to, polymers comprising at least polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, polyoxazoline (such as poly(2-alkyloxazoline) and its derivatives), etc. Exemplary amphiphilic compounds may specifically include poloxamer. Poloxamer is a nonionic triblock copolymer composed of a central hydrophobic chain of polyoxypropylene and two hydrophilic chains flanking it with polyoxyethylene. Poloxamer is often marketed under the trade name PLURONIC. ® To be mentioned. It should be understood that many aspects of copolymers can be varied, allowing these characteristics to be customized. An exemplary poloxamer is PLURONIC. ®F68 (a nonionic copolymer of ethylene and propylene oxide commercially available from BASF Corporation; also designated as F68 and poloxamer F68) refers to a poloxamer in solid form at room temperature with a polyoxypropylene molecular weight of approximately 1,800 g / mol and a polyoxyethylene content of approximately 80%, and a total molecular weight of approximately 8,400 g / mol, which is terminated with a primary hydroxyl group.

[0060] Exemplary additive components may further include compounds that stabilize pharmaceutical reagents that are poorly soluble in water. Exemplary additive components that provide such stability include biocompatible polymers, such as albumin. Additional additive components are described in US 7,034,765 (De et al.), the disclosure of which is incorporated herein by reference. The stability of suspensions and emulsions may also be provided by compounds, such as surfactants (e.g., F68).

[0061] Different additive components can be added as optional topcoats to the layer containing the hydrophobic surfactant. In some embodiments, the topcoat can be applied to modify the release characteristics of the hydrophobic surfactant. Other topcoats can be added as protective layers to reduce unintentional loss of the hydrophobic surfactant through friction or general abrasion. For example, the topcoat can act as a protective layer for handling purposes during packaging or to protect the hydrophobic surfactant until it can be delivered to its target site in the body, or both. For example, the optional topcoat may include polyvinylpyrrolidone (PVP), polyacrylic acid (PAA), and polyurethane.

[0062] Hydrophobic active agent It should be understood that the hydrophobic active agents (e.g., particulate hydrophobic therapeutic agents) of the embodiments herein may include agents having many different types of activity. As used herein, the terms "active agent" and "therapeutic agent" should have a common boundary unless the context otherwise indicates. Hydrophobic active agents may specifically include those having a solubility in water of less than about 100 µg / mL at 25°C and neutral pH. In various embodiments, hydrophobic active agents may specifically include those having a solubility in water of less than about 10 µg / mL at 25°C and neutral pH. In some embodiments, hydrophobic active agents may specifically include those having a solubility in water of less than about 5 µg / mL at 25°C and neutral pH.

[0063] In some exemplary embodiments, the active agent may include, but is not limited to, antiproliferative agents such as paclitaxel, sirolimus (rapamycin), zotamolimus, everolimus, tesimolimus, pimecrolimus, tacrolimus, and ridaforolimus; analgesics and anti-inflammatory agents such as aloprazine, aurinolone, azapromide, benorilate, diflunisal, etodoxacin, fenbufen, fenofibrate, fenofibrate calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen, hydroxyphenylbutazone, phenylbutazone, piroxicam, and sulindac; antiarrhythmic agents such as amiodarone hydrochloride, disopyramide, flecainide acetate, and quinidine sulfate; and antibacterial agents such as penicillin, cephalosporin, and sedatives. Norfloxacin, ciprofloxacin hydrochloride, clarithromycin, clofazimine, cloxacillin, demeclocycline, doxycycline, erythromycin, ethionamide, imipenem, nalidixic acid, nitrofurantoin, rifampin, spiramycin, sulphabenzamide, sulfadoxine, sulfamethazine, sulfamethoxazole, sulfapyridine, tetracycline, trimethoprim; anticoagulants such as dicumarol, dipyridamole, acetocoumarin, phenylindanedione; antihypertensive agents such as amlodipine, benidipine, darodipine, diltiazem hydrochloride, diazoxide, felodipine. Dihydropyridine, Guanadipine acetate, Iradipine, Minoxidil, Nicardipine hydrochloride, Nifedipine, Nimodipine, Phenoxybenzamine hydrochloride, Prazosin hydrochloride, Reserpine, Terazosin hydrochloride; Antimuscarinic agents: Atropine, Benhexol hydrochloride, Biperidone, Diethylpromethazine hydrochloride, Hyoscyamine, Bromomethrin, Hydroxybenzamine hydrochloride, Topiramate; Antitumor agents and immunosuppressants, such as Aminoglutamate, Acridil, Azathioprine, Busulfan, Chlorobenzin, Cyclosporine, Dacarbazine, Estrosturacil, Etoposide, Lomustine, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitotan, Mitoxantrone, Procarbazine hydrochloride, Tamoxifen citrate, Testrolide; β-blockers, such as Acetolol, Alpralonol, A Timolol, labetalol, metoprolol, naldolol, oxenolol, indololol, propranolol; myocardial systolic agents, such as amrinone, digoxin, enoxide, lanoside, methyldigoxin; corticosteroids, such as beclomethasone, betamethasone, budesonide, cortisone acetate, dexamethasone, fludrocortisone acetate, flunisolone, flucorone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone; lipid modulators, such as bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol; nitrates and other antianginal agents, such as amyl nitrate, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate.

[0064] Other exemplary embodiments of the active agent include, but are not limited to, active agents for the treatment of hypertension (HTN), such as guanethidine.

[0065] In one specific embodiment, these hydrophobic active agents are selected from the group consisting of paclitaxel, sirolimus (rapamycin), and mixtures thereof.

[0066] In some embodiments, a hydrophobic surfactant can be conjugated to a cationic agent. This conjugation may include a hydrophobic surfactant covalently linked to the cationic agent. In some embodiments where the hydrophobic agent is conjugated to the cationic agent, a linker may be used to attach the hydrophobic agent to the cationic agent. Suitable linkers include, but are not limited to, polyethylene glycol, polyethylene oxide, and peptides of naturally occurring and non-naturally occurring amino acids. In some embodiments, the linker may be a... In vivo Biodegradable or shearable compounds are used to facilitate the release of hydrophobic active agents. Exemplary linkers may further include alkane or aromatic compounds with heteroatom substitutions (such as N, S, Si, Se, or O).

[0067] The particle size and particle size distribution of particulate formulations can be determined using any of the various techniques known in the art. In one practical mode, laser diffraction can be used to measure particle size and distribution. In laser diffraction, a laser beam passes through a dispersed particulate sample, and the angular variation in the intensity of the scattered light is measured. Larger particles scatter light at larger angles, while smaller particles scatter light at smaller angles, and angular scattering intensity data can be collected and analyzed to produce a particle size map.

[0068] Particle size and distribution can be analyzed using laser scattering instruments such as the Malvern System 4700 (for particles from 1 nm to 3 µm) or the Horiba LA-930 (e.g., for particles from 100 nm to 2 mm). The output of such analyzers can provide information about the size of individual particles and the total number of particles of these sizes, reflecting their size distribution. Analysis of size distribution data can be provided in the form of histograms, graphically representing the size and size distribution of all particles in the formulation.

[0069] Exemplary particulate hydrophobic therapeutic agents can have different morphological characteristics. In some embodiments, the particulate hydrophobic therapeutic agent may be crystalline. In yet other embodiments of this disclosure, these particulate hydrophobic therapeutic agents may be amorphous. Additionally, a combination of crystalline and amorphous particulate hydrophobic therapeutic agents may be desirable in order to achieve, for example, a desired solubility of these particulate hydrophobic therapeutic agents.

[0070] In some embodiments, the particulate hydrophobic therapeutic agent may have an average diameter (“dn”) of less than about 30 µm or less than about 10 µm. Furthermore, in some embodiments, the particulate hydrophobic therapeutic agent may have an average diameter of about 100 nm or greater. For example, the microparticles associated with the expandable elastic portion may have an average diameter in the range of about 100 nm to about 10 µm, about 150 nm to about 2 µm, about 200 nm to about 5 µm, or even about 0.3 µm to about 1 µm.

[0071] Nucleic acid Nucleic acids used in conjunction with embodiments of the present invention may include different types of nucleic acids that can function to provide therapeutic effects. Exemplary types of nucleic acids may include, but are not limited to, ribonucleic acid (RNA), deoxyribonucleic acid (DNA), small interfering RNA (siRNA), microRNA (miRNA), piwi-interacting RNA (piRNA), short hairpin RNA (shRNA), antisense nucleic acids, aptamers, ribonucleases, locked nucleic acids, and catalytic DNA. In one specific embodiment, the nucleic acid used is siRNA and / or its derivatives.

[0072] In some exemplary embodiments disclosed herein, the percentage ratio of the hydrophobic surfactant to the cationic agent (e.g., % PTX / % PEI or % PTX / % DOTAP; wt / wt) ranges from about 99.9 / 0.1 to about 70 / 30. In yet other embodiments, it will be appreciated that the percentage ratio of the hydrophobic surfactant ranges from about 99 / 1 to about 73 / 27; from about 98 / 2 to about 75 / 25; from about 98 / 2 to about 86 / 14; from about 97 / 3 to about 88 / 12; from about 95 / 5 to about 90 / 10; and even in some exemplary embodiments, from about 93 / 7 to about 91 / 9.

[0073] Hydrophilic base coating In various embodiments herein, the matrix of the hydrophilic substrate coating and / or the device or a portion thereof may be formed from a hydrophilic material such as a hydrophilic polyether block amide copolymer. The polyether block amide copolymer may contain blocks having hydrophilic properties. In some embodiments, the polyether block amide copolymer may contain blocks of polyethylene glycol (PEG).

[0074] In various embodiments, the hydrophilic polyether block amide copolymer may have a water contact angle of less than or equal to 80 degrees. In various embodiments, the hydrophilic polyether block amide copolymer may have a water contact angle of less than or equal to 70 degrees. In various embodiments, the hydrophilic polyether block amide copolymer may have a water contact angle of less than or equal to 60 degrees. In some embodiments, the hydrophilic polyether block amide copolymer may have a water contact angle of greater than or equal to 20 degrees.

[0075] In some embodiments, the hydrophilic polyether block amide copolymer may have a water absorption rate (as measured by ISO 62) greater than or equal to 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, or 1.6% at equilibrium at 20°C and 50% relative humidity. In some embodiments, the hydrophilic polyether block amide copolymer may have a water absorption rate (as measured by ISO 62) less than 5.0%, 4.5%, 4.0%, 3.5%, 3.0%, 2.5%, 2.0%, or 1.6% at equilibrium at 20°C and 50% relative humidity.

[0076] Exemplary hydrophilic polyether block amide copolymers include PEBAX® MV1074 and MH1657, which are commercially available from Arkema. Some examples of hydrophilic polyether block amide copolymers are described in U.S. Patent No. 8,952,103 and U.S. Patent Application Publication No. US 2009 / 0221767 (the contents relating to hydrophilic polyether block amide copolymers are incorporated herein by reference).

[0077] Matrix In embodiments, the device matrix may be formed from hydrophilic polyether block amide copolymers as described above. However, in some embodiments, the hydrophilic polyether block amide copolymer does not form the matrix but exists as a layer disposed on the matrix. In such embodiments, it should be appreciated that the matrix can be formed from any desired material or combination of materials suitable for use in vivo. In some embodiments, the matrix is ​​formed from a compliant and flexible material, such as an elastomer (a polymer with elasticity). Exemplary elastomers can be formed from various polymers, including polyurethanes and polyurethane copolymers, polyethylene, styrene-butadiene copolymers, polyisoprene, isobutylene-isoprene copolymers (butyl rubber) (including halogenated butyl rubber), butadiene-styrene-acrylonitrile copolymers, siloxane polymers, fluorosiloxane polymers, polycarbonate, polyamide, polyester, polyvinyl chloride, polyether-polyester copolymers, polyether-polyamide copolymers, etc. The matrix may be made from a single elastomer material or a combination of materials.

[0078] Other materials used for the matrix include those formed from polymers, including oligomers, homopolymers, and copolymers derived from addition polymerization or condensation polymerization. Examples of suitable addition polymers include, but are not limited to, acrylic resins such as those polymerized from: methyl acrylate, methyl methacrylate, hydroxyethyl methacrylate, hydroxyethyl acrylate, acrylic acid, methacrylic acid, glyceryl acrylate, glyceryl methacrylate, methacrylamide, and acrylamide; and vinyl resins such as those polymerized from: ethylene, propylene, vinyl chloride, vinyl acetate, vinylpyrrolidone, vinylidene fluoride, and styrene. Examples of condensation polymers include, but are not limited to, nylons such as polycaprolactam, polylaurolactam, polyhexamethylene adipamide, and polyhexamethylene dodecanediamide, as well as polyurethanes, polycarbonates, polyamides, polysulfones, poly(ethylene terephthalate), polydimethylsiloxane, and polyetherketones.

[0079] In addition to polymers, and depending on the type of device, the matrix can also be formed from other inorganic materials such as metals (including metal foils and alloys), glass, and ceramics.

[0080] Processes for modifying the aforementioned matrix may include chemical modifications to improve its performance characteristics. Specific chemical processes that may be used include ozone treatment, chemical oxidation, acid chemical etching, alkaline chemical etching, plasma treatment and corona treatment, surface grafting, thermally activated coating processes (both covalent and non-covalent), and surface modifications, including coatings containing dopamine, tannins, plant polyphenols, and other catechols or catechol-containing derivatives with hydrophilic portions. Additionally, processes for forming the aforementioned matrix may include physical modifications, such as, but not limited to, sandblasting and surface texturing (e.g., during or after polymer molding processes).

[0081] In some embodiments, the modification of the matrix as described herein may allow the omission of a base coating layer (such as a hydrophilic layer) because the modified matrix surface will allow for improved adhesion of hydrophobic therapeutic agents and cationic agents compared to the adhesion of a hydrophilic layer.

[0082] Device It should be understood that the embodiments herein include, and may be used in combination, different types of devices including, but not limited to, drug delivery devices such as drug-eluting balloon catheters, drug-containing balloon catheters, stents, grafts, etc.

[0083] Some embodiments described herein can be used in conjunction with balloon-inflatable flow diverters and self-expanding flow diverters. Other embodiments may include use in contact with angioplasty balloons (e.g., but not limited to percutaneous transluminal coronary angioplasty and percutaneous transluminal angioplasty). Still other embodiments may include use in conjunction with sinoplasty balloons for ENT treatment, urethral balloons for urinary tract treatment and gastrointestinal treatment, and urethral stents (e.g., devices for colonoscopy). Hydrophobic active agents can be transferred from balloon-like inflatable devices or from patch-like devices into tissue. Other embodiments disclosed herein can be further used in conjunction with microinfusion catheter devices. In some embodiments, microinfusion catheter devices can be used to target active agents to the renal sympathetic nervous system to treat, for example, hypertension.

[0084] The examples included herein can also be used in conjunction with the application of different active agents to the skin (e.g., but not limited to transdermal drug delivery).

[0085] Other exemplary medical applications in which the embodiments disclosed herein may be used further cover the treatment of bladder neck stenosis (e.g., after transurethral resection of the prostate), laryngotracheal stenosis (e.g., in combination with serial endoscopic dilation to treat subglottic stenosis), oral cancer and cold sores, and bile duct stenosis (e.g., after hepatocellular carcinoma of the pancreas). As a further example, the embodiments herein may be used in conjunction with an applicator. Applicators may include those for use with various procedures, including surgical procedures, where the application of an active agent to a specific tissue location is required. Examples may include, but are not limited to, applicators that may be used in orthopedic surgery to apply an active agent to a specific surface of bone, cartilage, ligaments, or other tissue through physical contact between the applicator and those tissues. Applicators may include, but are not limited to, handheld applicators, medicated patches, drug stamps, drug application disks, etc.

[0086] In some embodiments, the applicator may include a surface having a hydrophilic polymer layer disposed thereon and coated therapeutic particles disposed on the hydrophilic polymer layer, the coated therapeutic particles comprising a particulate hydrophobic therapeutic agent; and a cationic agent disposed on the particulate hydrophobic therapeutic agent.

[0087] In use, the various embodiments included herein enable the rapid transfer of therapeutic agents to specific target tissues. For example, in some embodiments, a healthcare provider may create physical contact between a portion of a drug delivery device (including the therapeutic agent) and the targeted tissue, and the therapeutic agent will be rapidly transferred from the drug delivery device to the tissue. In this way, precise control over the tissue to which the therapeutic agent is delivered can be achieved.

[0088] One advantageous aspect of the various embodiments described herein is that the therapeutic agent can be transferred very rapidly from the drug delivery device or coating to the target tissue. In some embodiments, a large-scale transfer of the therapeutic agent from the drug delivery device or coating to the tissue occurs within 30 minutes or less. In some embodiments, a large-scale transfer of the therapeutic agent from the drug delivery device or coating to the tissue occurs within 15 minutes or less. In some embodiments, a large-scale transfer of the therapeutic agent from the drug delivery device or coating to the tissue occurs within 10 minutes or less. In some embodiments, a large-scale transfer of the therapeutic agent from the drug delivery device or coating to the tissue occurs within 5 minutes or less. In some embodiments, a large-scale transfer of the therapeutic agent from the drug delivery device or coating to the tissue occurs within 2 minutes or less. In some embodiments, a large-scale transfer of the therapeutic agent from the drug delivery device or coating to the tissue occurs within 1 minute or less.

[0089] It should be noted that, as used in this specification and the appended claims, the singular forms “a / an” and “the” include plural references unless otherwise clearly indicated. Thus, for example, a reference to a composition containing “one compound” includes two or more compounds. It should also be noted that the term “or” is generally used to mean “and / or” unless otherwise clearly indicated.

[0090] It should also be noted that, as used in this specification and the appended claims, the phrase “configuration” describes a system, device, or other structure constructed or configured to perform a specific task or take a specific configuration. The phrase “configuration” may be used interchangeably with other similar phrases such as “arrange and configure,” “build and arrange,” “build,” “manufacture and arrange,” etc.

[0091] All publications and patent applications in this specification indicate the level of skill of someone skilled in the art to which this invention pertains. All publications and patent applications are incorporated herein by reference to the same extent that each individual publication or patent application is precisely and individually indicated by reference. In the event of any discrepancy between the publications incorporated by reference and the patent applications, the information in this disclosure shall prevail.

[0092] The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications can be made, but these remain within the spirit and scope of the invention.

Claims

1. A drug delivery device, comprising: The matrix comprises a hydrophilic polyether block amide copolymer, wherein the hydrophilic polyether block amide copolymer comprises PEG; The coating, the coating comprising A therapeutic agent layer forming at least a portion of the outer surface of the drug delivery device, the therapeutic agent layer contacting the hydrophilic surface of the matrix, the therapeutic agent layer comprising: Particulate hydrophobic therapeutic agent; as well as Cationic agents.

2. The drug delivery device according to claim 1, wherein, The hydrophilic polyether block amide copolymer has a water contact angle of less than or equal to 60 degrees.

3. The drug delivery device according to claim 1, wherein, The hydrophilic polyether block amide copolymer contains a water absorption rate greater than 1.0% at equilibrium at 20°C and 50% relative humidity (ISO 62).

4. The drug delivery device according to claim 1, wherein, The hydrophilic polyether block amide copolymer contains a water absorption rate of 1.4% or greater at equilibrium at 20°C and 50% relative humidity (ISO 62).

5. The drug delivery device according to claim 1, wherein, The particulate hydrophobic therapeutic agent and the cationic agent form coated therapeutic agent particles.

6. The drug delivery device according to claim 1, wherein, The cationic agent is selected from the group consisting of: cationic lipids, neutral lipids having cationic groups, and cationic polymers.

7. The drug delivery device according to claim 1, wherein, The cationic agent is selected from the group consisting of: polyethyleneimine and DOTAP.

8. A drug delivery device, the drug delivery device comprising: Matrix; The coating comprises: A therapeutic agent layer forming at least a portion of the outer surface of the drug delivery device, the therapeutic agent layer contacting the surface of the matrix, the therapeutic agent layer comprising: Particulate hydrophobic therapeutic agents; and cationic agent, The drug delivery device does not have a base coating.

9. A method of manufacturing a medical device, the method comprising: A therapeutic agent layer is deposited onto at least a portion of the medical device, the medical device comprising a matrix containing a hydrophilic polyether block amide copolymer, the hydrophilic polyether block amide copolymer comprising PEG; the therapeutic agent layer is brought into contact with a surface of the matrix, the therapeutic agent layer comprising: Particulate hydrophobic therapeutic agents; and Cationic agents.

10. The method according to claim 9, wherein, The hydrophilic polyether block amide copolymer has a water contact angle of less than or equal to 80 degrees.

11. The method according to claim 9, wherein, The hydrophilic polyether block amide copolymer contains a water absorption rate greater than 1.0% at equilibrium at 20°C and 50% relative humidity (ISO 62).

12. The method according to claim 9, wherein, The therapeutic agent layer is deposited using a solvent that is not absorbed into the hydrophilic polyether block amide copolymer.

13. The method according to claim 9, wherein, The medical device has no base coating.

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