Delivery of hydrophobic active agent particles

Abstract

Embodiments of the invention include drug delivery coatings and devices including these drug delivery coatings. In one embodiment, the present invention comprises a drug delivery coating comprising a polymeric layer. The polymeric layer may include a hydrophilic outer surface. The coating may also include a matrix contacting the hydrophilic outer surface. The matrix may include a particulate hydrophobic therapeutic agent and a cationic agent. The polymeric layer may further include a hydrophilic polymer having pendant photoreactive groups and a photocrosslinker including two aryl ketone functionalities. Other embodiments are also included herein.

Description

[0001] This application is a divisional application of a Chinese application with application number 201680018726.5, filing date January 29, 2016, and invention title "Delivery of Hydrophobic Active Agent Particles", the entire content of which is incorporated herein by reference.

[0002] This application is being filed as a PCT international patent application on January 29, 2016, and is being filed in all designated states in the name of a U.S. state-owned company, SurModics, Inc., as applicant, and in the name of Joram Slager, a citizen of the Netherlands, Toni M. Heyer, a citizen of the United States, and David E. Babcock, a citizen of the United States, as inventors, and claims the priority of U.S. Patent Application No. 14 / 609,270 filed on January 29, 2015, the content of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present invention relates to devices (such as medical devices) and coatings for devices. More particularly, the present invention relates to devices and coatings for devices that include hydrophobic active agent particles. Background Art

[0004] Due to plaque in arteries, the vascular system of humans is prone to blockage. Partial and even complete arterial blockages caused by atherosclerotic plaque formation are a well-known and frequently occurring medical problem. Frequently, such blockages occur in the coronary arteries. Blockages can also occur secondarily after treatment at a specific site (restenosis - for example, restenosis caused by the rapid division of smooth muscle cells). Additionally, blockages can occur in the context of peripheral arteries.

[0005] The following can be used to treat blockages: atherectomy devices that mechanically remove plaque; thermal or cold lasers that vaporize plaque; stents that keep arteries open; and other devices and procedures designed to increase blood flow through arteries.

[0006] A common procedure for treating blocked 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 the coronary artery, the deflated, folded balloon is positioned at the site of stenosis, and then the balloon is inflated. The inflation of the balloon disrupts and destroys the plaque attached to the arterial wall and stretches the arterial wall, which results in an enlargement of the luminal access and an 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 in the vascular system other than the coronary arteries. In other related procedures, a small mesh tube called a stent is implanted at the site of stenosis to help keep the coronary artery open. In atherectomy procedures (also known as percutaneous coronary rotational atherectomy (PCRA)), a small, diamond-tipped drill-like device is inserted into the affected artery via 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 the fatty material into the arterial wall. During one or more of these procedures, it can be desirable to deliver a therapeutic agent or drug to the area where treatment is occurring to prevent restenosis, repair vascular dissections or microaneurysms, or provide other desired treatments.

[0007] Additionally, it can be desirable to transfer a therapeutic agent to other locations in a mammal, such as the skin, neurovascular system, nasal cavity, oral cavity, lung, mucosa, sinus, gastrointestinal tract, or perirenal vasculature. Summary of the Invention

[0008] Embodiments of the present invention include drug delivery coatings and devices including such drug delivery coatings. In one embodiment, the present invention includes a drug delivery coating that includes a polymeric layer. The polymeric layer can include a hydrophilic outer surface. The coating can further include a matrix contacting the hydrophilic outer surface. The matrix can include particulate hydrophobic therapeutic agents and cationic agents. The polymeric layer can further include a hydrophilic polymer having pendant photoreactive groups and a photocrosslinker including two aryl ketone functionalities. Other embodiments are also included herein.

[0009] In one embodiment, the present invention includes a drug delivery device that includes a matrix; a hydrophilic polymer layer disposed on the matrix; and coated therapeutic agent particles disposed on the hydrophilic polymer layer, the coated therapeutic agent particles comprising particulate hydrophobic therapeutic agents; and cationic agents disposed on the particulate hydrophobic therapeutic agents.

[0010] In one embodiment, the present invention includes a drug delivery coating that includes a polymeric layer that includes a hydrophilic surface; coated therapeutic agent particles disposed on the hydrophilic surface, the coated therapeutic agent particles including a particulate hydrophobic therapeutic agent core; and a cationic agent that surrounds the particulate hydrophobic therapeutic agent core and exhibits an affinity for the cell membrane surface.

[0011] In one embodiment, the present invention includes a method of forming a drug delivery coating, the method including applying a hydrophilic substrate coating to a substrate; forming coated therapeutic agent particles that include a particulate hydrophobic therapeutic agent and a cationic agent disposed on the particulate hydrophobic therapeutic agent core; and applying the coated therapeutic agent particles to the substrate.

[0012] This summary is a review of some of the teachings of this application and is not intended to be an exclusive or exhaustive treatment of the subject matter. Additional details can be found in the detailed description and the appended claims. Other aspects will be apparent to those of ordinary skill in the art when reading and understanding the following detailed description and viewing the drawings (which form a part thereof), each of which should not be considered to be of limiting significance. The scope of the present invention is defined by the appended claims and their legal equivalents. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The present invention can be more fully understood in conjunction with the following drawings, in which:

[0014] Figure 1 is a schematic cross-sectional view of a coating according to one embodiment herein.

[0015] Figure 2 is a schematic cross-sectional view of a coating according to one embodiment herein.

[0016] Figure 3 is a schematic cross-sectional view of a coating according to one embodiment herein.

[0017] Figure 4 is a schematic cross-sectional view of a coating according to one embodiment herein.

[0018] Figure 5 is a schematic view of an apparatus according to one embodiment herein.

[0019] Figure 6 is a schematic cross-sectional view of coatings according to different embodiments herein.

[0020] Figure 7 is a schematic cross-sectional view of coatings according to different embodiments herein.

[0021] Figure 8is a schematic cross - sectional view of a coating according to various embodiments herein.

[0022] Figure 9 is a schematic cross - sectional view of a coating according to various embodiments herein.

[0023] Figure 10 is a graph of the adhesion of microparticles to a plate without excipients and using polyethyleneimine (PEI) as an excipient and polyacrylic acid (PAA). plate.

[0024] Although the present invention is susceptible to various changes and alternative forms, specific embodiments thereof have been shown by way of example and in the accompanying drawings and will be described in detail. However, it should be understood that the present invention is not limited to the specific embodiments described. On the contrary, the intention is to cover various changes, equivalents, and alternatives falling within the spirit and scope of the present invention. Detailed Description

[0025] The embodiments of the invention described herein are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. On the contrary, the embodiments are selected and described so that other ordinary skilled artisans in the art can appreciate and understand the principles and practices of the invention.

[0026] All publications and patents mentioned herein are incorporated herein by reference. The publications and patents disclosed herein are provided solely for their disclosure. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate any publication and / or patent, including any publication and / or patent cited herein.

[0027] As described above, in connection with procedures such as percutaneous transluminal coronary angioplasty (PTCA), percutaneous transluminal angioplasty (PTA), etc., it can be desirable to deliver a therapeutic agent or drug to the area where treatment occurs to prevent restenosis, repair vascular dissections or small aneurysms, or provide other desired treatments. One way to accomplish this is to use a drug delivery device (such as a drug - eluting balloon catheter or a balloon catheter containing a drug) to deliver a therapeutic agent (or active agent) to the desired tissue site.

[0028] Drug delivery coatings for certain medical applications desirably exhibit different properties. By way of example, in the context of drug-eluting balloon catheters or balloon catheters containing drugs, the coating should maintain structural integrity during steps associated with the preparation of the balloon catheter device, including pleating, folding, and curing (such as heat treatment). Additionally, for the coating, it is desirable to maintain structural integrity (limited loss of active agent) during passage through the vasculature via a catheter and / or wire. Further, it is desirable when the balloon is inflated at the desired site to transfer a substantial amount of the active agent from the balloon to the vessel wall. Additionally, it is desirable to maximize uptake of the active agent in the tissue of the vessel wall and reduce the amount of the active agent flushed into the blood flowing through the treatment site in the vasculature.

[0029] Embodiments herein can be useful for enhancing one or more desirable properties of drug delivery coatings, 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 matrix and coated therapeutic agent particles disposed on the matrix. The coated therapeutic agent particles can include particulate hydrophobic therapeutic agents and cationic agents disposed on the particulate hydrophobic therapeutic agents.

[0030] Now referring to Figure 1 , a schematic cross-sectional view (not to scale) of a coating according to an embodiment herein is provided. In this embodiment, coated therapeutic agent particles 104 are disposed on a matrix 102. Exemplary matrices are described in more detail below. The coated therapeutic agent particles 104 can include a plurality of cationic agents 108 disposed on a particulate hydrophobic therapeutic agent 106. The coated therapeutic agent particles 104 can be continuously coated with the cationic agent 108. In other embodiments, the coating of the cationic agent 108 on the therapeutic agent particles 104 can be discontinuous. Additionally, the particulate hydrophobic agent 106 can coexist with the cationic agent 108 in the matrix, where the cationic agent 108 does not coat the particulate hydrophobic agent 106. Different mixtures of the above embodiments can be found in a particular matrix 102. By way of example and not limitation, the coating on the matrix can include coated therapeutic agent particles 104 that are continuously coated with the cationic agent 108 and the particulate hydrophobic agent 106 in a matrix having the cationic agent 108, where the cationic agent 108 does not coat the particulate hydrophobic agent 106. It should be appreciated that when in actual use, there will be many hydrophobic therapeutic agent microparticles within a given coating, and merely for purposes of illustration, in Figure 1A single microparticle is shown. Exemplary cationic agents and hydrophobic therapeutic agents are described in more detail below. The charge provided by the cationic agent 108 can be electrostatically attracted to the negative charges and / or polar groups associated with the lipid bilayer 110 of the cell membrane and to cell components within the lipid bilayer 110.

[0031] 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 more detail below. Now referring to Figure 2 , a schematic cross-sectional view (not to scale) of another embodiment herein is provided. In this embodiment, the coated therapeutic agent particle 204 is disposed on the matrix 202. The coated therapeutic agent particle 204 can include a plurality of cationic agents 208 disposed on the particulate hydrophobic therapeutic agent 206. The nucleic acid 212 can be associated with the cationic agent. The charge provided by the cationic agent 208 can be electrostatically attracted to the negative charges and / or polar groups associated with the lipid bilayer 210 of the cell membrane and to cell components within the lipid bilayer 210.

[0032] In some embodiments, additives can be included in the coatings herein along with the coated therapeutic agent particle 304. Now referring to Figure 3 , a schematic cross-sectional view (not to scale) of another embodiment is provided. In this embodiment, the coated therapeutic agent particle 304 is disposed on the matrix 302. The additive 314 can be disposed along with the coated therapeutic agent particle 304. The amount of the additive 314 can be greater than, less than, or equal to the amount of the coated therapeutic agent particle 304. In some embodiments, the additive 314 can form a matrix or layer in which the coated therapeutic agent particle 304 is disposed. In different embodiments, the additive can be hydrophilic. Exemplary additive components are described in more detail below. The coated therapeutic agent particle 304 can include a plurality of cationic agents 308 disposed on the particulate hydrophobic therapeutic agent 306. The charge provided by the cationic agent 308 can be electrostatically attracted to the negative charges and / or polar groups associated with the lipid bilayer 310 of the cell membrane and to cell components within the lipid bilayer 310.

[0033] In some embodiments, a hydrophilic polymer layer can be disposed on the surface of the matrix, between the surface of the matrix and these coated therapeutic agent particles. Exemplary polymers for the hydrophilic polymer layer are described in more detail below. Now referring to Figure 4, there is provided a schematic cross-sectional view (not to scale) of another embodiment herein. In this embodiment, the coated therapeutic agent particles 404 are disposed on the hydrophilic polymer layer 416, which in turn is disposed on the matrix 402. The coated therapeutic agent particles 404 may include a plurality of cationic agents 408 disposed on the particulate hydrophobic therapeutic agent 406. The charge provided by the cationic agent 408 may be electrostatically attracted to the negative charges and / or polar groups associated with the lipid bilayer 410 of the cell membrane and to cell components within the lipid bilayer 410.

[0034] Now referring to Figure 5 , there is shown a schematic view of an exemplary device according to one embodiment. The device 500 may be, for example, an angioplasty balloon catheter or a drug-eluting balloon catheter or a balloon catheter containing a drug. However, additional examples of the exemplary device are described in more detail below. The device 500 includes a catheter shaft 502 and a manifold end 505. The device 500 further includes an inflatable balloon 504 disposed around the catheter shaft 502. In Figure 5 , the balloon 504 is shown in an inflated configuration. The catheter shaft 502 may include a channel for delivering fluid through the catheter shaft 502 to or from the balloon 504 such that the balloon 504 can be selectively moved from a deflated configuration to an inflated configuration and back again from the inflated configuration to the deflated configuration.

[0035] The manufacture of inflatable balloons is well known in the art, and any suitable process may be employed to provide the inflatable matrix portion of the insertable medical device as described herein. Catheter balloon configurations 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. Typically, a molding process is employed for balloon construction. In an exemplary molding process, an extruded polymer tube is radially and axially expanded in a mold of a balloon having a desired shape at an elevated temperature. After the molding process, the balloon may be subjected to additional processing. For example, the formed balloon may be subjected to an additional heating step to reduce balloon shrinkage.

[0036] Returning to refer to Figure 5, the insertable medical device 500 may also have one or more non-inflatable (or inelastic) portions. For example, in a balloon catheter, the catheter shaft 502 portion may be a non-inflatable portion. The non-inflatable portion may be partially or entirely assembled from a polymer. Polymers include those formed from synthetic 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, 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, acrylic acid, methacrylic acid, glycerol acrylate, glycerol methacrylate, methacrylamide, and acrylamide; vinyl resins such as those polymerized from: ethylene, propylene, vinyl chloride, vinyl acetate, vinyl pyrrolidone, 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 polyether ketones. The non-inflatable portion may also be partially or entirely assembled from a metal.

[0037] Now referring to Figure 6 , a schematic cross-sectional view (not to scale) of a drug delivery coating according to various embodiments herein is provided. In this embodiment, particulate hydrophobic therapeutic agent 606 is disposed on matrix 602. Exemplary matrices are 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 appreciated that when in actual use, there may be more hydrophobic therapeutic agent microparticles within a given matrix. Exemplary cationic agents and hydrophobic therapeutic agents are described in more detail below. The charge provided by the cationic agent 608 may be electrostatically attracted to the negative charges and / or polar groups associated with the lipid bilayer 610 of the cell membrane and / or cell components within the lipid bilayer 610.

[0038] Now referring to Figure 7 , a schematic cross-sectional view (not to scale) of a drug delivery coating according to various embodiments herein is provided. In this embodiment, particulate hydrophobic therapeutic agent 706 is disposed on matrix 702. A plurality of cationic agents 708 are also disposed on the matrix. The particulate hydrophobic therapeutic agent 706 and the cationic agent 708 may form a matrix. The particulate hydrophobic therapeutic agent 706 and the cationic agent 708 may be associated with each other and, in some cases, may form a coated therapeutic agent particle 704 disposed on matrix 702. The coated therapeutic agent particle 704 may include a plurality of cationic agents 708 disposed on the particulate hydrophobic therapeutic agent 706. It should be appreciated that when in actual use, there may be many hydrophobic therapeutic agent microparticles within a given coating, and inFigure 7 The microparticles shown are for illustrative purposes only. The charge provided by the cationic agent 708 can be electrostatically attracted to the negative charges and / or polar groups associated with the lipid bilayer 710 of the cell membrane and to cell components within the lipid bilayer 710.

[0039] In some embodiments, a hydrophilic polymer layer can be disposed on the surface of the substrate, between the surface of the substrate and the therapeutic agent, the cationic agent, and / or the coated therapeutic agent particles. Exemplary polymers for the hydrophilic polymer layer are described in more detail below. Now referring Figure 8 FIG. , provides a schematic cross-sectional view (not to scale) of a drug delivery coating according to various embodiments herein. A hydrophilic polymer layer 816 is disposed on a substrate 802. Granular hydrophobic therapeutic agent 806 is disposed on the hydrophilic polymer layer 816. Multiple cationic agents 808 can also be disposed on the hydrophilic polymer layer 816. The granular hydrophobic therapeutic agent 806 and the cationic agent 808 can be associated with each other. The granular hydrophobic therapeutic agent 806 and the cationic agent 808 can form a matrix. The charge provided by the cationic agent 808 can be electrostatically attracted to the negative charges and / or polar groups associated with the lipid bilayer 810 of the cell membrane and to cell components within the lipid bilayer 810.

[0040] Now referring Figure 9 FIG. , provides a schematic cross-sectional view (not to scale) of a drug delivery coating according to various embodiments herein. A hydrophilic polymer layer 916 is disposed on a substrate 902. Granular hydrophobic therapeutic agent 906 can be disposed on the hydrophilic polymer layer 916. Multiple cationic agents 908 can be disposed on the hydrophilic polymer layer 916. The granular hydrophobic therapeutic agent 906 and the cationic agent 908 can form a matrix. The granular hydrophobic therapeutic agent 906 and the cationic agent 908 can be associated with each other and, in some cases, can form a coated therapeutic agent particle 904 disposed on the hydrophilic polymer layer 916. The coated therapeutic agent particle 904 can include multiple cationic agents 908 disposed on the granular hydrophobic therapeutic agent 906. The charge provided by the cationic agent 908 can be electrostatically attracted to the negative charges and / or polar groups associated with the lipid bilayer 910 of the cell membrane and to cell components within the lipid bilayer 910.

[0041] Cationic agent

[0042] The cationic agents used in the embodiments herein can include the following compounds, which contain moieties that have a positive charge in aqueous solution at neutral pH, along with moieties that exhibit an affinity for hydrophobic surfaces (such as hydrophobic or amphiphilic characteristics) and can thus interact with hydrophobic agents. In some embodiments, the cationic agents used in the embodiments herein can include those having the general formula X-Y, where X is a group that includes a group bearing a positive charge in aqueous solution at neutral pH and Y is a group that exhibits hydrophobic characteristics. In some embodiments, the cationic agent can include a hydrophilic head and a hydrophobic tail, along with one or more positively charged groups typically in the region of the hydrophilic head.

[0043] The cationic agents of the present disclosure can include salts of the cationic agents in different pH ranges, such as but not limited to halide salts, sulfates, carbonates, nitrates, phosphates, acetates, and mixtures thereof.

[0044] The cationic agents can specifically include cationic lipids and neutral lipids with a network of cationic groups (neutral lipids with cationic groups). Exemplary lipids can include but are not limited to 3β-[N-(N',N'-dimethylaminoethane)-carbamoyl] cholesterol hydrochloride (DC-cholesterol); 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP); dimethyldioctadecylammonium (DDAB); 1,2-dioleoyl-sn-glycero-3-choline phosphoethanolamine (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. Additional lipids can include but are not limited to 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE); cholesterol; 1,2-dioctadecanoyl-sn-glycero-3-phosphocholine (DSPC); 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE). Other cationic agents can include monoaminoalkanes or polyaminoalkanes, such as spermine and spermidine.

[0045] Cationic agents can specifically include cationic polymers. Cationic agents can also include cyclodextrins containing polycations (such as but not limited to amino cyclodextrins and their derivatives), aminodextrans, histones, protamines, cationized human serum albumin, aminopolysaccharides (such as chitosan), peptides (such as poly-L-lysine, poly-L-ornithine, and poly(4-hydroxy-L-proline ester)), and polyamines (such as polyethyleneimine (PEI; available from Sigma Aldrich), polyallylamine, polypropyleneimine, polyamidoamine dendrimers (PAMAM; available from Sigma Aldrich)), cationic polyoxazolines, and poly(β-amino esters). Cationic agents can also specifically include cationic lipidoids (such as those described by K.T. Love in the published document PNAS 107, 1864-1869 (2010) [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 the aminated cucurbit[n]uril family (where n = 5, 6, 7, 8, 10).

[0046] In other embodiments of the present disclosure, cationic agents comprising moieties that are positively charged in aqueous solution at neutral pH include the following compounds (A-I):

[0047]

[0048]

[0049] In addition, other cationic agents include a structure having the general formula I:

[0050]

[0051] Table 1. Values of the variables x+z, y, and R for compounds J-R having formula I.

[0052] Compound x + z y R Compound J 6 12.5 <![CDATA[C 12 H 25 > Compound K 1.2 2 <![CDATA[C 12 H 25 > Compound L 6 39 <![CDATA[C 12 H 25 > Compound M 6 12.5 <![CDATA[C 14 H 29 > Compound N 1.2 2 <![CDATA[C 14 H 29 > Compound O 6 39 <![CDATA[C 14 H 29 > Compound P 6 12.5 <![CDATA[C 16 H 33 > Compound Q 1.2 2 <![CDATA[C 16 H 33 > Compound R 6 39 <![CDATA[C 16 H 33 >

[0053] Cationic agents (such as those listed above) can generally be prepared by the reaction of a suitable hydrophobic epoxide (such as oleyl epoxide) with a polyfunctional amine (such as propylenediamine). Details of the synthesis of relevant cationic agents were described by K.T. Love in the published document PNAS 107, 1864 - 1869 (2010) [PNAS 107, 1864 - 1869 (2010)] and by Ghonaim et al. in Pharma Res 27, 17 - 29 (2010) [Pharmaceutical Research, 27, 17 - 29 (2010)].

[0054] It should be appreciated that polyamide derivatives of PEI (PEI - amides) can also be applied as cationic agents. PEI - amides can generally be prepared by reacting PEI with an acid or acid derivative (such as an acyl chloride) or an ester to form different PEI - amides. For example, PEI can be reacted with methyl oleate to form a PEI - amide.

[0055] In still other embodiments, the cationic agent can include moieties for condensing nucleic acids (such as lipids, peptides, and other cationic polymers). In some cases, these cationic agents can be used to form liposomes and polyplexes.

[0056] Exemplary embodiments of the cationic agent can 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.

[0057] 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 in some cases 750 kDa. 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 in some cases 2.5 - 2,000 kDa. Other embodiments include a molecular weight greater than 1.2 kDa, 2.5 kDa, 10 kDa, 25 kDa, 250 kDa, or even in some cases greater than 750 kDa. Other embodiments can include a cationic agent with a molecular weight up to 2,000 kDa.

[0058] 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 polymerized thermally or by UV radiation. Exemplary monomers include, but are not limited to, aziridines, vinylamines, allylamines, and oligomers from 80 g / mol to 1200 g / mol. Crosslinking agents (e.g., 1,2-dichloroethane, epichlorohydrin, 1,6-diisocyanatohexane) can be used to crosslink the oligomers.

[0059] Additive component

[0060] In some embodiments of the present disclosure, these additive components can be hydrophilic in nature. Exemplary hydrophilic polymers include, but are not limited to, PEG, PVP, and PVA.

[0061] Exemplary additive components can include saccharides. Saccharides can include monosaccharides, disaccharides, trisaccharides, oligosaccharides, and polysaccharides. Polysaccharides can be linear or branched polysaccharides. Exemplary saccharides can include, but are not limited to, dextran, sucrose, maltose, mannose, trehalose, etc. Exemplary saccharides can further include, but are not limited to, polysaccharides including pentose and / or hexose subunits, specifically including dextrans (such as glycogen and amylopectin); and dextrins, including maltodextrin, fructose, mannose, galactose, etc. Polysaccharides can also include gums, such as pullulan, arabinose, galactan, etc.

[0062] Saccharides can also include derivatives of polysaccharides. It should be appreciated that polysaccharides include a variety of functional groups that can act as attachment points or can otherwise be chemically modified to alter the characteristics of the saccharide. Merely as an example, it should be appreciated that the sugar backbone typically includes a significant number of hydroxyl groups that can be utilized to derivatize such a sugar.

[0063] Saccharides can also include copolymers and / or trimers, etc., that include sugars and / or sugar subunits and / or blocks.

[0064] Polysaccharides used in conjunction with the embodiments herein can have different molecular weights. By way of example, glycogen used in conjunction with the embodiments herein can have a molecular weight greater than about 250,000. In some embodiments, glycogen used in conjunction with the embodiments herein can have a molecular weight between about 100,000 and 10,000,000 daltons.

[0065] Dialfiltration can be used to refine the molecular weight of polysaccharides. Ultrafiltration membranes with different pore sizes can be used for the dialfiltration of polysaccharides such as maltodextrin. As an example, one or more cassettes with molecular weight cut-off membranes in the range of about 1K to about 500K can be used in a dialfiltration process to provide polysaccharide preparations having the following average molecular weights: in the range of less than 500 kDa, in the range of about 100 kDa to about 500 kDa, in the range of about 5 kDa to about 30 kDa, in the range of about 30 kDa to about 100 kDa, in the range of about 10 kDa to about 30 kDa, or in the range of about 1 kDa to about 10 kDa.

[0066] It should be appreciated that polysaccharides such as maltodextrin and amylose with different molecular weights can be commercially available from many different sources. For example, Glucidex TM 6 (average molecular weight about 95,000 Da) and Glucidex TM 2 (average molecular weight about 300,000 Da) are available from Roquette (France); and MALTRIN TM maltodextrin with different molecular weights (including molecular weights from about 12,000 Da to 15,000 Da) is available from GPC (Muscatine, Iowa). Examples of other hydrophobic polysaccharide derivatives are disclosed in U.S. Patent Application 2007 / 0260054 (Chudzik), which is incorporated herein by reference.

[0067] Exemplary additive components can include amphiphilic compounds. Amphiphilic compounds include those having a relatively hydrophobic moiety and a relatively hydrophilic moiety. Exemplary amphiphilic compounds can include, but are not limited to, block polymers including at least polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, polyoxazolines (such as poly(2-alkyl oxazolines) and derivatives), etc. Exemplary amphiphilic compounds can specifically include poloxamers. A poloxamer is a nonionic triblock copolymer consisting of a central hydrophobic chain of polyoxypropylene with two hydrophilic chains of polyoxyethylene on either side. Poloxamers are often referred to by the trade name It should be appreciated that many aspects of the copolymer can be varied so that these characteristics can be customized. An exemplary poloxamer is F68 (a nonionic copolymer of ethylene and propylene oxide commercially available from BASF Corporation; also designated as F68 and poloxamer F68), which refers to a poloxamer having a solid form at room temperature, with a polyoxypropylene molecular weight of approximately 1,800 g / mol and a polyoxyethylene content of approximately 80%, a total molecular weight of approximately 8,400 g / mol, and this copolymer ends with a primary hydroxyl group.

[0068] Exemplary additive components may further include compounds that stabilize a poorly water-soluble pharmaceutical agent. 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).

[0069] Different additive components may be added as an optional top coat on a layer comprising a hydrophobic active agent. In some embodiments, the top coat may be applied to modify the release characteristics of the hydrophobic active agent. Other top coats may be added as a protective layer to reduce the unintentional loss of the hydrophobic active agent through friction or general wear. For example, the top coat may serve as a protective layer for the purposes of handling during packaging or to protect the hydrophobic active agent until the hydrophobic active agent can be delivered to a target site in the body, or both. For example, the optional top coat may include polyvinylpyrrolidone (PVP), polyacrylic acid (PAA), and polyurethane.

[0070] Hydrophobic surfactant

[0071] It should be appreciated that the hydrophobic active agents of the embodiments herein (e.g., particulate hydrophobic therapeutic agents) may include agents having many different types of activity. As used herein, the terms "active agent" and "therapeutic agent" shall have a common boundary unless the context otherwise dictates. Hydrophobic active agents may specifically include those having a solubility in water of less than about 100 μg / mL at 25 degrees Celsius and neutral pH. In different embodiments, hydrophobic active agents may specifically include those having a solubility in water of less than about 10 μg / mL at 25 degrees Celsius 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 degrees Celsius and neutral pH.

[0072] In some exemplary embodiments, the active agent may include, but is not limited to, anti-proliferative agents such as paclitaxel, sirolimus (rapamycin), zotarolimus, everolimus, temsirolimus, pimecrolimus, tacrolimus, and ridaforolimus; analgesics and anti-inflammatory agents such as allopurinol, auranofin, azapropazone, benorilate, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxyphenbutazone, phenylbutazone, piroxicam, sulindac; antiarrhythmic agents such as amiodarone hydrochloride, disopyramide, flecainide acetate, quinidine sulfate; antibacterial agents such as benzylpenicillin, cinoxacin, ciprofloxacin hydrochloride, clarithromycin, clofazimine, cloxacillin, demeclocycline, doxycycline, erythromycin, ethionamide, imipenem, nalidixic acid, nitrofurantoin, rifampicin, spiramycin, sulphabenzamide, sulfadoxine, sulfamerazine, sulphacetamide, sulfadiazine, sulphafurazole, sulfamethoxazole, sulfapyridine, tetracycline, trimethoprim; anticoagulants such as dicoumarol, dipyridamole, acenocoumarol, phenindione; antihypertensive agents such as amlodipine, benidipine, darodipine, diltiazem hydrochloride, diazoxide, felodipine, guanabenz acetate, isradipine, minoxidil, nicardipine hydrochloride, nifedipine, nimodipine, phenoxybenzamine hydrochloride, prazosin hydrochloride, reserpine, terazosin hydrochloride; antimuscarinic agents: atropine, trihexyphenidyl hydrochloride, biperiden, diphenhydramine hydrochloride, hyoscyamine, brompheniramine maleate, oxybutynin chloride, tropicamide; antineoplastic and immunosuppressive agents such as aminoglutethimide, aclarubicin, azathioprine, busulfan, chlorambucil, cyclosporine, dacarbazine, estramustine, etoposide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, procarbazine hydrochloride, tamoxifen citrate, testolactone; β-blockers such as acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol; inotropic agents such as amrinone, digitoxin, digoxin, enoximone, lanatoside C, metildigoxin; corticosteroids such as beclomethasone, betamethasone, budesonide, cortisone acetate, desoxymethasone, dexamethasone, fludrocortisone acetate, flunisolide, fluocortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone; lipid regulators such as bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol; nitrates and other antianginal agents such as amyl nitrite, nitroglycerin trinitrate, isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate.

[0073] Other exemplary embodiments of the active agent include, but are not limited to, active agents for the treatment of hypertension (HTN), such as guanethidine.

[0074] In one specific embodiment, these hydrophobic active agents are selected from the group consisting of paclitaxel, sirolimus (rapamycin), and mixtures thereof.

[0075] In some embodiments, the hydrophobic active agent can be conjugated to a cationic agent. Such conjugation can include covalently linking the hydrophobic active agent to the cationic agent. In some embodiments in which the hydrophobe is conjugated to the cationic agent, a linker can be used to attach the hydrophobe to the cationic agent. Suitable linkers include, but are not limited to, polyethylene glycol, poly(ethylene oxide), and polypeptides of naturally occurring and non-naturally occurring amino acids. In some embodiments, the linker can be biodegradable or cleavable in vivo to assist in the release of the hydrophobic active agent. Exemplary linkers can further include alkane or aromatic compounds having heteroatom substitutions such as N, S, Si, Se, or O.

[0076] Any of a variety of techniques known in the art can be used to determine the particle size and particle size distribution of the particulate formulation. In one mode of practice, laser diffraction can be used to measure the particle size and distribution. In laser diffraction, a laser beam passes through a dispersed particulate sample, and the angular variation of the scattered light intensity is measured. Larger particles have a larger light scattering angle and smaller particles have a smaller light scattering angle, and the angular scattering intensity data can be collected and analyzed to produce a particle size plot.

[0077] Analysis of the particle size and distribution can be performed using a laser scattering device such as a Malvern System 4700 (for particles from 1 nm to 3 μm) or a Horiba LA-930 (e.g., for particles from 100 nm to 2 mm). The output of such an analyzer can provide information about the size of individual microparticles and the total amount of such microparticles reflecting the distribution of the microparticles in terms of size. Analysis providing data on the size distribution can be provided in the form of a histogram, graphically representing the size and size distribution of all microparticles in the formulation.

[0078] Exemplary particulate hydrophobic therapeutic agents can have different morphological characteristics. In some embodiments, the particulate hydrophobic therapeutic agent can be crystalline. In still other embodiments of the present disclosure, these particulate hydrophobic therapeutic agents can be amorphous. Additionally, a combination of crystalline and amorphous particulate hydrophobic therapeutic agents can be desirable, for example, to achieve the desired solubility of these particulate hydrophobic therapeutic agents.

[0079] In some embodiments, the particulate hydrophobic therapeutic agent can have an average diameter (“dn”, number average) of less than about 30 μm or less than about 10 μm. Also, in some embodiments, the particulate hydrophobic therapeutic agent can have an average diameter of about 100 nm or greater. For example, the microparticles associated with the expandable elastic portion can have an average diameter in the range of from about 100 nm to about 10 μm, from about 150 nm to about 2 μm, from about 200 nm to about 5 μm, or even from about 0.3 μm to about 1 μm.

[0080] Nucleic acid

[0081] The nucleic acids used in conjunction with embodiments of the present invention can include different types of nucleic acids that can function to provide a therapeutic effect. Exemplary types of nucleic acids can 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, ribozymes, locked nucleic acids, and catalytic DNA. In one specific embodiment, the nucleic acid used is siRNA and / or its derivatives.

[0082] In some exemplary embodiments of the present disclosure, the percentage ratio of the hydrophobic agent 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 still other embodiments, it can be appreciated that the percentage ratio of the hydrophobic agent 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.

[0083] Hydrophilic substrate coating

[0084] A class of hydrophilic polymers useful as polymeric materials for forming hydrophilic substrate coatings are synthetic hydrophilic polymers. Biostable synthetic hydrophilic polymers (i.e., synthetic hydrophilic polymers that do not exhibit appreciable degradation in vivo) can be prepared from any suitable monomers, including acrylic monomers, vinyl monomers, ether monomers, or combinations of any one or more of these types of monomers. Acrylic monomers include, for example, methacrylates, methyl methacrylate, 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, methacrylic acid, acrylic acid, glycerol acrylate, glycerol methacrylate, acrylamide, methacrylamide, dimethylacrylamide (DMA), and derivatives and / or mixtures of any of these. Vinyl monomers include, for example, vinyl acetate, vinyl pyrrolidone, vinyl alcohol, and derivatives of any of these. Ether monomers include, for example, ethylene oxide, propylene oxide, butylene oxide, and derivatives of any of these. Examples of polymers that can be formed from these monomers include poly(acrylamide), poly(methacrylamide), poly(vinyl pyrrolidone), poly(acrylic acid), poly(ethylene glycol), poly(vinyl alcohol), and poly(HEMA). Examples of hydrophilic copolymers include, for example, methyl vinyl ether / maleic anhydride copolymers and vinyl pyrrolidone / (meth)acrylamide copolymers. Mixtures of homopolymers and / or copolymers can be used.

[0085] Examples of some acrylamide-based polymers, such as poly(N,N-dimethylacrylamide-co-aminopropyl methacrylamide) and poly(acrylamide-co-N,N-dimethylaminopropyl methacrylamide), are described in Example 2 of U.S. Patent No. 7,807,750 (Taton et al.), the disclosure of which is incorporated herein by reference.

[0086] Other hydrophilic polymers that can be useful in the present disclosure are derivatives of acrylamide polymers having photoreactive groups. One such representative hydrophilic polymer can be the copolymerization of N-[3-(4-benzoylbenzamido)propyl]methacrylamide (Formula I) with N-(3-aminopropyl)methacrylamide (Formula II) to produce the polymer poly(N-3-aminopropyl)methacrylamide-co-N-[3-(4-benzoylbenzamido)propyl]methacrylamide (Formula III). The preparation of this polymer is disclosed in Example 1 of U.S. Patent Publication 2007 / 0032882 (Lodhi et al.), the entire content of which is incorporated herein by reference.

[0087]

[0088]

[0089] In some embodiments, the hydrophilic polymer can be a vinyl pyrrolidone polymer or a vinyl pyrrolidone / (meth)acrylamide copolymer, such as poly(vinyl pyrrolidone-co-methyl acrylamide). If a PVP copolymer is used, it can be a copolymer of vinyl pyrrolidone and a monomer selected from the group of acrylamide monomers. Exemplary acrylamide monomers include (meth)acrylamide and (meth)acrylamide derivatives, such as alkyl (meth)acrylamide, as exemplified by dimethylacrylamide; and

[0090] aminoalkyl (meth)acrylamide, as exemplified by aminopropyl methacrylamide and dimethylaminopropyl methacrylamide. For example, poly(vinyl pyrrolidone-co-N,N-dimethylaminopropyl methacrylamide) is described in Example 2 of U.S. Patent No. 7,807,750 (Taton et al.).

[0091] In one embodiment, the polymers and copolymers as described are derivatized with one or more photoactivatable groups. Exemplary photoreactive groups that can dangle from the biostable hydrophilic polymer include aryl ketones, such as acetophenone, benzophenone, anthraquinone, anthrone, quinone, and anthrone-like heterocycles. The aryl ketones herein can specifically include diaryl ketones. The polymers herein can provide a hydrophilic polymer having dangling activatable photoreactive groups (photogroups) that can be applied to an inflatable and foldable structure and then sufficiently treated with photochemical radiation to activate the photoreactive groups and result in covalent bonding to a target, such as the inflatable and foldable structural material. The application of the photo-hydrophilic polymer can be used to provide a durable coating of a flexible hydrogel matrix, wherein the hydrophilic polymeric material is covalently bonded to the inflatable and foldable structural material.

[0092] The flexible hydrogel coating can be prepared using a hydrophilic polymer having dangling photoreactive groups. Methods for preparing hydrophilic polymers having photoreactive groups are known in the art. For example, a method for preparing photo-PVP is described in U.S. Patent No. 5,414,075, which is incorporated herein by reference. Hydrophilic photo-polyacrylamide polymers, such as poly(acrylamide-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide), "photo-PAA"), and their derivatives can be used to form the hydrophilic substrate coatings in the exemplary embodiments of the present disclosure. A method for preparing photo-polyacrylamide is described in U.S. Patent No. 6,007,833, which is incorporated herein by reference.

[0093] Other embodiments of the hydrophilic substrate coating include derivatives of photo-polyacrylamide polymers incorporating additional reactive moieties. Some exemplary reactive moieties include N-oxysuccinimide and glycidyl methacrylate. Representative photo-polyacrylamide derivatives incorporating additional reactive moieties include poly(acrylamide-co-maleic acid-6-aminohexanoic acid-N-oxysuccinimide-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide) and poly(acrylamide-co-(3-(4-benzoylbenzamido)propyl)methacrylamide)-co-glycidyl methacrylate. Additional photo-polyacrylamide polymers incorporating reactive moieties are described in U.S. Patent Nos. 6,465,178 (Chappa et al.), 6,762,019 (Swan et al.), and 7,309,593 (Ofstead et al.), the disclosures of which are incorporated herein by reference.

[0094] Other embodiments of exemplary hydrophilic substrate coatings including derivatives of photo-polyacrylamide polymers incorporating additional reactive moieties can be found in U.S. Patent No. 6,514,734 (Clapper et al.), the disclosure of which is incorporated herein in its entirety by reference.

[0095] In still other embodiments, the hydrophilic substrate coating can include derivatives of photo-polyacrylamide polymers incorporating charged moieties. Charged moieties include both positively charged species and negatively charged species. Exemplary charged species include, but are not limited to, sulfonates, phosphates, and quaternary amine derivatives. Some examples include the negatively charged species N-acetylated poly(acrylamide-co-sodium 2-acrylamido-2-methylpropanesulfonate-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide)-co-methoxypoly(ethylene glycol) monomethacrylate. Other negatively charged species that can be incorporated into the hydrophilic substrate coating are described in U.S. Patent No. 4,973,993, the disclosure of which is incorporated herein in its entirety by reference. Positively charged species can include poly(acrylamide-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide)-co-(3-(methacryloylamino)propyl)trimethylammonium chloride. Other positively charged species that can be incorporated into the hydrophilic substrate coating are described in U.S. Patent No. 5,858,653 (Duran et al.), the disclosure of which is incorporated herein in its entirety by reference.

[0096] In another embodiment, the described polymers and copolymers are derivatized with one or more polymerizable groups. Polymers having pendant polymerizable groups are generally referred to as macromonomers. The polymerizable group or groups can be present at one or more end portions (termini) of the polymer chain or can be present along the length of the polymer. In one embodiment, the polymerizable groups are randomly positioned along the length of the polymer.

[0097] Exemplary hydrophilic polymer coatings can be prepared using polymer grafting techniques. Polymer grafting techniques can include applying a non-polymerizable grafting agent and monomers to the surface of a substrate and then polymerizing the monomers on the surface of the substrate after appropriately activating (e.g., but not limited to UV radiation) the grafting agent. Examples of grafting methods for producing hydrophilic polymer surfaces are described in U.S. Patent Nos. 7,348,055, 7,736,689, and 8,039,524 (all to Chappa et al.), the entire disclosures of which are incorporated herein by reference.

[0098] Optionally, the coating can include a crosslinking agent. The crosslinking agent can promote the association of the polymer in the coating or the binding of the polymer to the coated surface. The choice of specific crosslinking agent can depend on the composition of the coating composition.

[0099] Suitable crosslinking agents can include two or more activatable groups that can react with the polymers in the composition. Suitable activatable groups can include photoreactive groups as described herein, such as aryl ketones, such as acetophenone, benzophenone, anthraquinone, anthrone, quinone, and anthrone-like heterocycles. Crosslinking agents that include photoreactive groups can be referred to as photocrosslinking agents or photoactivatable crosslinking agents. The photoactivatable crosslinking agent can be ionic and can have good solubility in aqueous compositions. In some embodiments, at least one ionic photoactivatable crosslinking agent can be used to form the coating. Ionic crosslinking agents can include acid groups or their salts, such as selected from sulfonic acids, carboxylic acids, phosphonic acids, their salts, etc. Exemplary counterions include alkali metals, alkaline earth metals, ammonium, protonated amines, etc.

[0100] Exemplary ionic photoactivatable crosslinking agents include 4,5-bis(4-benzoylbenzylideneoxy)benzene-1,3-disulfonic acid or salts; 2,5-bis(4-benzoylbenzylideneoxy)benzene-1,4-disulfonic acid or salts; 2,5-bis(4-benzylideneoxy)benzene-1-sulfonic acid or salts; N,N-bis[2-(4-benzoylbenzyloxy)ethyl]-2-aminoethanesulfonic acid or salts, etc. See U.S. Patent Nos. 6,077,698 (Swan et al.), 6,278,018 (Swan), 6,603,040 (Swan), and 7,138,541 (Swan), the disclosures of which are incorporated herein by reference.

[0101] Other exemplary ionic photoactivatable crosslinking agents include ethylenebis(4-benzoylbenzyl dimethylammonium) dibromide and hexamethylenebis(4-benzoylbenzyl dimethylammonium) dibromide, among others. See U.S. Patent No. 5,714,360 (Swan et al.), the disclosure of which is incorporated herein by reference.

[0102] In still other embodiments, restricted multifunctional reagents having photoactivatable crosslinking groups can be used. In some instances, these restricted multifunctional reagents include tetra(4-benzoylbenzyl ether) of pentaerythritol and tetra(4-benzoylbenzoate) of pentaerythritol. See U.S. Patent Nos. 5,414,075 (Swan et al.) and 5,637,460 (Swan et al.), the disclosures of which are incorporated herein by reference.

[0103] Additional crosslinking agents can include those having the formula Photo 1 -LG-Photo 2 where Photo 1 and Photo 2 independently represent at least one photoreactive group and LG represents a linking group containing at least one silicon or at least one phosphorus atom, wherein a degradable linker comprises a covalent bond between at least one photoreactive group and the linking group, wherein the covalent bond between at least one photoreactive group and the linking group is interrupted by at least one heteroatom. See U.S. Patent No. 8,889,760 (Kurdyumov et al.), the disclosure of which is incorporated herein by reference. Additional crosslinking agents can include those having a core molecule (the core molecule having one or more charged groups) and one or more photoreactive groups covalently attached to the core molecule via one or more degradable linkers. See U.S. Published Patent Application No. 2011 / 0144373 (Swan et al.), the disclosure of which is incorporated herein by reference.

[0104] Crosslinking agents used according to the embodiments herein can include those having at least two photoreactive groups. Exemplary crosslinking agents are described in U.S. Patent No. 8,889,760, the content of which is incorporated herein by reference in its entirety.

[0105] In some embodiments, the first and / or second crosslinking agent can have a molecular weight of less than about 1500 kDa. In some embodiments, the crosslinking agent can have a molecular weight of less than about 1200, 1100, 1000, 900, 800, 700, 600, 500, or 400.

[0106] In some embodiments, at least one of the first and second crosslinking agents comprises a linker having the formula Photo 1 -LG-Photo 2 where Photo 1 and Photo2 independently represents at least one photo-reactive group and LG represents a linking group containing at least one silicon or at least one phosphorus atom, there is a covalent bond between at least one photo-reactive group and the linking group, wherein the covalent bond between at least one photo-reactive group and the linking group is interrupted by at least one heteroatom.

[0107] In some embodiments, at least one of the first and second cross-linking agents comprises a linker having a formula selected from:

[0108] (a)

[0109]

[0110] wherein R1, R2, R8 and R9 are any substituents; R3, R4, R6 and R7 are alkyl, aryl or a combination thereof; R5 is any substituent; and each X is independently O, N, Se, S or alkyl or a combination thereof;

[0111] (b)

[0112]

[0113] wherein R1 and R5 are any substituents; R2 and R4 can be any substituents except OH; R3 can be alkyl, aryl or a combination thereof; and X is independently O, N, Se, S, alkylene or a combination thereof;

[0114] (c)

[0115]

[0116] wherein R1, R2, R4 and R5 are any substituents; R3 is any substituent; R6 and R7 are alkyl, aryl or a combination thereof; and each X can be independently O, N, Se, S, alkylene or a combination thereof; and

[0117] (d)

[0118]

[0119] In a specific embodiment, the cross-linking agent can be bis(4-benzoylphenyl) phosphate.

[0120] In some embodiments, the photoactivatable cross-linking agent can be ionic and can have good solubility in an aqueous composition (such as the first and / or second coating composition). In some embodiments, at least one ionic photoactivatable cross-linking agent is used to form a coating. In some cases, the ionic photoactivatable cross-linking agent can cross-link a polymer within the second coating, which can also improve the durability of the coating.

[0121] Any suitable ionic photoactivatable crosslinker can be used. In some embodiments, the ionic photoactivatable crosslinker is a compound having Formula I: X 1 --Y--X 2 , wherein Y is a group comprising at least one acid group, base group, or salt of an acid group or base group. X 1 and X 2 are each independently a group comprising a latent photoreactive group. These photoreactive groups can be the same as those described herein. The spacer together with the latent photoreactive group can also be part of X 1 or X 2 . In some embodiments, the latent photoreactive group comprises an aryl ketone or quinone.

[0122] The group Y in Formula I provides the desired water solubility for the ionic photoactivatable crosslinker. The water solubility (at room temperature and optimal pH) is at least about 0.05 mg / ml. In some embodiments, the solubility is about 0.1 to about 10 mg / ml or about 1 to about 5 mg / ml.

[0123] In some embodiments of Formula I, Y is a group comprising at least one acid group or a salt thereof. Such a photoactivatable crosslinker can be anionic, depending on the pH of the coating composition. Suitable acid groups include, for example, sulfonic acid, carboxylic acid, phosphonic acid, etc. Suitable salts of such groups include, for example, sulfonates, carboxylates, and phosphates. In some embodiments, the ionic crosslinker comprises a sulfonic acid or sulfonate group. Suitable counterions include alkali metals, alkaline earth metals, ammonium, protonated amines, etc.

[0124] For example, a compound having Formula I can have a group Y comprising a sulfonic acid or sulfonate group; X 1 and X 2 can comprise photoreactive groups, such as aryl ketones. Such compounds include 4,5-bis(4-benzoylbenzylideneoxy)benzene-1,3-disulfonic acid or salt; 2,5-bis(4-benzoylbenzylideneoxy)benzene-1,4-disulfonic acid or salt; 2,5-bis(4-benzylideneoxy)benzene-1-sulfonic acid or salt; N,N-bis[2-(4-benzoylbenzyloxy)ethyl]-2-aminoethanesulfonic acid or salt, etc. See U.S. Patent No. 6,278,018. The counterion of the salt can be, for example, ammonium or an alkali metal (such as sodium, potassium, or lithium).

[0125] In other embodiments of Formula I, Y can be a group comprising a base or a salt thereof. Such Y groups can include, for example, ammonium, phosphonium, or sulfonium groups. The group can be neutral or positively charged, depending on the pH of the coating composition. In some embodiments, the group Y includes an ammonium group. Suitable counterions include, for example, carboxylates, halides, sulfates, and phosphates. For example, a compound having Formula I can have a Y group comprising an ammonium group; X 1 and X 2 Photoreactive groups may be included, including aryl ketones. Such photoactivatable crosslinkers include ethylene bis (4-benzoylbenzyldimethylammonium) salt; hexamethylene bis (4-benzoylbenzyldimethylammonium) salt; 1,4-bis (4-benzoylbenzyl) -1,4-dimethylpiperazine diium) salt, bis (4-benzoylbenzyl) hexamethylenetetramine diium salt, bis [2- (4-benzoylbenzyldimethylammonium) ethyl] -4-benzoylbenzylmethylammonium salt; 4,4-bis (4-benzoylbenzyl) morpholinium salt; ethylene bis [ (2- (4-benzoylbenzyldimethylammonium) ethyl) -4-benzoylbenzylmethylammonium] salt; and 1,1,4,4-tetrakis (4-benzoylbenzyl) piperazine diium salt. See US Pat. No. 5,714,360. The counterion is typically a carboxylate ion or a halide. In one embodiment, the halide is bromide.

[0126] In other embodiments, the ionic photoactivatable crosslinker can be a compound having the formula:

[0127]

[0128] Where X 1 comprising a first photoreactive group; X 2 includes a second photoreactive group; Y includes a core molecule; Z includes at least one charged group; D 1 comprising a first degradable linker; and D 2 A second degradable linker is included. Additional exemplary degradable ionic photoactivatable crosslinkers are described in U.S. Patent Application Publication No. US2011 / 0144373 (Swan et al., “Water Soluble Degradable Crosslinker”), the disclosure of which is incorporated herein by reference.

[0129] In some aspects, a nonionic photoactivatable crosslinker can be used. In one embodiment, the nonionic photoactivatable crosslinker has the formula XR 1 R 2 R 3 R 4, wherein X is a chemical backbone, and R 1 、R 2 、R 3 and R 4 are groups that include a latent photoreactive group. Exemplary nonionic crosslinkers are described, for example, in U.S. Patent Nos. 5,414,075 and 5,637,460 (Swan et al., “Restrained Multifunctional Reagent for Surface Modification”). Chemically, the first and second photoreactive groups and the corresponding spacers can be the same or different.

[0130] In other embodiments, the nonionic photoactivatable crosslinker can be represented by the following formula:

[0131] PG 2 -LE 2 -X-LE 1 -PG 1

[0132] wherein PG 1 and PG 2 independently include one or more photoreactive groups, such as aryl ketone photoreactive groups, including but not limited to aryl ketones such as acetophenone, benzophenone, anthraquinone, anthrone, anthrone-like heterocycles, their substituted derivatives, or combinations thereof; LE 1 and LE 2 independently are linking units, including, for example, segments including urea, carbamate, or combinations thereof; and X represents a core molecule, which can be polymeric or non-polymeric, including but not limited to hydrocarbons, including straight-chain, branched-chain, cyclic, or combinations thereof; aromatic, non-aromatic, or combinations thereof; monocyclic, polycyclic, carbocyclic, heterocyclic, or combinations thereof; benzene or its derivatives; or combinations thereof. Other nonionic crosslinkers are described, for example, in U.S. Application No. 13 / 316,030, filed December 9, 2011 (Publication No. US 2012 / 0149934) (Kurdyumov, “Photocrosslinker”), the disclosure of which is incorporated herein by reference.

[0133] Additional embodiments of nonionic photoactivatable crosslinkers can include, for example, those described in U.S. Patent Publication 2013 / 0143056 (Swan et al., “Photo-Vinyl Primers / Crosslinkers”), the disclosure of which is incorporated herein by reference. Exemplary crosslinkers can include nonionic photoactivatable crosslinkers having the general formula R 1 –X–R 2 wherein R 1 is a group containing a vinyl group, X is a group containing from about one to about twenty carbon atoms, and R 2 is a group containing a photoreactive group.

[0134] A single photoactivatable crosslinker or any combination of photoactivatable crosslinkers can be used to form a coating. In some embodiments, at least one nonionic crosslinker (such as tetra(4-benzoylbenzyl ether) of pentaerythritol) can be used with at least one ionic crosslinker. For example, at least one nonionic photoactivatable crosslinker can be used with at least one cationic photoactivatable crosslinker (such as ethylenebis(4-benzoylbenzyl dimethylammonium) salt) or at least one anionically photoactivatable crosslinker (such as 4,5-bis(4-benzoyl-phenylmethyleneoxy)benzene-1,3-disulfonic acid or a salt). In another example, at least one nonionic crosslinker can be used with at least one cationic crosslinker and at least one anionic crosslinker. In yet another example, at least one cationic crosslinker can be used with at least one anionic crosslinker, but not with a nonionic crosslinker.

[0135] An exemplary crosslinker is disodium 4,5-bis[(4-benzoylbenzyl)oxy]-1,3-benzenedisulfonate (DBDS). This reagent can be prepared by combining 4,5-dihydroxybenzyl-1,3-disulfonate (CHBDS) with 4-bromomethyldibenzoyl ketone (BMBP) in THF and sodium hydroxide, then refluxing and cooling the mixture, followed by purification and recrystallization (also described in U.S. Patent No. 5,714,360, incorporated herein by reference).

[0136] Additional crosslinkers can include those described in U.S. Published Patent Application No. 2010 / 0274012 (Guire et al.) and U.S. Patent No. 7,772,393 (Guire et al.), the entire contents of which are incorporated herein by reference.

[0137] In some embodiments, the crosslinking agent can include boron-containing linking agents, including but not limited to the boron-containing linking agents disclosed in U.S. Patent Publication 2013 / 0302529 to Kurdyumov et al. entitled "Boron-Containing Linking Agents", the content of which is incorporated herein by reference. By way of example, the linking agent can include boric acid, borazine, or borate groups, as well as coatings and devices incorporating such linking agents and related methods. In one embodiment, the linking agent includes a compound having structure (I):

[0138]

[0139] wherein R 1 is a group containing a photoreactive group; R 2 is selected from OH and groups containing a photoreactive group, an alkyl group, and an aryl group; and R 3 is selected from OH and groups containing a photoreactive group. In some embodiments, the bonds B-R 1 , B-R 2 and B-R 3 can be independently selected to be interrupted by a heteroatom such as O, N, S, or a mixture thereof.

[0140] Additional reagents for use with the embodiments herein can include stilbene-based reactive compounds, including but not limited to those disclosed in U.S. Patent No. 8,487,137 to Kurdyumov et al. entitled "Stilbene-Based Reactive Compounds, Polymeric Matrices Formed Therefrom, and Articles Visualizable by Fluorescence", the content of which is incorporated herein by reference.

[0141] Additional photoreagents, crosslinking agents, hydrophilic coatings, and related reagents are disclosed in U.S. Patent Nos. 8,513,320 (Rooijmans et al.), 8,809,411 (Rooijmans), and 2010 / 0198168 (Rooijmans), the entire content of which is incorporated herein by reference.

[0142] It is also possible to use natural polymers to form a hydrophilic substrate coating. Natural polymers include polysaccharides such as dextran, carboxymethyl cellulose, and hydroxyethyl cellulose; mucopolysaccharides such as hyaluronic acid; polypeptides such as soluble proteins like collagen, albumin, and avidin; and combinations of these natural polymers. Combinations of natural polymers and synthetic polymers can also be used.

[0143] In some cases, an adhesion layer can be used to form a hydrophilic base layer. In still other cases, the adhesion layer can be added to the hydrophilic base layer. The adhesion layer can function to increase the adhesion of the hydrophilic base layer to the substrate. In other embodiments, the adhesion layer can function to increase the adhesion of a hydrophobic active agent to the hydrophilic base layer. Exemplary adhesion layers include, but are not limited to, silanes, butadienes, polyurethanes, and parylenes. The silane adhesion layer is described in U.S. Patent Publication 2012 / 0148852 (Jelle et al.), the content of which is incorporated herein by reference.

[0144] In an exemplary embodiment, the hydrophilic base layer can include a material containing tannic acid, polydopamine, or other catechols.

[0145] Matrix

[0146] The substrate can be formed from any desirable material or combination of materials suitable for use in the body. In some embodiments, the substrate is formed from a compliant and flexible material such as an elastomer (a polymer having elasticity). Exemplary elastomers can be formed from different polymers, including polyurethanes and polyurethane copolymers, polyethylene, styrene-butadiene copolymers, polyisoprene, isobutylene-isoprene copolymers (butyl rubber) (including halogenated butyl rubber), butadiene-styrene-acrylonitrile copolymers, silicone polymers, fluorosilicone polymers, polycarbonates, polyamides, polyesters, polyvinyl chloride, polyether-polyester copolymers, polyether-polyamide copolymers, and the like. The substrate can be made of a single elastomeric material or a combination of materials.

[0147] Other materials 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, 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, acrylic acid, methacrylic acid, glycerol acrylate, glycerol methacrylate, methacrylamide, and acrylamide; vinyl resins, such as those polymerized from: ethylene, propylene, vinyl chloride, vinyl acetate, vinyl pyrrolidone, 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 polyether ketone.

[0148] 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.

[0149] Processes for modifying the above-described matrix can include chemical modification to improve the performance characteristics of the matrix. Specific chemical processes that can be used include ozone treatment, chemical oxidation, acid chemical etching, base chemical etching, plasma treatment, and corona treatment, surface grafting, thermal activation coating processes (both covalent and non-covalent), and surface modification, including coatings of catechol-containing derivatives that include dopamine, tannic acid, plant polyphenols, and other catechols or hydrophilic moieties. Additionally, processes for forming the above-described matrix can include physical modification, such as, but not limited to, sandblasting and surface texturing (e.g., during or after the molding process of a polymer).

[0150] In some embodiments, modification of the matrix as described herein can allow for the omission of a substrate coating layer (such as a hydrophilic layer), since the modified matrix surface will allow for improved adhesion of hydrophobic therapeutic agents and cationic agents compared to adhesion to a hydrophilic layer.

[0151] Device

[0152] It should be appreciated that the embodiments herein include, and different types of devices that can be used in combination include, but are not limited to, drug delivery devices, such as drug-eluting balloon catheters, drug-containing balloon catheters, stents, grafts, and the like.

[0153] Some of the embodiments described herein can be used in combination with balloon-expandable flow diverters and self-expanding flow diverters. Other embodiments can include contact use with angioplasty balloons (such as, but not limited to, percutaneous transluminal coronary angioplasty and percutaneous transluminal angioplasty). Still other embodiments can include use in combination with sinusplasty balloons for ENT treatment, urethral balloons and urethral stents for urinary tract and gastrointestinal tract treatment (such as, for example, devices for colonoscopy). A hydrophobic active agent can be transferred from a balloon-like inflatable device or from a patch-like device to tissue. Other embodiments of the present disclosure can further be used in combination with a microinfusion catheter device. In some embodiments, a microinfusion catheter device can be used to target an active agent to the renal sympathetic nerves to treat, for example, hypertension.

[0154] The embodiments included herein can also be used in combination with the administration of different active agents to the skin (such as, but not limited to, transdermal drug delivery).

[0155] Other exemplary medical applications in which the embodiments of the present disclosure can be used further encompass the treatment of bladder neck strictures (such as, for example, after transurethral resection of the prostate), laryngotracheal strictures (such as, in combination with serial endoscopic dilation to treat subglottic stenosis), oral cancer and cold sores, and biliary strictures (such as, after pancreatic, hepatocellular cholangiocarcinoma). As a further example, the embodiments herein can be used in combination with an applicator. The applicator can include those for use with different procedures, including surgical procedures, where an active agent needs to be administered to a specific tissue location. Examples can include, but are not limited to, applicators that can be used in orthopedic surgery to administer an active agent to a specific surface of bone, cartilage, ligament, or other tissue through physical contact of the applicator with those tissues. The applicator can include, but is not limited to, hand-held applicators, drug patches, drug stamps, drug application disks, and the like.

[0156] In some embodiments, the applicator can include a surface having a hydrophilic polymer layer disposed thereon and coated therapeutic agent particles disposed on the hydrophilic polymer layer, the coated therapeutic agent particles comprising particulate hydrophobic therapeutic agent; and a cationic agent disposed on the particulate hydrophobic therapeutic agent.

[0157] In use, the different embodiments included herein can enable an active agent to be rapidly transferred to a specific target tissue. For example, in some embodiments, a healthcare provider can create physical contact between a portion of a drug delivery device (including the active agent) and the tissue being targeted, and the active agent will rapidly transfer from the drug delivery device to the tissue. As such, precise control over the tissue to which the active agent is provided can be achieved.

[0158] One beneficial aspect of the different embodiments described herein is that the therapeutic agent can be transferred from the drug delivery device or coating to the target tissue very rapidly. In some embodiments, a substantial 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 substantial 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 substantial 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 substantial 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 substantial 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 substantial transfer of the therapeutic agent from the drug delivery device or coating to the tissue occurs within 1 minute or less.

[0159] Additional embodiments

[0160] As described above, some embodiments may include a hydrophilic substrate coating or layer. In some embodiments, a hydrophilic polymer solution can be formed by combining a hydrophilic polymer with one or more solvents. Exemplary hydrophilic polymers are described in more detail above. The hydrophilic polymer solution can then be applied to a suitable substrate, such as an expandable balloon disposed on a catheter shaft. Many different techniques can be used to apply the hydrophilic polymer solution to the substrate. By way of example, exemplary techniques can include brush coating, drop coating, knife coating, dip coating, spray coating, microdispersion, etc.

[0161] In some embodiments, such as embodiments where a photopolymer is used to form the hydrophilic layer, a photochemical radiation application step can be performed to activate latent photoreactive groups on the hydrophilic polymer or on a crosslinker, thereby covalently binding the hydrophilic polymer to the substrate surface. By way of example, after applying the hydrophilic polymer solution to the substrate, the device can be subjected to UV exposure at a desired wavelength for a period of time.

[0162] Next, a hydrophobic active agent can be obtained and processed to prepare the hydrophobic active agent for deposition. In some embodiments, the processing of the hydrophobic active agent can include steps such as milling of the active agent. In some embodiments, the processing of the hydrophobic active agent can include steps such as recrystallization of the active agent. In some embodiments, the processing of the hydrophobic active agent can include lyophilization of the active agent.

[0163] In various embodiments, a hydrophobic active agent in particulate form can be suspended in water. The hydrophobic active agent and a cationic agent can be used to form coated therapeutic agent particles. By way of example, a cationic agent in water or a different solvent can be added to the hydrophobic active agent suspension. In various embodiments, a mixing or agitation step can be carried out to allow the hydrophobic active agent to interact with the cationic agent. In some embodiments, the cationic agent will surround the particulate hydrophobic active agent.

[0164] In some embodiments, a nucleic acid solution can be added to the mixture before or after the addition of the cationic agent and the mixing / agitation step. In some embodiments, an additive component (such as those described above) can be added to the mixture. The mixture can be applied to a substrate of the device, either directly or on top of a hydrophilic substrate coating. By way of example, exemplary techniques for application can include brush coating, drop coating, scrape coating, dip coating, spray coating, microdispersion, and the like.

[0165] After application, the composition can be allowed to dry. For example, in the context of a drug-eluting balloon catheter or a balloon catheter containing a drug, these balloons can be folded, pleated, and encapsulated in a sheath. In some embodiments, the balloon can be placed in an oven for a period of time.

[0166] In some embodiments of the present disclosure, a non-hydrophobic active agent can be modified to be substantially hydrophobic for configuration on the hydrophilic polymer layer. Exemplary modifications can include the preparation of prodrugs, whereby the hydrophobicity of the active agent can be modified by covalent bonds to the polymer. Other exemplary prodrugs can include active agents formed in situ by cleavage of the prodrug. Other exemplary modifications can include, but are not limited to, particles (such as nanoparticles or microparticles) containing an active agent encapsulated in a hydrophobic polymer. In some embodiments, the hydrophobic polymer can be biodegradable and release the active agent when delivered to the target tissue. Other exemplary modifications can include, but are not limited to, having altered hydrophobicity, micelles or other constructs formed as a result of the interaction between the active agent and a lipid additive, and the like.

[0167] The particulate formulations of the present disclosure can include additional excipients for modifying the surface of the particles for a specific application. For example, it can be advantageous to surface-modify the particles to produce particles having a positive or negative ζ potential. Exemplary materials that can be used to adjust the ζ potential of the particle surface include, but are not limited to, polyacrylic acid (PAA), polyglutamic acid, polyaspartic acid, heparin, alginate, hyaluronic acid, and polyvinyl sulfonic acid. The above cationic polymers can also be used as exemplary materials for adjusting the ζ potential of the particle surface.

[0168] The present invention can be better understood with reference to the following examples. These examples are intended to represent specific embodiments of the present invention and are not intended to limit the scope of the present invention.

[0169] Examples

[0170] Example 1: Paclitaxel preparation and balloon coating procedure

[0171] "Milled paclitaxel": Paclitaxel (LC Laboratories) was suspended in water at 65 mg / mL and milled using 5 mm stabilized zirconia 5 x 5 mm cylindrical beads (Stanford Materials Corp). After 18 hours of milling, the slurry was removed from the beads and lyophilized.

[0172] "Sonication-treated paclitaxel": Paclitaxel crystals were obtained by suspending paclitaxel (LC Laboratories) in water at 50 mg / mL. The paclitaxel was micronized using a sonication probe for 30 seconds, and the resulting suspension was left on an orbital shaker at room temperature for three days, during which it was sonicated in a sonication bath for 1 hour each day. The mixture was lyophilized.

[0173] Unless otherwise specified, the following nylon balloons were used in all studies: 20 x 3.5 mm.

[0174] A hydrophilic substrate coating (R) was deposited on the surface of the nylon balloon. The hydrophilic substrate coating solution in a solvent solution of 85:15 water / isopropanol included 6.25 g / L polyvinylpyrrolidone (PVP) having a benzoylbenzoic acid group; 1.25 g / L polyacrylamide; 2.5 g / L PVP (K90); and 0.05 g / L photo-crosslinker. For Examples 1-15, the crosslinker was prepared as described in US 6,278,018, Swan. For Examples 16-24, the crosslinker was prepared as described in US Patent Application Publication 2012 / 0046384, Kurdyumov et al. and US 6,278,018, Swan. After coating, the substrate coating material was dried at room temperature for 15 minutes and then irradiated with UV light for 3 minutes.

[0175] Typically, for any given formulation, an amount of 3 μg / mm of paclitaxel 2 (660 μg of paclitaxel per balloon) was attempted to be coated on these balloons. The paclitaxel containing the coating mixture was applied to the top of the cured hydrophilic substrate coating (R) using a positive displacement pipette and dried using a heat gun.

[0176] Dry all balloons overnight at room temperature. Fold, pleat, and encapsulate these balloons in a nylon sheath. Subsequently, place these balloons in an oven at 55 °C for 1 hour.

[0177] Unless otherwise stated, chemicals were obtained from Sigma-Aldrich. For Examples 2–15, the amount (μg) of active agent transferred to tissue and the standard deviation are listed in Table 3. For Examples 16 - 24, the amount (μg) of active agent transferred to tissue and the standard deviation are listed in Table 9.

[0178] Example 2: Formulations using DOTAP and siRNA

[0179] Grind freeze-dried paclitaxel in a vial and suspend it in water at 67 mg / mL. Add 31 μL of 20 mg / mL DOTAP (Avanti Polar Lipids) in ethanol to 100 μL of the suspension and sonicate in a sonication bath for 10 minutes. Then add 4.4 μL of 1 mM non-coding siRNA (0.065 mg). According to the procedure described in Example 1, three balloons received a hydrophilic substrate coating (R) and a top coating containing paclitaxel. 8 μL of the mixture containing paclitaxel was used for the top coating.

[0180] Add 3.7 mg of glycogen (obtainable from VWR) (a 50 mg / mL solution in 74 μL of water) to 130 μL of the mixture containing paclitaxel / DOTAP / siRNA. According to the procedure described in Example 1, four balloons received a hydrophilic substrate coating (R) and a top coating containing paclitaxel with glycogen. The mixture containing paclitaxel (8 μL) was used for the top coating.

[0181] Dry all balloons overnight at room temperature. Fold, pleat, and encapsulate these balloons in a nylon sheath. Subsequently, place these balloons in an oven at 55 °C for 1 hour.

[0182] Then, the release of paclitaxel from the coating was evaluated according to the following procedure. Ex vivo porcine coronary arteries (Pel-Freez Biologicals) were prepared and maintained at 37°C. After the sheaths were removed from these balloons, the balloons were soaked in PBS at 37°C for 30 seconds and then removed from the PBS. Next, the balloons were inflated in the arterial tissue at 37°C, at 60 - 80 psi for 30 seconds, and after deflating and removing the balloon, the arterial tissue was rinsed with PBS at 37°C. After removing the balloon from the tissue and rinsing, the tissue was placed in methanol / 0.1% acetic acid solution. The paclitaxel content in the resulting methanol and acetic acid solution was tested using HPLC ("Drug Transfer to Tissue"). Example 3: Formulations using DOTAP and siRNA Formulations

[0183] Formulation 1 - "PAX + DOTAP 1x”

[0184] Milled paclitaxel from the can was suspended in water at 65 mg / mL and sonicated with a sonicator probe for 30 seconds. 100 mg of the suspension (6.35 mg paclitaxel) was weighed out and 32 μL of a 20 mg / mL solution of DOTAP in ethanol was added. The mixture was sonicated for 10 minutes. According to the procedure described in Example 1, the balloon received a hydrophilic base coating (R) and a top coating containing paclitaxel. The mixture containing paclitaxel (10 μL) was used for the top coating.

[0185] Formulation 2 - "PAX + DOTAP 2x”

[0186] Milled paclitaxel from the can was suspended in water at 65 mg / mL and sonicated with a sonicator probe for 30 seconds. 100 mg of the suspension (6.35 mg paclitaxel) was weighed out and 64 μL of a 20 mg / mL solution of DOTAP in ethanol was added. The mixture was sonicated for 10 minutes. According to the procedure described in Example 1, the balloon received a hydrophilic base coating (R) and a top coating containing paclitaxel. The mixture containing paclitaxel (10 μL) was used for the top coating.

[0187] Formulation 3 - "PAX + DOTAP 1x + si”

[0188] 60 μg of siRNA (4.2 μL of a 1 mM solution) was added to Formulation 1. According to the procedure described in Example 1, the balloon received a hydrophilic base coating (R) and a top coating containing paclitaxel. The mixture containing paclitaxel (10 μL) was used for the top coating.

[0189] Formulation 4 - "PAX + DOTAP 2x + si”

[0190] Add 120 μg of siRNA to Formulation 2: 8.4 μL of a 1 mM solution. According to the procedure described in Example 1, the balloon received a hydrophilic substrate coating (R) and a top coating containing paclitaxel. A mixture containing paclitaxel (10 μL) was used for the top coating.

[0191] Formulation 5 - "PAX + DOTAP 1x + si + F68”

[0192] Add 4 μL of F68 in water (400 μg, approximately 6% w / w of the total formulation) to Formulation 3 at 100 mg / mL. According to the procedure described in Example 1, the balloon received a hydrophilic substrate coating (R) and a top coating containing paclitaxel. A mixture containing paclitaxel (10 μL) was used for the top coating.

[0193] Formulation 6 - "PAX + DOTAP 2x + si + F68”

[0194] Add 4 μL of F68 in water (400 μg, approximately 6% w / w of the total formulation) to Formulation 4 at 100 mg / mL. According to the procedure described in Example 1, the balloon received a hydrophilic substrate coating (R) and a top coating containing paclitaxel. A mixture containing paclitaxel (10 μL) was used for the top coating.

[0195] Dry all balloons overnight at room temperature. Fold, pleat, and encapsulate the balloons in a nylon sheath. Subsequently, place the balloons in a 55 °C oven for 1 hour.

[0196] Then, evaluate the release of paclitaxel from the coating according to the procedure described in Example 2.

[0197] Example 4: Formulations using DOTAP

[0198] Use canned ground paclitaxel (as above). Alternatively, micronize paclitaxel using a Netsch micronizer and lyophilize.

[0199] Suspend the Netsch ground particles of paclitaxel in water at 67 mg / mL and sonicate for 10 minutes.

[0200] Suspend the canned ground particles of paclitaxel in water at 67 mg / mL and sonicate for 10 minutes.

[0201] Formulation 1

[0202] Weigh out a suspension of 67 mg / mL of Netsch-milled paclitaxel in 100 mg of DDW (6.28 mg of paclitaxel) and sonicate until well dispersed. Add a 20 mg / mL solution of DOTAP in ethanol (31.4 μL) and sonicate in a sonication bath for 10 minutes. According to the procedure described in Example 1, each of the two balloons received a hydrophilic substrate coating (R) and a top coating containing paclitaxel. A mixture containing paclitaxel (14 μL) was used for the top coating.

[0203] Formulation 2

[0204] Weigh out a suspension of 67 mg / mL of Netsch-milled paclitaxel in 100 mg of DDW (6.28 mg of paclitaxel) and sonicate until well dispersed. Add 0.628 mg of DOTAP (in ethanol, 31.4 μL of 20 mg / mL DOTAP) and sonicate in a sonication bath for 10 minutes. Then, add 0.063 mg of siRNA: 4.4 μL of 1 mM, 14.2 mg / ml siRNA and vortex well; sonicate for 5 minutes. Add 4 μL of 10 mg / ml F68 in water. According to the procedure described in Example 1, each of the two balloons received a hydrophilic substrate coating (R) and a top coating containing paclitaxel. A mixture containing paclitaxel (15 μL) was used for the top coating.

[0205] Formulation 3

[0206] Weigh out a suspension of 67 mg / mL of jar-milled paclitaxel in 100 mg of DDW (6.28 mg of paclitaxel) and sonicate until well dispersed. Add 31.4 μL of a 20 mg / mL solution of DOTAP in ethanol and sonicate in a sonication bath for 10 minutes. According to the procedure described in Example 1, each of the two balloons received a hydrophilic substrate coating (R) and a top coating containing paclitaxel. A mixture containing paclitaxel (14 μL) was used for the top coating. Only one balloon was tested.

[0207] Formulation 4

[0208] Weigh out a suspension of 67 mg / mL of jar-milled paclitaxel in 200 mg of DDW (12.56 mg of paclitaxel) and sonicate until well dispersed. Add 2.51 mg of DOTAP (in ethanol, 126 μL of 20 mg / mL DOTAP) and sonicate in a sonication bath for 10 minutes. According to the procedure described in Example 1, each of the two balloons received a hydrophilic substrate coating (R) and a top coating containing paclitaxel. A mixture containing paclitaxel (17.5 μL) was used for the top coating.

[0209] Formulation 5

[0210] Weigh out a 67 mg / mL suspension of milled paclitaxel in DDW (6.28 mg paclitaxel) in 100 mg and sonicate until well dispersed. Add 0.628 mg DOTAP (in ethanol, 31.4 μL DOTAP 20 mg / mL) and sonicate in a sonication bath for 10 minutes.

[0211] Add 4 μL of 10 mg / ml F68 in water (0.6% relative to paclitaxel, or overall). According to the procedure described in Example 1, two balloons each receive a hydrophilic base coating (R) and a top coating containing paclitaxel. The mixture containing paclitaxel (15 μL) is used for the top coating.

[0212] Formulation 6

[0213] Transfer 130 μL of formulation 4 to a new test tube and add 4 μL of 100 mg / ml F68 in water (0.5%). According to the procedure described in Example 1, two balloons receive a hydrophilic base coating (R) and a top coating containing paclitaxel. The mixture containing paclitaxel (17.5 μL) is used for the top coating.

[0214] Formulation 7

[0215] Weigh out a 67 mg / mL suspension of milled paclitaxel in DDW (12.56 mg paclitaxel) in 200 mg and sonicate until well dispersed. Add 1.26 mg DOTAP: 63 μL DOTAP 20 mg / mL in ethanol and sonicate in a sonication bath for 10 minutes. Then, add 0.126 mg siRNA: 8.8 μL of 1 mM, 14.2 mg / ml siRNA and vortex well; sonicate for 5 minutes. Add 8 μL of 10 mg / ml F68 in water. According to the procedure described in Example 1, two balloons each receive a hydrophilic base coating (R) and a top coating containing paclitaxel. The mixture containing paclitaxel (15 μL) is used for the top coating.

[0216] Dry all balloons overnight at room temperature. Fold, pleat, and encapsulate these balloons in a nylon sheath. Subsequently, place these balloons in an oven at 55 °C for 1 hour. Then, evaluate the release of paclitaxel from the coating according to the procedure described in Example 2.

[0217] Example 5: Transfer of coating from rod

[0218] The top surface of a 5 cm long rod with a 5 mm diameter was coated with the hydrophilic substrate coating (R) as described above. The coating was applied by brushing the surface of these rods with the solution, drying at room temperature for 15 minutes and then irradiating with UV for 3 minutes. Three formulations were prepared:

[0219] Formulation 1

[0220] Taxol ground in a jar was suspended in water at 67 mg / mL. 100 mg of the suspension (6.28 mg taxol) was weighed out and sonicated until well dispersed. 1.26 mg of DOTAP (in ethanol, 62.8 μL DOTAP 20 mg / mL) was added and sonicated in a sonication bath for 10 minutes.

[0221] Formulation 2

[0222] Taxol ground in a jar was suspended in water at 67 mg / mL. 100 mg of the suspension (6.28 mg taxol) was weighed out and sonicated until well dispersed. 1.26 mg of DOTAP (in ethanol, 62.8 μL DOTAP 20 mg / mL) was added and sonicated in a sonication bath for 10 minutes. Then, F68 at 5% w / w of the total formulation as a 100 mg / mL solution in water was added.

[0223] Formulation 3

[0224] Taxol ground in a jar was suspended in water at 67 mg / mL. 100 mg of the suspension (6.28 mg taxol) was weighed out and sonicated until well dispersed. 1.26 mg of DOTAP (in ethanol, 62.8 μL DOTAP 20 mg / mL) was added and sonicated in a sonication bath for 10 minutes. Then, 62.8 μL of dextran (100 mg / mL, in water) was added.

[0225] In triplicate, the rods received a top coating containing taxol by pipetting 5 μL of one of these formulations and drying overnight at room temperature.

[0226] Ex vivo porcine skin tissue from fat was trimmed and excised with an 8 mm tissue excision tool (Sklar) and maintained at 37 °C. The rods were soaked in PBS at 37 °C for 30 seconds. Subsequently, the rods were pressed into the excised tissue for 30 seconds. The tissue samples were placed in a methanol / 0.1% acetic acid solution in a vial with tissue disruption medium. The tissue was disrupted to extract the transferred taxol.

[0227] Example 6: Variable ratios of components

[0228] Ten nylon balloon stubs were received with a hydrophilic substrate coating (R) according to the procedure described in Example 1.

[0229] The milled paclitaxel was suspended in water at 65 mg / mL. 25 mg / mL of DOTAP dissolved in ethanol was added to a formulation of 20% or 40% w / w paclitaxel and sonicated in a sonication bath for 10 minutes. Gelatin B, glycogen or dextran as a 100 mg / mL solution in water as 33% or 50% w / w of the total matrix was added to some of the resulting mixtures. These formulations were applied as a top coating to the balloons (following the procedure in Example 1) with the goal of approximately 700 μg of total paclitaxel in the coating. The balloons were folded, pleated and encapsulated in a nylon sheath. Subsequently, the balloons were placed in an oven at 55 °C for 1 hour.

[0230] Then, the release of paclitaxel from the coating was evaluated according to the procedure described in Example 2.

[0231] Example 7: Using Formulations of F68

[0232] A formulation was prepared by suspending the milled paclitaxel in water at 65 mg / mL. 25 mg / mL of DOTAP dissolved in ethanol was added to a formulation of 20% w / w paclitaxel. To the resulting mixture was added F68 (BASF) as a 10 mg / mL or 100 mg / mL solution in water to reach 0.6% - 5% w / w of the total matrix. As described in Experiment 1, these formulations were top-coated onto the balloons with the hydrophilic substrate coating R.

[0233] All balloons were dried overnight at room temperature. The balloons were folded, pleated and encapsulated in a nylon sheath. Subsequently, the balloons were placed in an oven at 55 °C for 1 hour.

[0234] Then, the release of paclitaxel from the coating was evaluated according to the procedure described in Example 2.

[0235] Example 8: Amorphous paclitaxel nanoparticles using DOTAP or polyethylenimine

[0236] (i) Preparation of amorphous paclitaxel particles:

[0237] In triplicate, 6.2 mg of paclitaxel on average was dissolved in 50 μL of chloroform. This solution was dispersed in 1 mL of BSA in water at 50 mg / mL using a sonication probe for 20 seconds. The resulting emulsion was spun in a centrifuge at 5000 rpm for 15 minutes. The clear supernatant was aspirated; the residue was frozen and lyophilized. These residues weighed 9.8 mg on average. To remove the remaining BSA, the solid was dispersed in 1 mL of fresh water using a sonication bath and then spun at 10,000 rpm for 10 minutes. The supernatant was aspirated.

[0238] (ii) Preparation of the DOTAP dispersion in water:

[0239] A 5 mL solution of 25 mg / mL of DOTAP in ethanol was placed in a glass round-bottom container and evaporated under vacuum to obtain a film. The DOTAP was dispersed in 12.5 mL of water by adding several batches of 4.2 mL of water to this glass container and sonicating briefly in a sonication bath. These batches were combined, sonicated in a sonication bath for 10 minutes and filtered through a 0.45 μm filter.

[0240] Following the procedure described in Example 1, the balloons were base-coated and top-coated. To obtain the formulation for the top coating containing paclitaxel, as follows, DOTAP dispersed in water or an aqueous solution of PEI was added to the obtained amorphous paclitaxel particles:

[0241] 1. 114 μL of a 10 mg / mL dispersion of DOTAP in water was added to 5.7 μg of paclitaxel. 15 μL was used to coat the balloon material.

[0242] 2. 62 μL of low molecular weight polyethyleneimine (PEI-LMW) at 20 mg / mL and 31 μL of water were added to 6.2 μg of paclitaxel. 10 μL was used to coat the balloon material.

[0243] 3. 67 μL of 750 kDa polyethyleneimine (PEI-HMW) at 20 mg / mL and 33 μL of water were added to 6.7 μg of paclitaxel. 10 μL was used to coat the balloon material.

[0244] All balloons were dried overnight at room temperature. The balloons were folded, pleated and encapsulated in a nylon sheath. Subsequently, the balloons were placed in an oven at 55 °C for 1 hour.

[0245] Then, the release of paclitaxel from the coating was evaluated according to the procedure described in Example 2.

[0246] Example 9: Z - potential measurement

[0247] Dissolve paclitaxel (5 mg) in 10 μL of benzyl alcohol. Using a sonication probe, disperse this solution in 1 mL of BSA in water at 50 mg / mL for 20 seconds. Divide the resulting emulsion into 5 portions of 200 μL each, and centrifuge these portions at 10,000 rpm for 10 minutes in a centrifuge (residues A–E). Aspirate the clear supernatant.

[0248] A. Resuspend the residue in 1 mL of DDW. Dilute this mixture 10-fold.

[0249] B. Add 10 μL of a 10 mg / mL chitosan solution in 1% acetic acid and 10 μL of DDW. Dilute the resulting suspension 10-fold in DDW.

[0250] C. Add 1 mL of a 1 mg / mL protamine solution in DDW. Dilute the resulting suspension 10-fold in DDW.

[0251] D. Disperse the solid in 500 μL of DDW using a sonication bath and then centrifuge at 10,000 rpm for 10 minutes. Aspirate the supernatant. Place 5 mL of a 25 mg / mL DOTAP solution in ethanol in a glass round-bottom container and evaporate it under vacuum to obtain a film. Disperse DOTAP in 12.5 mL of water by adding several batches of 4.2 mL of water to this glass container and briefly sonicate in a sonication bath. Combine these batches, sonicate in a sonication bath for 10 minutes, and filter through a 0.45 μm filter. Add 25 μL of the DOTAP dispersion in water at 10 mg / mL to the amorphous paclitaxel residue and sonicate in a sonication bath. Dilute the resulting dispersion 10-fold in DDW.

[0252] Z-potential measurements were performed using a Zetasizer (obtainable from Malvern), which showed the formation of negatively charged droplets when dissolved PTX was dispersed in the BSA solution. After adding the chitosan, protamine, or DOTAP solution, positively charged particles were obtained.

[0253] Table 2. Temperature (°C) and ZP values (mV) for Example 9.

[0254] Sample name T(℃) ZP (mV) PTX / BSA in water 25 -23.1 Chitosan 25 +63.8 DOTAP 25 +58 Protamine 37 +12.3

[0255] Example 10: F68 on PTX / DOTAP formulations

[0256] A formulation was prepared by suspending milled paclitaxel in water at 65 mg / mL. 25 mg / mL of DOTAP dissolved in ethanol was added to the formulation of 20% w / w paclitaxel. 2 - 16 μL of a 100 mg / mL solution of F68 in water was added to the resulting mixture to achieve a total matrix of 5% - 34% w / w (50% w / w PTX). Following the procedure described in Example 1, the balloon shaft ends were base - coated and top - coated. Additionally, PTX / DOTAP 80%:20% w / w formulations were tested. These formulations were top - coated on balloon shaft ends with a hydrophilic base - coating F (n = 2 / formulation).

[0257] These balloons were folded, pleated, and encapsulated in a nylon sheath. Subsequently, these balloons were placed in an oven at 55 °C for 1 hour.

[0258] Then, the release of paclitaxel from the coatings was evaluated according to the procedure described in Example 2.

[0259] Example 11: Use of amorphous PTX and different cationic moieties

[0260] Following the procedure described in Experiment 1, four balloons were base - coated and top - coated. The following formulations were top - coated on balloon shaft ends with a hydrophilic base - coating R (n = 1 / formulation).

[0261] In each of 4 test tubes, 5 - 7 mg of paclitaxel was dissolved in 50 μL of chloroform. The solution was dispersed in 1 mL of BSA in water at 50 mg / mL using a sonication probe for 20 seconds. The resulting emulsion was spun in a centrifuge at 5000 rpm for 10 minutes. The clear supernatant was aspirated and the residue was frozen on dry ice and then lyophilized. ("Paclitaxel residue").

[0262] A. Start with 4.8 μg of paclitaxel. Reconstitute the paclitaxel residue in 96 μL of DDW. Use 14 μL to coat the balloon material.

[0263] B. Start with 7.1 μg of paclitaxel. The solid was dispersed in 1 mL of fresh water using a sonication bath to remove residual BSA and then spun at 10,000 rpm for 10 minutes. The supernatant was aspirated. 5 mL of a DOTAP solution at 25 mg / mL in ethanol was placed in a glass round-bottom container and evaporated under vacuum to obtain a film. The DOTAP was dispersed in 12.5 mL of water by adding several batches of 4.2 mL of water to the glass container and sonicating briefly in a sonication bath. These batches were combined, sonicated in the sonication bath for 10 minutes and filtered through a 0.45 μm filter. 142 μL of the DOTAP dispersion at 10 mg / mL in water was added to the paclitaxel residue. 14 μL was used to coat the balloon material.

[0264] C. Start with 7.1 μg of paclitaxel. Chitosan was dissolved at 100 mg / mL in 1% acetic acid and 57 μL was added to the paclitaxel residue. Then, 57 μL of DDW was added. The particles were dispersed using a sonication bath. 14 μL of this material was used to coat the balloon.

[0265] D. Start with 5.1 μg of paclitaxel. Protamine was dissolved at 10 mg / mL in DDW. 51 μL of the protamine solution and an additional 51 μL of DDW were added to the paclitaxel residue. The particles were dispersed using a sonication bath. 14 μL of this material was used to coat the balloon.

[0266] These balloons were folded, pleated and encapsulated in a nylon sheath. Subsequently, these balloons were placed in an oven at 55 °C for 1 hour.

[0267] Then, the release of paclitaxel from the coating was evaluated according to the procedure described in Example 2.

[0268] Example 12: Study of IV flow experiment

[0269] Full-length balloon catheters received a hydrophilic base coating as described in Experiment 1. Formulations containing paclitaxel were coated on the full-length catheter balloons and tested in an in vitro porcine coronary artery in a flow experiment.

[0270] 1.) Flow system: Two open flow loops using PBS were used in this system. Circulated at 70 mL / min, total of 2 L and at 37 °C, one open flow loop for the artery in which the balloon was tested. Circulated at 280 mL / min, total of 1 L and at 37 °C, the other open flow loop for a manifold that supported four arteries simultaneously (the flow at the output was thus 70 mL / min).

[0271] 2.) Arterial connection: Porcine coronary arteries were prepared for testing by trimming and gluing (using cyanoacrylate gel (“super glue”)) to the tip of a 200 μL pipette. The tip was trimmed at the short end such that the diameter of the opening at the tip was approximately 2 - 3 mm. After gluing, the artery was trimmed to 30 mm from the end of the pipette tip towards the free end of the artery. Before testing, the artery was stored in PBS at room temperature.

[0272] Each piece of tubing was capped in the tip of a 1 mL pipette that served as a tool to which the artery would adhere. At the test site, the tip was trimmed to fit into the tubing at the large end and be larger than the diameter of a 7F guiding catheter at the small end. In the manifold, the tip was trimmed to fit tightly onto the Y - connector at the large end but not trimmed at the small end. The resistance provided by the small tip orifice ensured equal flow through the four ports.

[0273] For testing, the artery was placed at the end of the flow tubing by press - fitting a smaller yellow pipette tip onto a larger blue tip.

[0274] 10 mL of PBS was aspirated into a syringe (on a hemostat Y - connector) and flushed through the guiding catheter to ensure that the catheter was filled with PBS. The prepared porcine coronary artery was placed on the test loop by pressing it against the pipette tip. Then, when the hemostat was opened, the coated balloon catheter was introduced. The catheter was pushed until the guide exited the catheter and the wire was removed. The hemostat was closed slightly to reduce back - flow. Then, the balloon catheter was pushed to the treatment site within the prepared coronary artery and the hemostat was closed tightly. The balloon was inflated to 6 ATM and held for 30 seconds. The hemostat was opened and the balloon catheter was deflated and removed. Then the artery was removed from the test loop and placed at the second flow manifold (one of four spaces) and left there for 13 minutes, starting the count from the time the balloon was deflated. The artery placed in methanol / 0.1% acetic acid solution was excised from the pipette tip. The paclitaxel content in the resulting methanol and acetic acid solution was tested using HPLC (“Drug Transfer to Tissue”).

[0275] Example 13: Release of paclitaxel from full - length balloon catheter

[0276] One full - length balloon catheter and 2 balloon shaft ends received the hydrophilic base coating (R) according to Example 1 and were coated with the following formulation:

[0277] A) The milled paclitaxel was suspended in water at 67 mg / mL. 100 mg of the suspension (6.28 mg paclitaxel) was weighed out and sonicated until well-dispersed. 1.26 mg of DOTAP (in ethanol, 62.8 μL of 20 mg / mL DOTAP) was added and sonicated in a sonication bath for 10 minutes. Then, 62.8 μL of dextran (100 mg / mL, in water) was added. 22.5 μL of this material was used to coat the balloon.

[0278] B) The milled paclitaxel was suspended in water at 67 mg / mL. 100 mg of the suspension (6.28 mg paclitaxel) was weighed out and sonicated until well-dispersed. 1.26 mg of DOTAP (in ethanol, 62.8 μL of 20 mg / mL DOTAP) was added and sonicated in a sonication bath for 10 minutes. Then, 62.8 μL of glycogen (100 mg / mL, in water) was added. 22.5 μL of this material was used to coat the balloon.

[0279] C) The milled paclitaxel was suspended in water at 67 mg / mL. 100 mg of the suspension (6.28 mg paclitaxel) was weighed out and sonicated until well-dispersed. 1.26 mg of DOTAP (in ethanol, 62.8 μL of 20 mg / mL DOTAP) was added and sonicated in a sonication bath for 10 minutes. The solution of type A gelatin (100 mg / mL, in water) was warmed to 37 °C. Then, 62.8 μL was added to the mixture. 22.5 μL of this material was used to coat the balloon.

[0280] D) The milled paclitaxel was suspended in water at 67 mg / mL. The suspension (100 mg; 6.28 mg paclitaxel) was weighed out and sonicated until well-dispersed. A mixture of 953 μg of DOTAP and 318 μg of cholesterol in 51 μL of ethanol was added and sonicated in a sonication bath for 10 minutes. 15.5 μL of this material was used to coat the balloon.

[0281] The top coating was dried under hot air and left to dry further at room temperature overnight. Then, the balloons were folded, pleated and encapsulated in a nylon sheath. Subsequently, the balloons were placed in an oven at 55 °C for 1 hour.

[0282] The full-length catheter was tested according to the procedure in Example 12.

[0283] The release of paclitaxel from the coating at the two balloon shaft ends was evaluated according to the procedure described in Example 2.

[0284] Example 14: Release of paclitaxel from balloon

[0285] Three full-length balloon catheters / articles received the hydrophilic base coating (R) according to Example 1 and were top-coated with the following formulations:

[0286] A) Comminuted paclitaxel was suspended in water at 67 mg / mL. 100 mg of the suspension (6.28 mg paclitaxel) was weighed out and sonicated until well dispersed. 1.26 mg of DOTAP (in ethanol, 62.8 μL DOTAP 20 mg / mL) was added and sonicated in a sonication bath for 10 minutes. Then, 62.8 μL of dextran (100 mg / mL, in water) was added. The balloon was coated with 22.5 μL of this material.

[0287] B) Comminuted paclitaxel was suspended in water at 67 mg / mL. 100 mg of the suspension (6.28 mg paclitaxel) was weighed out and sonicated until well dispersed. 1.26 mg of DOTAP (in ethanol, 62.8 μL DOTAP 20 mg / mL) was added and sonicated in a sonication bath for 10 minutes. Then, 62.8 μL of glycogen (100 mg / mL, in water) was added. The balloon was coated with 22.5 μL of this material.

[0288] C) Comminuted paclitaxel was suspended in water at 67 mg / mL. 100 mg of the suspension (6.28 mg paclitaxel) was weighed out and sonicated until well dispersed. 1.26 mg of DOTAP (in ethanol, 62.8 μL DOTAP 20 mg / mL) was added and sonicated in a sonication bath for 10 minutes. Pluronic® F68 (available from BASF Corporation), as a 100 mg / mL solution in water, was added to the resulting mixture to a total coating formulation of 5% w / w. F68 (available from BASF Corporation), as a 100 mg / mL solution in water, was added to the resulting mixture to a total coating formulation of 5% w / w.

[0289] The top coating was dried under hot air and left to dry further overnight at room temperature. The balloons were then folded, pleated and encapsulated in a nylon sheath. Subsequently, the balloons were placed in an oven at 55 °C for 1 hour.

[0290] The full-length catheters were tested according to the procedure in Example 12.

[0291] Example 15: Release of paclitaxel from balloon

[0292] Three full-length balloon catheters / articles received the hydrophilic base coating (R) according to Example 1 and were top-coated with the following formulations:

[0293] For each formulation, 5 - 6 mg of paclitaxel was dissolved in 50 μL of chloroform. This solution was dispersed in 1 mL of BSA in water at 50 mg / mL using a sonicator probe for 20 seconds. The resulting emulsion was spun in a centrifuge at 5000 rpm for 15 minutes. The clear supernatant was aspirated; the residue was frozen and lyophilized. These residues weighed an average of 9.8 mg. To remove the remaining BSA, the solid was dispersed in 1 mL of fresh water using a sonication bath and then spun at 10,000 rpm for 10 minutes. The supernatant was aspirated ("paclitaxel residue").

[0294] 5 mL of a 25 mg / mL solution of DOTAP in ethanol was placed in a glass round-bottom container and evaporated under vacuum to obtain a film. DOTAP was dispersed in 12.5 mL of water by adding several batches of 4.2 mL of water to the glass container and sonicating briefly in a sonication bath. These batches were combined, sonicated in a sonication bath for 10 minutes and filtered through a 0.45 μm filter.

[0295] High molecular weight 50% w / w polyethylenimine (Sigma) in water was diluted to a 2% w / w or 20 mg / mL solution in DDW.

[0296] The following additions were made to amorphous paclitaxel residue, DOTAP, or PEI in water:

[0297] 1. (5 μg paclitaxel) 100 μL of a 10 mg / mL dispersion of DOTAP in water was added to the paclitaxel residue. 15.8 μL was used to coat the balloon material.

[0298] 2. (6 μg paclitaxel) 60 μL of high molecular weight polyethylenimine (PEI-HMW) at 20 mg / mL and 30 μL of water were added. 11.8 μL was used to coat the balloon material.

[0299] 3. (5 μg paclitaxel) 100 μL of a 10 mg / mL dispersion of DOTAP in water was added to the paclitaxel residue. Then, 50 μL of dextran (100 mg / mL, in water) was added. 23.8 μL of this material was used to coat the balloon.

[0300] 4. 5 mg of milled paclitaxel was suspended in 75 μL of water and sonicated until well dispersed. 1 mg of DOTAP (in ethanol, 40 μL of 25 mg / mL DOTAP) was added and sonicated in a sonication bath for 10 minutes. 18.2 μL was used to coat the balloon material.

[0301] The top coating is dried under hot air and left at room temperature for further drying overnight. Then, these balloons are folded, pleated and encapsulated in a nylon sheath. Subsequently, these balloons are placed in an oven at 55 °C for 1 hour.

[0302] The full-length catheter is tested according to the procedure in Example 12.

[0303] Table 3. Tissue transfer (μg) and standard deviation for Examples 2 - 15.

[0304]

[0305]

[0306]

[0307] Example 16: PEI and PAMAM dendrimers

[0308] Twelve balloon tips are coated with the hydrophilic substrate coating (R) as described in Example 1. The following formulations are applied to the top of the substrate coating:

[0309] Tip #1 and #2: Apply a coating from a 25% ethanol / 75% methanol solution containing 75 mg / mL of paclitaxel and 6.25 mg / mL of polyethylenimine (PEI-HMW) with a molecular weight of 750 kDa. The total drug target is 660 μg.

[0310] Tip #3 and #4: Apply a coating from a 25% ethanol / 75% methanol solution containing 75 mg / mL of paclitaxel and 6.25 mg / mL of polyamidoamine dendrimer (PAMAM, generation 4). The total drug target is 660 μg.

[0311] Tip #5, #6 and #7: Dissolve paclitaxel at 100 mg / mL in chloroform. Using a sonication probe, 400 μL of this solution is emulsified at 50 mg / mL in 10 mL of aqueous BSA solution for 60 seconds. The resulting emulsion is freeze-dried. The BSA is removed from the amorphous paclitaxel by washing these solids three times with secondary distilled water. To 6.5 mg of amorphous paclitaxel, 33 μL of water and 65 μL of an aqueous solution of PEI-HMW at 20 mg / mL are added. The coating solution is vortexed and sonicated in a sonication bath. The total drug target for the tip coating is 660 μg.

[0312] Tip #8, #9 and #10: Add 70 μL of an aqueous solution of PEI-HMW at 20 mg / mL to a mixture of 7 mg of mortar-ground paclitaxel in 70 μL of water. The total drug target is 660 μg.

[0313] Shaft ends #11 and #12: A mixture of 50 mg / mL of milled paclitaxel in DDW and 10 mg / mL of PAMAM in ethanol. PAMAM was added to the paclitaxel suspension until a PAMAM to paclitaxel wt / wt ratio of 17:83 was reached. The total drug was targeted at 660 μg.

[0314] The top coatings were dried under hot air and left to dry further overnight at room temperature. Then, the balloons were folded, pleated, and encapsulated in a nylon sheath. Subsequently, the balloons were placed in a 55 °C oven for 1 hour.

[0315] Then, the release of paclitaxel from the coating was evaluated according to the procedure described in Example 2.

[0316] Example 17: Release of paclitaxel from full - length balloon catheter

[0317] Nine full-length balloon catheters received a hydrophilic base coating (R) according to Example 1 and were top-coated with the following formulations (n = 3 / formulation):

[0318] 1. 19 mg of milled paclitaxel was combined with 283.6 μL of distilled water and sonicated twice for 20 seconds each at power setting "3" using a sonicator probe. 99.5

[0319] mg of the mixture was weighed out and 62.9 μL of a 20 mg / mL solution of PEI 750 kDa in distilled water was added. Each of the three catheters was top-coated with 20.5 μL of the formulation.

[0320] 2. 103.4 mg of paclitaxel in aqueous suspension was weighed out. 65.4

[0321] μL of 20 mg / mL PEI 750 kDa in aqueous solution and 65.4 μL of 100 mg / mL dextran solution in water were added. Each of the three catheters was top-coated with 28 μL of the formulation.

[0322] 3. Starting with 8 mg of paclitaxel, amorphous paclitaxel was obtained according to the procedure described in Example 8. 80 μL of 20 mg / mL PEI 750 kDa of PEI in aqueous solution and 80 μL of 100 mg / mL dextran solution in water were added to the paclitaxel residue. Each of the three catheters was top-coated with 15.8 μL of the formulation.

[0323] The top coatings were dried under hot air and left to dry further overnight at room temperature. Then, the balloons were folded, pleated, and encapsulated in a nylon sheath. Subsequently, the balloons were placed in a 55 °C oven for 1 hour.

[0324] The full-length catheter was tested according to the procedure in Example 12.

[0325] According to the procedure described in Example 2, the release of paclitaxel from the coating at the shaft end was evaluated.

[0326] Example 18A: Top - coated balloon using oleylamine

[0327] Eight balloon shaft ends of 15 mm in length were coated with the hydrophilic substrate coating (R) as described in Example 1. The following formulations were applied on top of the substrate coating.

[0328] 1. 49.5 mg of milled paclitaxel in a vial was suspended in 495 μL of distilled water, vortexed and sonicated twice for 20 seconds each using a sonication probe. Then, 495

[0329] μL of 20 mg / mL PEI 750 kDa was added and the pH was neutralized to 7 with 6N HCl. Two shaft ends were top-coated with 10 μL of the formulation per shaft end.

[0330] 2. Paclitaxel was dissolved in methanol at 100 mg / mL. 50 μL of a 25 mg / mL PEI 750 kDa solution in ethanol was added to 50 μL of the paclitaxel solution. Two shaft ends were top-coated with 10 μL of the formulation per shaft end.

[0331] 3. Oleylamine was dissolved in ethanol at 20 mg / mL. 25 μL was added to 75 μL of a 100

[0332] mg / mL paclitaxel solution in methanol. Two shaft ends were top-coated with 7 μL of the formulation per shaft end.

[0333] The top coating was dried under hot air and left to dry further at room temperature overnight. Then, the balloons were folded, pleated and encapsulated in a nylon sheath. Subsequently, the balloons were placed in an oven at 55 °C for 1 hour.

[0334] Then, the release of paclitaxel from the coating was evaluated according to the procedure described in Example 2.

[0335] Example 18B: Top - coated balloon using polyol diol, trimethyl octyl ammonium chloride, trimethylolpropane ethoxylate, pentaerythritol ethoxylate, and polyetheramine ED - 900 (Jeffamine ED - 900) Example 18B: Top - coated balloon using polyol diol, trimethyl octyl ammonium chloride, trimethylolpropane ethoxylate, pentaerythritol ethoxylate, and polyetheramine ED - 900 (Jeffamine ED - 900)

[0336] Ten balloon shaft ends of 15 mm in length were coated with the hydrophilic substrate coating (R) and top-coated as described in Example 1. The following formulations were applied on top of the substrate coating. 100 mg of milled paclitaxel in a vial was suspended in 1 mL of distilled water and completely dispersed using vortex and a sonication probe.

[0337] 1. Dissolve 88 wt% of polyurethane diol in water at 25 mg / mL. Weigh out 55.7 mg of paclitaxel suspension and add 40.7 μL of the polyurethane diol solution. Top coat both shaft ends with 12.6 μL of the formulation / shaft end.

[0338] 2. Dissolve trimethyl octyl ammonium chloride in ethanol at 25 mg / mL. Weigh out 77.4

[0339] mg of paclitaxel suspension and add 56 μL of the trimethyl octyl ammonium solution. Top coat one shaft end with 12.6

[0340] μL of the formulation.

[0341] 3. Disperse trimethylolpropane ethoxylate 20 / 3 EO / OH in water at 25 mg / mL. Weigh out 57.4 mg of paclitaxel suspension and add 41.7 μL of the trimethylolpropane ethoxylate solution. Top coat both shaft ends with 12.6 μL of the formulation / shaft end.

[0342] 4. Dissolve pentaerythritol ethoxylate 15 / 4 EO / OH in water at 25 mg / mL. Weigh out 67.9 mg of paclitaxel suspension and add 49.4 μL of the pentaerythritol ethoxylate solution. Top coat both shaft ends with 12.6 μL of the formulation / shaft end.

[0343] 5. Dissolve polyetheramine ED-900 in water at 25 mg / mL. Weigh out 59.8 mg of paclitaxel suspension and add 43.5 μL of the polyetheramine solution. Top coat both shaft ends with 12.6 μL of the formulation / shaft end.

[0344] Fold, pleat, and encapsulate these balloons in a nylon sheath. Subsequently, place these balloons in an oven at 55 °C for 1 hour.

[0345] Then, evaluate the release of paclitaxel from the coating according to the procedure described in Example 2.

[0346] Example 19: Synthetic linear and branched PEI

[0347] Synthesize the following compounds based on the dodecane-epoxidation of spermine, triethylamine ethylene glycol, 1-methyl-propane diamine, or other amine derivatives

[0348]

[0349]

[0350] Coat the balloon shaft ends (22) with a hydrophilic base coating (R) and subject them to the top coating as described in Example 1.

[0351] Preparation of the formulation for the top coating: Taxol ground in a mortar was suspended in water at 100 mg / mL and completely dispersed using vortexing and two probe sonication treatments at setting "2.5" for 20 seconds. All of the following formulations were prepared by weighing out the Taxol suspension and adding a solution of the additive such that the w / w ratio of Taxol to additive was 83%:17% w / w. Before applying the coating, the resulting mixture was thoroughly vortexed and placed in a sonication bath for 10 minutes. The formulation (12.6 μL) was applied on top of the bottom coating of each of the two shaft ends and on one metal coupon for each formulation. Subsequently was the procedure for shaft end coating as described in Example 1. After the coating was completely dry, the coating on the metal coupon was weighed.

[0352] Table 4. Variable values for Example 19.

[0353]

[0354]

[0355] Numbers 5 - 10 (PEI polymers) in Table 4 were purchased from Polysciences, Inc.

[0356] The coated balloon shaft ends were dried under hot air and left to dry further overnight at room temperature. The balloons were then folded, pleated and encapsulated in a nylon sheath. Subsequently, the balloons were placed in an oven at 55 °C for 1 hour.

[0357] Then, the release of paclitaxel from the coating was evaluated according to the following procedure. Ex vivo porcine coronary arteries (Pavillion Biologics) were prepared, placed in plastic test tubes and maintained at 37 °C. After removing the sheath from the balloon shaft ends, these shaft ends were fixed to a motor and rotated at a speed of 125 rpm and immersed in fetal bovine serum (FBS) at 37 °C for 30 seconds. The balloon was removed from the FBS (to dissolve paclitaxel, methanol was then added to the FBS at a volume ratio of 1:3 FBS / methanol). Next, when immersed in normal PBS at 37 °C, the balloon was inflated in the arterial tissue at 60 - 80 psi for 30 seconds, and after deflating and removing the balloon, the arterial tissue was removed from the plastic test tube and rinsed with PBS at 37 °C. After removing the balloon from the tissue and rinsing the tissue, it was placed in a methanol / 0.1% acetic acid solution. Using HPLC, the paclitaxel content in the resulting methanol and acetic acid solution was tested ("Drug Transfer to Tissue"). The balloon was also placed in a methanol and 0.1% acetic acid solution.

[0358] Example 20: Crystalline paclitaxel (milled in jar vs. sonicated) vs. amorphous paclitaxel

[0359] The balloon shaft ends (22) were coated with a hydrophilic substrate coating (R) and subjected to a top coating containing paclitaxel as described in Example 1. The following formulations were coated on the balloon shaft ends having the hydrophilic substrate coating R (n = 2 / formulation).

[0360] a) Paclitaxel (75 mg) was dissolved in 750 μL of methanol. The paclitaxel solution (75 μL) was mixed with 25 μL of a 25 mg / mL PEI 750 kDa solution in ethanol. 8.8 μL of the resulting solution was applied as a top coating to two shaft ends.

[0361] b) Milled paclitaxel was suspended in water at 100 mg / mL and completely dispersed using vortexing and two probe sonication treatments at setting

[0362] "2.5" for 20 seconds. All the following formulations were prepared by weighing out the paclitaxel suspension and adding a solution of the additive such that the w / w ratio of paclitaxel to the additive was 83%:17% w / w. Before applying the coating, the resulting mixture was thoroughly vortexed and placed in a sonication bath for 10 minutes. 13.9 μL of the resulting solution was applied as a top coating to two shaft ends.

[0363] Table 5. Variable values for Example 20.

[0364]

[0365]

[0366] The coated balloon shaft ends are dried under hot air and left at room temperature for further drying overnight. These balloons are folded, pleated and encapsulated in a nylon sheath. Subsequently, these balloons are placed in an oven at 55 °C for 1 hour.

[0367] Then, the release of paclitaxel from the coating is evaluated according to the following procedure. Ex vivo porcine coronary arteries (obtainable from Parafree Biologics) are prepared, placed in plastic test tubes and maintained at 37 °C. After the sheath is removed from the balloon shaft ends, these shaft ends are fixed to a motor and rotated at a speed of 125 rpm and immersed in horse serum (HS) at 37 °C for 30 seconds. These balloons are removed from the HS. Next, when immersed in normal PBS at 37 °C, the balloons are inflated in arterial tissue at 60 - 80 psi for 30 seconds, and after deflating the balloon and removing it, the arterial tissue is removed from the plastic test tube and rinsed with PBS at 37 °C. After removing the balloon from the tissue and rinsing the tissue, it is placed in methanol / 0.1% acetic acid solution. Using HPLC, the paclitaxel content in the resulting methanol and acetic acid solution ("Drug Transfer to Tissue") is tested. The balloons are also placed in methanol and 0.1% acetic acid solution.

[0368] Example 21: PEI, L - citrulline, poly - L - ornithine, and poly - L - glutamate

[0369] Nine balloon shaft ends are coated with a hydrophilic substrate coating (R) and subjected to the top coating as described in Example 1.

[0370] Preparation of the top coating: The milled paclitaxel is suspended in water at 100 mg / mL and completely dispersed using vortexing and two probe sonication treatments at setting "2.5" for 20 seconds. All the following formulations are prepared by weighing out 50 mg of the paclitaxel suspension and adding 45.5 μL of a 20 mg / mL aqueous solution of these additives such that the w / w ratio of paclitaxel to the additives is 83%:17% w / w. Before applying the coating, the resulting mixture is thoroughly vortexed and placed in a sonication bath for 10 minutes. The following additives are used:

[0371] (1) PEI 750 kDa; HCl is added to pH 7.0

[0372] (2) L-citrulline

[0373] (3) Poly-L-ornithine

[0374] (4) Poly-L-glutamic acid

[0375] The resulting formulation (13.9 μL) was applied as a top coat to the shaft ends (n = 3 for PEI, n = 2 / formulation for other additives).

[0376] The coated shaft ends were dried under hot air and left to dry further overnight at room temperature. These balloons were then folded, pleated, and encapsulated in a nylon sheath. Subsequently, these balloons were placed in an oven at 55 °C for 1 hour.

[0377] The release of paclitaxel from the coating was evaluated according to the procedure described in Example 20.

[0378] Example 22: Branched PEI with oleic acid graft and amino acid methyl ester

[0379] Eight balloon shaft ends were coated with a hydrophilic substrate coating (R) and received a top coat as described in Example 1. Canned milled paclitaxel was suspended in water at 100 mg / mL and completely dispersed using vortexing and two probe sonication sessions at setting "2.5" for 20 seconds each. All of the following formulations were prepared by weighing out the paclitaxel suspension and adding the solution of the additive such that the w / w ratio of paclitaxel to additive was 83%:17% w / w.

[0380] Table 6. Variable values for Example 22.

[0381]

[0382] Before applying the coating, the resulting mixture was thoroughly vortexed and placed in a sonication bath for 10 minutes. The resulting solution (13.8 μL) was applied as a top coat to each of two shaft ends. The coated shaft ends were dried under hot air and left to dry further overnight at room temperature. These balloons were then folded, pleated, and encapsulated in a nylon sheath. Subsequently, these balloons were placed in an oven at 55 °C for 1 hour.

[0383] The release of paclitaxel from the coating was evaluated according to the procedure described in Example 20.

[0384] Example 23: PAMAM derivatives

[0385] In this study, various different PAMAMs were investigated using acid (COOH) end groups with different structural units or similar generation-4 amine end groups.

[0386] The chemical formula of the generation-4 PAMAM - polyamide - amine dendrimer based on an ethylenediamine core is as follows:

[0387]

[0388] Fifteen balloon shaft ends were coated with the hydrophilic substrate coating (R) as described in Example 1.

[0389] Preparation of the top coating:

[0390] Approximately 10 mg of sonicated paclitaxel (see Experiment 1) was weighed out and suspended in water at 100 mg / mL. A solution of PAMAM was added to the paclitaxel suspension such that the w / w ratio of paclitaxel to additive was 83%:17% w / w. Prior to use for the top coating, the resulting mixture was vortexed thoroughly and probe sonicated twice at setting "2.5" for 20 seconds and placed in a sonic bath for 10 minutes (applied according to the procedure in Example 1). Three shaft ends / formulations were coated.

[0391] Table 7. Variable values for Example 23

[0392]

[0393]

[0394] The top coating was dried under hot air and left to dry further overnight at room temperature. The balloons were folded, pleated and encapsulated in a nylon sheath. Subsequently, the balloons were placed in an oven at 55 °C for 1 hour.

[0395] The release of paclitaxel from the coating was evaluated according to the procedure described in Example 20.

[0396] Example 24: PAMAM with different molecular weights

[0397] PAMAM is a polyamidoamine dendrimer (i.e., containing both amide groups and amine groups; see the exemplary chemical structure below).

[0398]

[0399] PAMAM is a globular protein polymer and is synthesized generation by generation: one generation after another, with an exponential increase in the number of branches as the molecular weight increases. In this example, a series of generations were tested at both 90:10 and 75:25 PTX / PAMAM.

[0400] Twenty-eight balloon shaft ends were coated with the hydrophilic substrate coating (R) and received the top coating as described in Example 1.

[0401] Preparation of the top coating:

[0402] Obtain PAMAM solutions of generation 0, 1, 2, 3, 4, 5, and 7 with an ethylenediamine core (available from Sigma) and dilute to 50 mg / mL in methanol. Sonicate paclitaxel (see Experiment 1) at 50 mg / mL in water and use vortexing and two probe sonications at setting "2.5" for 20 seconds each to fully disperse.

[0403] Table 8. CAS numbers of PAMAM derivatives

[0404] PAMAM generation CAS number 0 155773-72-1 1 142986-44-5 2 93376-66-0 3 153891-46-4 4 163442-67-9 5 163442-68-0 7 163442-70-4

[0405] A. Paclitaxel / PAMAM formulation at a 90:10 w / w ratio.

[0406] Weigh out the paclitaxel (50 mg) suspension and add 5.3 μL of the 50 mg / mL PAMAM solution in methanol. Place it in a sonication bath for 10 minutes before using the formulation to apply the top coating. Coat both shaft ends / formulations.

[0407] B. Paclitaxel / PAMAM formulation at a 75:25 w / w ratio.

[0408] Weigh out the paclitaxel suspension (50 mg) and add 15.9 μL of the 50 mg / mL PAMAM solution in methanol. Place it in a sonication bath for 10 minutes before using the formulation to apply the top coating. Coat each of the two shaft ends / formulations.

[0409] Dry the top coating under hot air and leave it at room temperature to dry further overnight. Fold, pleat, and encapsulate the balloons in a nylon sheath. Subsequently, place the balloons in an oven at 55 °C for 1 hour. Evaluate the release of paclitaxel from the coating according to the procedure described in Example 20.

[0410] Table 9. Tissue transfer (μg) and standard deviation for Examples 16 - 24.

[0411]

[0412]

[0413]

[0414]

[0415] Example 25: Particles with regulated ζ potential

[0416] By dissolving rapamycin (100 mg; available from LC Laboratories, Woburn, MA) and SYNBIOSYS TM polymer (200 mg; GAPEGCL-GALA; available from InnoCore Pharmaceuticals, Groningen, the Netherlands) in ethyl acetate, microparticles with rapamycin were prepared. The aqueous continuous phase (1% or 0.1% polyacrylic acid; available from Sigma Chemicals; in water, pH 7) was saturated with ethyl acetate. 3 mL of the rapamycin-SYNBIOSYS TM polymer-ethyl acetate solution was homogenized (for 1 minute at 5000 rpm) into one of 100 mL of the continuous phase. The subsequent mixture was poured into 500 mL of deionized water and the microparticles were separated by centrifugation and washed 3 times with deionized water.

[0417] The coated 96-well plates (Corning) were conditioned with 100 μL of ECM cell culture medium at 37 °C for 1 hour. A suspension of 11 mg / mL microspheres in an aqueous solution of 1 mg / ml or 2 mg / mL of PEI 70 kDa (Polysciences) was prepared and the pH of the solution was adjusted to pH 7 with HCl. 5 μL of the formulation was pipetted into 100 μL of the medium in the wells of the coated well plates and left to stand for 3 minutes. Then all the wells were rinsed 3 times with 200 μL of PBS. The rapamycin adsorbed to the 96-well surface was dissolved in acetonitrile / 0.1% AcOH and quantified by HPLC. Figure 10 Adhesion of the microparticles to the plate is shown in the continuous phase in the absence of excipients and using PEI as an excipient at 92:8 or 83:17 w / w particle / excipient ratios and 1.0% w / w and 0.1% w / w of polyacrylic acid (PAA).

[0418] It should be noted that, as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a composition that refers to "a compound" includes a mixture of two or more compounds. It should also be noted that the term "or" is generally used in its inclusive sense of "and / or" unless the context clearly dictates otherwise.

[0419] It should also be noted that, as used in this specification and the appended claims, the phrase "configured" describes a system, apparatus, or other structure that is constructed or assembled to perform a particular task or to take on a particular configuration to perform a particular task. The phrase "configured" may be used interchangeably with other similar phrases, such as "arranged" with "configured", "constructed" with "arranged", "constructed", "manufactured" with "arranged", etc.

[0420] All of the disclosure documents and patent applications in this specification indicate the level of ordinary skill in the art to which the present invention pertains. All of the disclosure documents and patent applications are incorporated herein by reference to the same extent as if each individual disclosure document or patent application was specifically and individually indicated to be incorporated by reference. In the event of any conflict to a certain extent between the disclosure documents and patent applications incorporated by reference, the information in this disclosure shall prevail.

[0421] The present 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 while still remaining within the spirit and scope of the present invention.

Claims

1. A drug delivery coating, the drug delivery coating comprising a polymeric layer, the polymeric layer comprising a hydrophilic outer surface; a substrate in contact with the hydrophilic outer surface, the substrate comprising granular hydrophobic therapeutic agent; and a cationic agent; wherein the polymeric layer further comprises a hydrophilic polymer having pendant photoreactive groups; and a photo-crosslinking agent comprising at least two aryl ketone functionalities.

2. The drug delivery coating according to any one of claims 1 and 3-9, wherein the hydrophilic polymer having pendant photoreactive groups comprises photo-polyacrylamide.

3. The drug delivery coating according to any one of claims 1-2 and 4-9, wherein the photo-polyacrylamide is selected from poly(N-3-aminopropyl)methacrylamide-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide; poly(acrylamide-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide), poly(acrylamide-co-maleic acid-6-aminohexanoic acid-Noxysuccinimide-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide) and poly(acrylamide-co-(3-(4-benzoylbenzamido)propyl)methacrylamide)-co-glycidyl methacrylate.

4. The drug delivery coating according to any one of claims 1-3 and 5-9, wherein the photo-polyacrylamide is poly(N-3-aminopropyl)methacrylamide-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide.

5. The drug delivery coating according to any one of claims 1-4 and 6-9, wherein the photo-crosslinking agent is selected from ethylenebis(4-benzoylbenzyl dimethylammonium) dibromide: and sodium bis(4-benzoyl)phosphate:

6. The drug delivery coating according to any one of claims 1-5 and 7-9, wherein the photo-polyacrylamide is poly(N-3-aminopropyl)methacrylamide-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide and the photo-crosslinking agent is ethylenebis(4-benzoylbenzyl dimethylammonium) dibromide.

7. The drug delivery coating according to any one of claims 1-6 and 8-9, wherein the granular hydrophobic therapeutic agent and the cationic agent form coated therapeutic agent particles.

8. The drug delivery coating according to any one of claims 1-7 and 9, wherein the cationic agent is selected from the group consisting of : cationic lipids, neutral lipids having cationic groups, and cationic polymers.

9. The drug delivery coating according to any one of claims 1-8, wherein the cationic agent is selected from the group consisting of : polyethyleneimine and DOTAP.

10. A drug delivery coating, the drug delivery coating comprising a polymeric layer, the polymeric layer comprising a hydrophilic outer surface; a substrate in contact with the hydrophilic outer surface, the substrate comprising granular hydrophobic therapeutic agent; a cationic agent selected from the group consisting of polyethyleneimine and DOTAP; and A ζ-potential regulator selected from the group consisting of polyacrylic acid (PAA), polyglutamic acid, polyaspartic acid, heparin, alginate, hyaluronic acid, and polyvinylsulfonic acid.

11. The drug delivery coating according to any one of claims 10 and 12 - 18, wherein the ζ-potential regulator comprises polyacrylic acid (PAA).

12. The drug delivery coating according to any one of claims 10 - 11 and 13 - 18, wherein the polymeric layer further comprises a hydrophilic polymer having pendant photoreactive groups; and a photo-crosslinking agent comprising at least two aryl ketone functionalities.

13. The drug delivery coating according to any one of claims 10 - 12 and 14 - 18, wherein the hydrophilic polymer having pendant photoreactive groups comprises photo-polyacrylamide.

14. The drug delivery coating according to any one of claims 10 - 13 and 15 - 18, wherein the photo-polyacrylamide is selected from poly(N-3-aminopropyl)methacrylamide-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide; poly(acrylamide-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide), poly(acrylamide-co-maleic acid-6-aminohexanoic acid-N-oxysuccinimide-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide), and poly(acrylamide-co-(3-(4-benzoylbenzamido)propyl)methacrylamide)-co-glycidyl methacrylate.

15. The drug delivery coating according to any one of claims 10 - 14 and 16 - 18, wherein the photo-polyacrylamide is poly(N-3-aminopropyl)methacrylamide-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide.

16. The drug delivery coating according to any one of claims 10 - 15 and 17 - 18, wherein the photo-crosslinking agent is selected from ethylenebis(4-benzoylbenzyl dimethylammonium) dibromide: and sodium bis(4-benzoyl)phosphate:

17. The drug delivery coating according to any one of claims 10 - 16 and 18, wherein the photo-polyacrylamide is poly(N-3-aminopropyl)methacrylamide-co-N-(3-(4-benzoylbenzamido)propyl)methacrylamide and the photo-crosslinking agent is ethylenebis(4-benzoylbenzyl dimethylammonium) dibromide.

18. The drug delivery coating according to any one of claims 10 - 17, wherein the particulate hydrophobic therapeutic agent and the cationic agent form a coated therapeutic agent particle.

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