Medical device coating

Abstract

Coatings having a particularly advantageous use in the field of implantable medical devices, compositions that form these coatings, methods of making these coatings, methods of applying these coatings to, for example, medical devices, medical devices that include these coatings, and uses of such coated medical devices are described. The coatings and compositions are useful in inhibiting or preventing infection generally, including at an orthopedic surgical site, advantageously at sites where a device is inserted through the skin.

Description

[0001] MEDICAL DEVICE COATING

[0002] CROSS-REFERENCE TO RELATED APPLICATION

[0003] This application claims the benefit of U.S. patent appl. no. 63 / 699,194, filed on September 26, 2024, the entirety of which is incorporated herein by reference.

[0004] BACKGROUND INFORMATION

[0005] Controlling infection, including at the site of implantation of a medical device, is a subject of ongoing efforts by physicians and medical device manufacturers.

[0006] U.S. Patent No. 10,646,623 describes an implantable medical device coated with an antibiotic under a protective layer that is said to protect the coating prior to device implantation and capable of being degraded or solubilized after the device has been implanted, thereby making available the previously protected antibiotic.

[0007] That which remains desirable is a medical device durably resistant to microbial attachment or establishment, preferably without the need for an included antibiotic.

[0008] SUMMARY

[0009] Provided herein are coatings, compositions from which these coatings can be provided, methods of making these compositions and coatings, methods of applying the compositions to substrates so as to form coatings, coated medical devices, and methods of making and using such coated medical devices.

[0010] The coatings and compositions can reduce, slow, attenuate, inhibit, halt, eliminate and / or reverse microbial colonization in or on a coated device, surface, etc., as well as in, on or around the area of a wound resulting from implantation, particularly or in and around the locus where a medical device extends through the skin (entry / exit point) from inside the body. Prevention or inhibition of biofilm growth on implanted devices also can be achieved. Without being bound by theory, the antimicrobial properties and effectiveness of such coatings and compositions is believed to result from an ability to lyse bacterial cell walls.

[0011] The described coatings and compositions preferably include at least one polyester, at least one surfactant, and at least one organic polyacid. Generally, more polyester being present than either surfactant or polyacid enhances coatability and durability. The presence of a drug or other therapeutic agent, such as an antibiotic, while possible, generally is not required for efficacy.

[0012] In a preferred embodiment, the coatings and compositions include a polyester such as poly(lactic-co-glycolic acid) (PLGA), a surfactant such as cetylpyridinium chloride (CPC), and an organic polyacid such as citric acid.

[0013] A coating can have a concentration of polyacid and / or surfactant and / or organic polyacid that varies with distance from the substrate, i.e., a gradient, with such gradient not necessarily being continuous or smooth / gradual. Useful gradient coatings can be conceptualized as being composed of multiple layers, with any single layer optionally differing from any other layer with regard to any one or more of its number and type of components, amounts thereof, etc. (compositionally different), but at least two such layers differing from one another in this way, the sum of all such layers providing a coating that includes a polyester, a surfactant, and an organic polyacid.

[0014] A coating can include two or more layers, can have a substantially constant or varied thickness, and / or can have a substantially constant or varied composition.

[0015] As used herein, the term “antimicrobial” means tending to or capable of kilting, inhibiting, or stopping the growth and / or reproduction of microbes, including preventing, reducing, slowing, attenuating, inhibiting, stopping, eliminating, reversing, etc., the presence of microbes (for example, bacterial colonization and / or biofilm formation).

[0016] The articles “a,” “an” and “the” preceding an element or component are intended to be nonrestrictive regarding the number of instances (i .e., occurrences) of the element or component. Therefore “a,” “an” and “the” should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.

[0017] The terms “comprise(s),” “'include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional features, components, acts, steps, groups, structures, etc. As used herein, including within the claims, the term “comprising” is intended to include embodiments encompassed by the terms “consisting essentially of’ and “consisting of.” Similarly, the term “consisting essentially of1is intended to include embodiments encompassed by the term “consisting of.” An amount, concentration, or other value or parameter given as a range, or in a list of same, is to be understood as including endpoints, as specifically disclosing all ranges formed from any pair of any upper and lower values, and as specifically disclosing all integers and fractions within the range, regardless of whether separately disclosed. For example, both a range of 3-10 and a listing of values such as 3, 6, 7, 9, and 10 specifically disclose and include ranges such as 5-7 and 6-9 as well as individual values such as 4.7 and 8.3. Recited numerical limitations include an appropriate degree of precision based on the number of significant places used; for example, “up to 5.0” can be read as setting a lower absolute ceiling than “up to 5.”

[0018] Any listing or grouping of coating or coating composition components and their possible loading or weight percentages is based on total weight of coating or composition, and their sum is understood to be limited to 100%. (Unless the surrounding text explicitly indicates a contrary intention, all values given in the form of percentages are w / w.) For example, a coating comprising 80 to 99% polyester, 0.1 to 1% quaternary ammonium compound, 0 to 2% polyol, and 1 to 3% citric acid based on total weight of coating requires the presence of at least three components, with the sum of the amounts capable of being less than 100% but not greater than 100%, and to describe a coating requiring the presence of, or having been provided from a mixture including, each listed component in at least the lowest listed amount thereof.

[0019] The terms “about” and “substantially,” as well as the symbol, used with reference to a quantity include variations in the recited quantity that are equivalent to the quantity recited, such as an amount that is insub stanti ally different from a recited quantity for an intended purpose or function .

[0020] The term “effective amount” refers to an amount of an ingredient sufficient to achieve a desired effect without causing an undesirable side effect, with the severity of the latter (in type or degree) sometimes needing to be taken into account when deciding on an appropriate balance. The amount of active ingredient used can vary depending upon the type of active ingredient and the intended use of a. particular composition or coating.

[0021] The term “coating” herein, unless otherwise indicated, refers generally to a thin solid layer positioned over or in direct contact with at least a portion of a surface of a substrate such as an implantable medical device. A “finished coating” is a coating that is substantially free of solvent, typically being provided after a coating has undergone a drying process. Unless the surrounding text specifically refers to a coating embodiment that specifically includes one or more solvents, the term “coating” is inclusive of “finished coating.”

[0022] The relevant portion! s) of any specifically referenced patent and / or published patent application are incorporated herein by reference.

[0023] DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0024] Preferred coatings contain little or no solvent, although they often are provided from compositions that include significant amounts of solvent. Coatings optionally can contain up to 30% (w / w), preferably no more than 15% (w / w), solvent based on total weight of the coating. A combination of polyester, surfactant, polyacid, and at least 15% (w / w) solvent, is herein considered a composition, regardless of thickness.

[0025] Conversely, a combination of polyester, surfactant, and polyacid is herein considered a composition if thicker than 1.25 cm (-0.5 in.) or, if existing in a physical form other than a coating, regardless of whether it contains no more than the aforementioned weight percentage of solvent.

[0026] The general physical size and shape characteristics of coatings and compositions are not limited and can be easily varied. For ease of discussion, as used herein the terms “coating” and “coating layer” refer to a thin material layer that may be the sum of several layers as discussed above, having a thickness of - 1.25 cm (0.5 in.) or less including, for example, 1 to 10,000 pm, 10 to 7500 pm, 25 to 5000 pm, 33 to 2500 pm, 50 to 1000 pm, 60 to 750 pm, 75 to 500 pm, 80 to 400 pm, or 90 to 300 pm. Compositions in the form of a thicker layer have no upper limit on thickness, although additional thickness often provides no particular benefit and, in fact, might result in easier removal from the substrate.

[0027] Especially for implantable medical device coatings, the thickness of the coating typically is at least -3 pm and preferably at least -5 pm, often at least -7 pm and typically not more than-75, -'65, - 55, -50, -40, -'30 pm or even -25 pm, for example not more than -20, -15, or even -10 pm. A preferred coating layer can have a thickness in the range of 5 to 20 pm, preferably -7 to - 15 pm. Thinner coatings have been recognized as being less susceptible to removal from most substrates and, accordingly, are preferred.

[0028] Compositions and coatings preferably contain at least one polyester, for example polylactic acid; polyglycolic acid; polybutylene succinate; polyhydroxybutyrate, including poly- 3 -hydroxybutyrate, poly-4-hydroxybutyrate, polyhydroxyvalerate, polyhydroxy hexanoate, and polyhydroxy octanoate; poly caprolactone, poly(ethylene adipate), PLGA, and poly(3-hy- droxybutyrate-co-3-hydroxyvalerate). Polyesters accepted or approved for use in implantable medical devices by regulatory bodies such as the U.S. Food and Drug Administration (FDA) constitute a preferred class herein.

[0029] Preferred coatings and compositions contain PLGA, which can be represented by the general formula where x and y are selected such that the of the resulting copolymer is 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200 and 225 kDa or is from -3 < M» < -250 kg / mol, including 5 < Mw < 200, 10 < Mw< 150, 15 < Mw < 125, 20 < Mw < 100, and 25 < Mw < 75 kg / mol, with each of the listed values being ±5%. Preferred polyesters in terms of providing a balance of performance (e.g., resistance to abrasion) and adhesion are those having 20 < Mw < 45, 21 < Mw < 43, 22 < Mw< 41, 23 < Mw < 39 or, particularly, 24 < Mw < 38 kg / mol.

[0030] Although many PLGA copolymers can be used, particularly suitable are those copolymers where the molar ratio of x:y in formula (I) is from about 10:90 to 90: 10, for example 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25, 80:20, and 85:15. In one embodiment, the PLGA copolymer is a random copolymer and does not have substantial (in terms of size) or significant (in terms of number) blocks of either lactic acid or glycolic acid mer. Additionally or alternatively, the PLGA copolymer can be amorphous. The lactic acid in the PLGA copolymer can be in lactide form.

[0031] In some embodiments, the only polyester is PLGA.

[0032] Based on the total weight of a finished coating, the polyester component preferably accounts for at least 50, 60, 65, 70, 75, 80, 85, 90, 92, 94, 95, 96, 97 or, particularly, 98, 98.5% or even 99%. Because the compositions can include solvent, even substantial amounts of solvent, the polyester component can account for as little as 5, 6, 7, or 8%, preferably 9, 9.5 or 10% and sometimes as high as 50, 60, 70 or even 80% or more of preferred compositions.

[0033] The compositions and coatings contain at least one surfactant, typically cationic, preferably quaternary ammonium compound(s), more preferably quaternary ammonium compounds containing long (C8-C26) alkyl chains. Surfactants approved for dermal and / or mucosal contact by regulatory bodies such as the FDA constitute a preferred class.

[0034] In one embodiment, one or more of benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, cetalkonium chloride, CPC, cetrimonium, cetrimide, dofanium chloride, tetraethylammonium bromide, didecyldimethylammonium chloride and domiphen bromide is present in the composition and / or coating. In addition, one or more quaternary' ammonium compounds of pyridine such as those described in Al-Khalifa et al., “The Development of Next-Generation Pyridinium -Based multiQAC Antiseptics,” Chem Med Chem, vol. 12(4), pp. 280-83, 2017 (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany). In a preferred embodiment, the compositions and coatings contain CPC. Quaternary ammonium compounds, including CPC, can be in any form, including anhydrous and monohydrate forms.

[0035] Surfactants) can constitute 0.2, 0.3, 0 / 4, 0.5, 1, 2, 3, 4, or 5%, or from 0.005 to 7.5%, 0.007 to 5%, 0.01 to 4%, 0.02 to 3%, 0.05 to 2%, 0.07 to 1%, 0.08 to 0.8%, 0.09 to 0. / %, and preferably 0.1 to 0.5% or 0.1 to 0.3% of the total weight of a finished coating. Because compositions can include up to substantial amounts of solvent, surfactani(s) can account for as little as 0.003% but preferably at least 0.004, 0.006, 0.008, 0.01, 0.015 or 0.02% of their total weight.

[0036] The compositions and coatings contain at least one weak acid, typically an organic polyacid. Preferred examples include di- and tri-protic acids such as oxalic acid and substituted variants (including oxamic acid), butanedioic acid and substituted variants (e.g., malic acid, aspartic acid, tartaric acid, citramalic acid, and the like), pentanedioic acid and substituted variants (e.g., glutamic acid, 2-ketoglutaric acid, and the like), hexanedioic acid and substituted variants (e.g., mucic acid), butenedioic acid (both cis and trans isomers), iminodiacetic acid, phthalic acid, ketopinielic acid, and the like, citric acid, 2-rnethylpropane- 1,2,3 - tricarboxylic acid, benzenetricarboxylic acid, nitrilotriacetic acid, and the like, tetra-protic acids like prehnitic acid, pyromellitic acid, and the like, and even higher degree acids (e.g., penta-, hexa-, heptaprotic, etc.). Where a tri-, tetra-, or higher acid is used, one or more of the carboxyl protons can be replaced by cationic atoms or groups (e.g., alkali metal ions), which can be the same or different These acids can be used in any form, including the anhydrous and monohydrate forms, salt form, etc. Polyacids approved for dermal and / or mucosal contact by regulatory bodies such as the FDA constitute a preferred class herein. In certain embodiments, preference can be given to tartaric acid, citric acid, and citramalic acid. Citric acid is particularly preferred based on a combination of performance, cost and availability factors.

[0037] Based on the total weight of a finished coating, the organic poly acid component can account for 0.05 to 10%, including for example at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0% and up to 1.1, 1.3, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5, 6, 7, 8, or even 9% of preferred coatings, with 0.5 to 1.2% or 0.6 to 1.1% being preferred ranges; a multiplicity'' of ranges by combining a value from the first set with a value from the second set are contemplated. Depending on the acid and the particular polyester / s) employed, the amount of acid(s) might be limited by adhesion, i.e., high concentrations of some polyacids might begin to interfere with the ability of the coati ng to a dhere to a substra te.

[0038] Because compositions can include solvent, even substantial amounts of solvent, the organic polyacid component can account for as little as 0.001 or 0.002%, preferably at least 0.01%, more preferably 0.05, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4 or 0.5% up to, for example, 1 , 2, 3, 4, or 5% or more of their total wei ght.

[0039] The solvent component includes at least one organic liquid, each preferably being readily removed by drying / evaporation.

[0040] Preferably, the solvent is an organic liquid that includes at least one oxygen atom and has a Hildebrand solubility parameter of from -8 to -11 cali / 2 / cm3 / 2and / or a dipolar intermo- lecular force (polarity) Hansen solubility parameter (5P) of from ~5 to ~12 MPa1 / 2and preferably from ~6 to ~9 MPa1 / 2. Useful organic liquids include alcohols such as methanol, ethanol, 1 -propanol, and 2-propanol; ketones such as methyl ethyl ketone and acetone; acetonitrile; formaldehyde; any of a variety of ethers; and acetates such as ethyl acetate. Ethyl acetate is preferred in some embodiments. Acetone and 2-propanol can be less effective when using PLGA.

[0041] The amount of solvent is not particularly limited and can vary from minimal to substantial, for example as little as 0.1 to 3% or more, including 5%, and sometimes 9% or more such as for example 10 to 15%, of the total weight of a composition, and can also be in the range of 20, 30, 40, 50, 60, 70, 80, 90, 95, 97, or 99% or even more.

[0042] As described in further detail below, a coating can be "‘built up” on a substrate by iterative application(s) of one or more compositions that include a solvent, followed by partial or complete drying and / or evaporation of the solvent prior to the next application of composition. Because each successive composition application includes solvent, each can at least partially solubilize a prior coating layer. In this manner, even if a subsequent composition has significantly more of one or more components (e.g., surfactant), the amount of that component in the subsequent layer might not be as great as predicted from its concentration in the composition because a portion of that component ultimately can be located in the preceding layer. This assists in providing the aforementioned gradient coating.

[0043] As contemplated herein, each application of composition (or even solvent) forms a new inventive coating, as long as the total amount of solvent therein is less than 30% or even 15% based on total weight and the material is present in a thin layer. As such, a multi-step iterative application / coalescence cycle provides multiple preferred coating embodiments herein .

[0044] Based on the total weight of a finished coating, optional components can account for up to, for example, 0.001, 0.01 or 0.1 to 5%, including for example an amount that is effective up to 0.2, 0.3, 0.4, 0.5, 1, 2, 3, or 4%. Because the compositions can include solvent, including substantial amounts of solvent, the optional components of preferred compositions can account for as little as 0.01 or 0.02%, often from 0.05 to 2.5%, of the total weight of the composition.

[0045] Among the optional components that can be included in a composition and / or coating are those which contribute to flexibility of the coating. Representative examples include organic polyols, i.e., an organic compound containing two or more hydroxyl groups. Examples include glycerol, threitol, erythritol, arabitol, ribitol, xylitol, galactitol, mannitol, sorbitol, and maltitol. Preferred polyols include those which are C2-C18, more preferably C2-C12, and even more preferably C2-C6. Glycerol, also known as glycerin, constitutes a preferred polyol.

[0046] Pigments, dyes, antioxidants, and other such adjuvants also can be included. Inclusion of one or more such colorants open the possibility of a coating that can indicate degree of wear and / or remaining thickness (e.g., two or more different colors throughout the thickness of a given coating).

[0047] In situations where a substrate is intended for partial or full implantation, use of regu- latorily cleared adjuvants is preferable. Optional components can be used in arty fashion, need not be in each region or layer of a given coating, and may for example form a concentration gradient across the thickness of a given coating.

[0048] The coatings and compositions preferably do not contain any drug or therapeutic agent. To any extent that any one or more of the polyester, surfactant, organic polyacid, and solvent is considered to be a drug or a therapeutic agent, in a preferred embodiment no other, further, or additional drug or therapeutic agent, such as a taxane, antibiotic, sporicide, antifungal, etc., is present. Nevertheless, although not preferred, the composition and coating can contain one or more antibiotics; anticoagulants such as coumarins and indandiones; and / or antifungals. Any such other, further, or additional drug or therapeutic agent is present in a composition or coating can be present in any form and any concentration, and any location, including in a concentration gradient across the thickness of a composition of coating.

[0049] A composition can be made by a variety of techniques including dissolution, stirring, compounding, extrusion, melt mixing, etc., and the addition of constituent components can be simultaneous or varied or staged in any manner desired.

[0050] A composition can be applied to the surface of a substrate or other material(s) separating it from a substrate so as to form a coating or layer. Coatings can be positioned over, or in direct physical contact with, any portion of any substrate surface, interior and / or exterior, including a luminal surface, an abluminal surface, and any portion or combination thereof.

[0051] Solvent, if any, can be removed from each applied layer by techniques such as the application of heat, exposure to an air stream, exposure to vacuum, etc., including combinations thereof such as placement in a vacuum oven. One useful drying technique can involve exposure to radiation from an infrared source, preferably while positioned in an airstream. If a vacuum is to be applied to assist in drying, it preferably is weak so as to not produce excessively fast evaporation, which can lead to discontinuities in the coalescing coating layer.

[0052] Friction or wear surfaces of implantable medical devices, are, while not excluded, less preferred due to coating durability concerns.

[0053] Preferably, a layer or coating composition contains ah of the ingredients desired in any given layer or coating, or in any given single layer or coating layer, preferably contains solvent, and preferably is in the form of a solution. The concentration of layer / coating ingredients present in the solution is not limited, and preferably is at least '-0.1% (wdw) ingredients to solvent, more preferably at least about 1 .0%, especially at least about 5%, or 10%. The layer / coating ingredients are preferably present in the solution in a concentration of not more than about 70%, preferably not more than about 50%. for example about 10-40% (all w / w). When a more dilute solution is used, longer application times / multiple applications can be required to achieve a specified thickness of coating / layer.

[0054] Coatings and coating layers are described in further detail below. Every instance of a discussion of a coating applies to and includes layers.

[0055] When a composition is initially applied as a solution, it can be applied in any manner, such as by dipping, rolling, brushing, electrostatic coating, or spraying, for example in which the solution is atomized and then driven towards a substrate using a stream of an inert gas (for example air, N2, Ar or He). Dip coating typically has been found to produce the thinnest coatings which, for reasons discussed above, are preferable.

[0056] The coatings described herein can be applied directly to a surface of a desired substrate, such as an implantable medical device. The coatings also can be applied to an intermediate layer which is first provided or which is already on the substrate. In certain situations, for example when the substrate includes a material that gives rise to an adverse tissue reaction when the device is implanted, providing a sealing layer on a substrate, or using a substrate with such a sealing layer, might be preferable. Such an intermediate layer might be provided by a polymer which is inert towards materials with which it conies into contact when the device is implanted. In other situations, providing a protecting overcoating which can be sorbed or degraded under physiological conditions (e.g., digestive tract, post-surgery, etc.) can be useful .

[0057] In one embodiment a coating can be deposited on a substrate using an electrostatic coating processes, during which the substrate is grounded so as to attract charged coating particles. Use of an electrostatic process can help to provide a uniformly thin coating that conforms to the surface features of die substrate. This technology prevents the masking of the features and the high conformal nature of the coating layer results in coverage with minimal decrease in surface area of the substrate (e.g., implant). As is known in the art, the morphology of the coating is affected by the flow rate of the solution into the nozzle. For uniformly thin, film-like, and conformal coating layers, lower flow rates, for example 1 to 4 mL / hour, are preferred. Voltage, distance between the nozzle and the substrate, and length of time of coating also require controlled and specified values for optimal morphology of the protective layer. In certain circumstances, applying the coating composition via a spray coat or electrocoat technique with control over droplet size can be desirable.

[0058] An alternative that does not involve charges is any of a variety of physical vapor deposition techniques performed under vacuum in which coating material transitions from a condensed phase to a vapor phase and then re-condenses so as to form a thin coating on a substrate of interest.

[0059] A coaling (or layer) once applied, and once optionally dried if, for example, it was formed from a coating solution (composition), can be subjected to a heating step, as can compositions. This is particularly preferred after a finished coating is applied to a substrate, such as an implantable medical device surface. If desired, the heating can be a continuation of a solvent drying / evaporation step and can occur at a different temperature than drying / evapora- tion. In a preferred embodiment, a heating step is performed after application of coating to a substrate and after removal of solvent from the applied coating.

[0060] The heating step can help to eliminate discontinuities in a coating, cause a hardening or toughening of the coating material, cause a chemical transformation within the coating such as crosslinking, etc., increase interrnolecular forces such as hydrogen bonding within the coating, etc. These advantages are similarly conferred upon compositions.

[0061] The heating of a coating or composition can be accomplished at any temperature, in any manner, and for any amount of time, but combinations of excessively high temperatures and exposure times that induce degradation of the coating / composition preferably are avoided. Typical heating conditions include heating the coated substrate at 37° to 300°C, preferably 50° to 100°C, 60° to 90°C or 70° to 80°C for from less than -60 minutes to 3000 or more minutes, typically I to 30, 2 to 28, 3 to 26, 4 to 24, 5 to 22, or 6 to 20 hours, often 10 to 25, 12 to 21, or 14 to 20 hours. (Temperatures here refer to that of the environment to which the coating / composition is exposed, not necessarily the temperature reached by the coating.) Although the use of reduced pressures (e.g., heating under vacuum) can reduce the amount of time required, caution again is recommended so as to not evaporate any remaining solvent(s) so quickly that surface discontinuities in the coating develop. Any type of heating device or technique can be used, such as a heating and drying oven, vacuum oven, furnace, convection oven, etc., including those techniques to remove solvent from a coating solution.

[0062] A coating preferably is either in direct physical contact with and / or overlies at least a portion of a substrate surface. Surfaces of implantable medical devices form a preferred group of surfaces. As noted above, application of a coating can be directly to an uncoated “bare” substrate surface such as a metal or alloy surface (e.g., stainless steel, titanium, titanium alloy, aluminum, copper, cobalt chrome, cobalt chromium molybdenum, magnesium, etc.), a ceramic surface, etc., can be to a substrate surface having a coating different from an inventive coating thereon, or can be in direct physical contact with or overlie a substrate presenting both bare and coated surfaces. T hus, in some embodiments, a coatings are in direct contact with both a bare substrate surface and a portion of the substrate which is coated. Where a coating is “built up” from individual layers at least some of which are in physical contact with one another such layers are described as being in contact, while a layer which lies above but is not in contact with a lower layer (that is closer to the substrate) is described as overlying the lower layer. Such layers can be coextensive or not coextensive.

[0063] Implantable medical devices capable of being coated in whole or in part include those that typically attract infections, such as orthopedic joints, implants for orthopedic trauma, cra- nio-maxillofacial implants, cardiology pacemakers, cardiology implantable defibrillators, neuro stimulators, and spine implants.

[0064] The substrate can be a component of an orthopedic implant, for example a component of a joint prosthesis, a component such as a nail or a bone plate for use in treatment of bone fractures and other traumas, a fixation component such as a bone screw or pin, and a spinal implant device. For example, the device might be a component or part of a hip joint prosthesis or a knee joint prosthesis or an elbow joint prosthesis or a shoulder joint prosthesis or a finger joint prosthesis or an ankle joint prosthesis.

[0065] Devices that do not qualify as implants but that are intended for extended dwell times within a body also can benefit from application of an inventive coating. For example, at least one surface of an indwelling catheter can have such a coating applied. Such catheters can have different coatings on different lumens or on different surfaces (e.g., outer surface having an inventive coating versus an inner surface with a coating providing anticoagulative properties).

[0066] Additional substrates that can benefit from an inventive coating include, but are not limited to, railings of hospital beds and water delivery or handling equipment.

[0067] Typically, the surface of the substrate on which the coating is provided at least in part by a metal, for example a stainless steel or a cobalt chromium molybdenum alloy or a titanium alloy. Such materials are known for use in the manufacture of orthopedic joint prosthesis components. The surface of the substrate can have applied to it. a layer of a material which promotes favorable reaction when the device is implanted, for example to promote ingrowth of bone tissue into the surface of the substrate to secure the device in a bone cavity. For example, the device might have applied to it a layer of a ceramic material such as a hydroxyapatite. All such material s / surf aces can be coated with the invention coatings, partially coated, and / or left uncoated.

[0068] The physical state of the surface of the substrate on which the invention coating is provided is not limited. Examples include polished, roughened (for example by sand blasting), porous (for example as a result of the application of sintered metal beads as in Poro- coat™ components (DePuy Orthopaedics Inc.; Raynham, Massachusetts)), or open cell.

[0069] In a preferred embodiment, the implantable medical device substrate surface to be coated contain features to facilitate bone in-growth, and in a preferred embodiment the coating does not mask these surface features.

[0070] Where a coated device or article is intended for implantation, the entire device or article typically is sterilized. Autoclaving preferably is avoided so as to reduce the risk of hydro- lyzation of the polyester(s) of the coating, leaving irradiation, exposure to ethylene oxide and dry' heat sterilization as preferred methods.

[0071] Coated implantable medical devices can be used in a method of surgery in which the device is implanted in a patient, for example where the device is exposed to bodily fluids or contacted to bone, tissue, etc. At least any portion(s) of such devices that extend from within to outside the body preferably include an invention coating, at least at the entrance-exit locus where the device extends through the skin, i.e., at least those portions of medical devices that extend through the skin from outside to inside the body preferably include a coating sufficiently extensive in such areas to provide protection against infection entering the body at such points. External fixation devices are one such example of such devices.

[0072] Coated implantable devices designed or intended to be affixed in a solid object or article (e.g., bone) have exhibited a particular advantage. As the device is forced into a pilot hole created in an object / article, particularly via a direct force such as hammering as well as (perhaps to a somewhat lesser extent) via rotational force applied to a threaded substrate, some of the coating has been observed to peel from the device and gather or “bunch” at the site of object / article entry. This can be advantageous in that the coating material accumulates at the location where the device enters the object / article (bone / wound interface), which is a point of particular concern with respect to bacterial colonization and, in a worst-case scenario, biofilm formation because it provides conditions (e.g., nutrients, moisture and air) that permit bacterial proliferation and growth. Coatings that flake or crack do not accumulate similarly and therefore do not provide as much protection against infection. Additionally, the newly lesser-coated or even uncoated portion of the device is not negatively impacted because, after insertion, that portion is protected within the bone.

[0073] As noted above and described in further detail below, a layer can be “built up” on a substrate by the successive application of an invention composition followed by the optional partial or complete drying / evaporation of any solution solvent prior to the next application of composition. In a preferred embodiment, at least two different compositions are used, for example in succession to form a concentration gradient of at least one component across the thickness of, e.g., a coating.

[0074] Such multiple layer gradient coatings can be made incrementally, for example by applying and drying successive coating composition layers on a given substrate surface (e.g., apply / dry / apply / dry / apply / dry, etc.). Gradient coatings can also be made continuously or semi-continuously by, for example, applying a coating material on the surface of a substrate optionally under conditions providing essentially immediate drying while changing the composition of the coating material applied, for example by adding an ingredient to the coating composition during application, or by moving the substrate along a path of multiple sprayers fed by different material sources under quick drying conditions, etc. (e.g., continuous spray coating, vapor deposition, etc.). Such “continuous” gradient coatings contain layers that have different concentrations of components throughout their thickness in the same way that “incrementally” made gradient layers do, but with concentration boundaries that can be more difficult to discern due to the generally smaller thickness of the “layer” or “region” in such instances.

[0075] In a preferred embodiment, a gradient coating is provided by applying a first coating composition including solvent, preferably ethyl acetate, and PLGA to a substrate surface, followed by partial or complete drying to provide a first layer coating including 30% or less solvent based on total coating layer weight, after which a second coating composition comprising ethyl acetate (typically 80-90%), PLGA (typically 7.5 - 12.5%) , CPC (typically 0.015 - 0.03%) and citric acid (typically 0.1 - 0.3%) is applied to the first layer coating, followed by optional drying to provide a second layer coating comprising 30% or less solvent thereon. In a highly preferred embodiment this two layer gradient coating is then heat treated at 60° to 85°C, preferably 70° ± 5°C, for up to 25, preferably 12-24, most preferably 15-21 hours to provide a finished coating that preferably includes at least 98.8 - 99.4% polyester, 0.05 - 0.15% surfactant and 0.5 - 1.0% polyacid. Because the second layer composition contains a solvent with good solvating power for the first layer and different ingredients compared to the first, a sharp distinction between the first and second coatings with regard to the concentration of, e.g., CPC and / or citric acid, likely is not present; in other words, some CPC and citric acid likely migrate or penetrate into the PLGA laid down in the first step, but not to a sufficient degree such that the concentration(s) in the first match those in the second. These issues must be considered when the terms “layer” and “region” are used herein with regard to a gradient coating.

[0076] In gradient coatings the concentrations or amounts of ingredients vary through the thickness thereof. For example, in one embodiment of a gradient PLGA / CPC / citric acid coating the contact surface side thereof can be pure PLGA with the concentration of both CPC and citric acid increasing towards the exterior surface side. Analysis of such films can be done by excising different regions of the coating and analyzing them or can be estimated from the concentrations of ingredients in the compositions or solutions used to form the regions.

[0077] A preferred embodiment is a composition including at least one of a polyester, a surfactant, an organic polyacid, and a solvent. Another preferred embodiment is a composition comprising a polyester, a surfactant, an organic polyacid, and optionally a solvent. Another preferred embodiment of the present invention is a coating comprising a polyester, a surfactant, an organic polyacid, and optionally a solvent. In each of these preferred embodiments preference is given to the inclusion of PLGA as the polyester, the inclusion of CPC as surfactant, and the inclusion of citric acid as organic polyacid. Preferred solvents include ethyl acetate, acetone, and ethanol. Such coatings are preferably subjected to heat treatment after formation, as discussed above.

[0078] Another preferred embodiment involves a coating comprising a lower layer and an upper layer, the lower layer overlying or contacting at least a portion of a substrate surface, the lower layer comprising a polyester, and optionally a surfactant, the upper layer overlying or contacting at least a portion of the lower layer, the upper layer comprising a polyester, a surfactant, and an organic polyacid, the lower layer being compositionally different from, and closer to the substrate surface than, the upper layer. In this embodiment, preference is given to the inclusion of PLGA as polyester, the inclusion of CPC as surfactant, and the inclusion of citric acid as organic polyacid. Preferred solvents include ethyl acetate and ethanol. Preferably, the substrate surface is a surface of an implantable medical device. Such coatings are preferably subjected to heat treatment after formation, as discussed above.

[0079] A preferred gradient coating embodiment is made from a composition that includes a polyester, a surfactant, and an organic polyacid and exhibits concentrations of surfactant and organic polyacid that are greater at an exterior surface side thereof than at the side of the coating closer to a substrate surface (the contact surface side of the coating).

[0080] In preparing solutions herein, mixed solvents may be used, especially where solubility of an ingredient favors one solvent over another. For example, because CPC is more easily solvated by ethanol (absolute or 95%) than in ethyl acetate, dissolving CPC in ethanol and then combining this solution with ethyl acetate and optionally other ingredients can give a mixed ethyl acetate / ethanol solution useful in forming coatings and layers herein.

[0081] A preferred coating can be provided according to a procedure that includes at least solvating the polyester (preferably containing or being PLGA) in ethyl acetate to provide a first solution; adding citric acid to the first solution; solvating CPC in ethanol to provide a second solution; combining the first and second solutions; and stirring.

[0082] An alternative approach involves solvating polyester (preferably containing or being PLGA) in ethyl acetate to provide a first solution; solvating CPC in ethanol to provide a second solution; adding citric acid to the second solution; combining the first and second solutions; and stirring.

[0083] The coatings and compositions described herein are preferably biocompatible and capable of biosorption or degradation. Preferred implantable medical devices are configured to contact bone and are configured to control infection at an orthopedic surgical site, and particularly where an implantable medical device exits / enters the body through the skin.

[0084] The foregoing description provides a manner of making and using the inventions such that any ordinarily skilled artisan is enabled to make and use the same, this enablement being provided in particular for the subject matter of the appended claims. This description is provided in the context of a particular application and its requirements, so a variety of modifications to the embodiments can be envisioned.

[0085] Although exemplary embodiments have been described, the invention defined by the claims which follow is not to be limited to such embodiments. While such embodiments illustrate the application of the principles, the equipment and processes can be embodied otherwise without departing from the exemplified principles, and modifications and variations that can be envisioned by those familiar with coatings and implantable devices are to be understood as encompassed thereby. Thus, this invention is not intended to be limited to the embodiments shown but is to be accorded the widest scope consistent with the principles and features disclosed herein. In this regard, certain embodiments within the invention may not show every benefit of the invention, considered broadly. Each embodiment, preferred embodiment, etc., described herein can be used in combination with every and any oilier embodiment described herein, preferred or otherwise.

[0086] Some of the aforedescribed features can be used to advantage without a corresponding use of other features in certain embodiments while, in other embodiments, an advantage can be obtained by using all features together.

[0087] The following preferred embodiments are specifically contemplated. An embodiment relating to a coating or composition is intended to be read as also relating to methods of making and using, respectively, that coating or composition, as well as to articles that include that coating or composition.

[0088] Embodiment [1] relates to an implantable medical device comprising a metallic or ceramic substrate and a coating overlying the metallic or ceramic substrate, with the coating including a polyester such as PLGA, a surfactant such as CPC, and an organic polyacid such as citric acid. The substrate can be wholly metallic or ceramic or can include at least one surface which is, with that surface being the one which is overlain with the coating.

[0089] Embodiment [2] relates to the device of Embodiment [1] wherein the device includes a metallic surface and the coating is in direct contact with at least a portion of that metallic surface.

[0090] Embodiment [3] relates to the device of any of Embodiments [1] and [2] wherein the coating is a gradient coating optionally comprising multiple layers. The concentration of the surfactant and / or the concentration of the organic polyacid are greater at an exterior surface side thereof than at a side of the coating closer to or in contact with a surface of the device (the contact surface side of the coating). Particular preference is given to those devices where concentration(s) of the surfactant and / or polyacid are greater at an exterior side of the coating than at a side of the coating closer to or in contact with the substrate surface.

[0091] Embodiment [4] relates to the device of any of Embodiments [1] to [3] which is a screw, a pin, a wire, a rod, a plate, or an artificial joint component. Embodiment [5] relates to the device of any of Embodiments [1] to [3] where the device is one designed to extend through a patient’s skin when implanted and wherein the coating overlies or is in contact with at least that surface of the device intended to extend through the skin.

[0092] Embodiment [6] relates to the device of any of Embodiments [1] to [5] wherein the coated device has been heat treated at 60° to 85°C, preferably 70°C, for sufficient time to remove at least 95% (w / w) of any solvent contained therein prior to heating.

[0093] Embodiment [7] relates to a composition comprising a polyester such as PLGA, a surfactant such as CPC, an organic polyacid, such as citric acid, and optionally a solvent such as ethyl acetate, each in any amount, proportion and / or concentration. Included in this embodiment is a composition that specifically includes PLGA, CPC and citric acid.

[0094] Embodiment [8] relates to a coating comprising a lower layer and an upper layer, the lower layer overlying or contacting at least a portion of a substrate surface, the lower layer comprising a polyester and optionally a surfactant, preferably a cationic surfactant, the upper layer overlying or contacting at least a portion of the lower layer, the upper layer comprising a polyester, a surfactant (preferably a cationic surfactant), and an organic polyacid, the lower layer being compositionally different from the upper layer.

[0095] Embodiment [9] relates to a method of making a coating that involves applying the composition of Embodiment [7] over or on a surface of a bare or coated substrate, removing some or all of any solvent present, and subjecting the resulting article to the heat treatment from Embodiment [6],

[0096] Embodiment

[0010] relates to a method of making a gradient coating on a substrate involving sequentially applying first and second compositions that are compositionally different. The first composition includes a polyester such as PLGA and optionally a solvent such as ethyl acetate. The second composition includes a polyester such as PLGA, a surfactant such as CPC, an organic polyacid such as citric acid, and optionally a solvent such as ethyl acetate. Before the second composition is applied over the first, at least 75% of the solvent from the first composition is permitted to evaporate so as to permit the polyester component of the first composition to coalesce into a first layer. Prior to a heating step, at least 75% of the solvent from the second composition is permitted to evaporate so as to permit the polyester component of the second composition to coalesce into a second layer. Embodiment

[0011] is directed to the method of Embodiment

[0010] wherein the heating step is the heat treatment from Embodiment [6],

[0097] Embodiment

[0012] is directed to the method of any of Embodiments

[0010] to

[0011] in which the amount, proportion, or concentration of at least one of, and preferably both of, the surfactant and the organic polyacid in the second layer is greater than that in the first layer.

[0098] Embodiment

[0013] is directed to implantation in a patient in need thereof that involves of the medical device of any of Embodiments [1] to [6], with the implanted device optionally being orthopedic hardware.

[0099] Embodiment

[0014] relates to an implantable medical device that includes a metallic or ceramic surface and, overlying or in contact with at least a part of that surface, a coating that includes a polyester, a cationic surfactant, and an organic polyacid.

[0100] Embodiment

[0015] relates to the device of Embodiment

[0014] which includes a metallic surface, the coating optionally being in direct contact with at least a portion of that metallic surface, and / or the device is a screw, a pin, a wire, a rod, a plate, or an artificial joint component.

[0101] Embodiment

[0016] relates to the device of any of Embodiments

[0014] to

[0015] wherein the device is one that extends through the skin when implanted and the coating overlies or is in contact with the surface of the device at least where the device extends through the skin.

[0102] Embodiment

[0017] relates to the device of any of Embodiments

[0014] to

[0016] wherein the concentration of cationic surfactant, and optionally the concentration of the organic polyacid, are greater at an exterior side of the coating than at a side of the coating closer to or in contact with the metallic or ceramic surface.

[0103] Embodiment

[0018] relates to the device of Embodiment

[0014] wherein the polyester includes polylactic-co-glycolic acid, the surfactant includes cetylpyridinium chloride, and the polyacid includes citric acid.

[0104] Embodiment

[0019] relates to a method in which the device of any of Embodiments

[0014] to

[0018] is implanted in a patient in need thereof.

[0105] Embodiment

[0020] relates to a coating that includes compositionally different lower and upper regions, the lower region overlying or contacting at least a portion of a substrate surface, the lower region comprising polyester and optionally cationic surfactant, the upper region overlying or contacting at least a portion of the lower region, the upper region comprising polyester, cationic surfactant, and organic polyacid. EXAMPLES

[0106] Five gradient coatings were prepared by sequentially forming a first layer from a Group A composition and a second layer from a Group B composition, shown below in Tables 1 and 2, respectively. In these compositions, the identities of the components were kept identical, which facilitated direct comparisons of physical and performance properties of the resulting coatings, although this is not to be considered limiting in view of the foregoing disclosure. In each case, the polyester was Resomer™ RG 503H PLGA, a 50:50 mer copolymer having 24 < Mw < 38 kDa (Sigma- Aldrich, Inc; St. Louis, Missouri), surfactant was CPC, first dissolved in ethanol (95%), with that solution being added to ethyl acetate, and poly acid was anhydrous citric acid.

[0107] The order of addition to anhydrous ethyl acetate was polyester, glycerin (for Al composition only), ethanol-surfactant solution and, for B compositions only, polyacid.

[0108] All amounts are weights, in grams.

[0109] Table 1 : Group A compositions

[0110] Table 2: Group B compositions In each case, a Group A composition was pipetted onto a stainless steel substrate and given sufficient time to coalesce (permit the majority of solvent to evaporate) before a Group B composition was applied similarly and also given sufficient time to coalesce. The resulting article was transferred to an oven set to 70°C for ~18 hours.

[0111] Coated articles for microbial inhibition evaluation were prepared in a somewhat simpler two-step manner using the following compositions, with all constituent components being the same as listed above. In the following tables, numerical values represent the weight percentage of each component relative to the total weight of solution (i.e., w / w%).

[0112] The first composition was made by direct addition of PLGA to ethyl acetate followed by vortexing, all at room temperature.

[0113] Table 3: glycerol-free composition for first application

[0114] The other composition was made by combining two separately made solutions, each of which was prepared at room temperature. The first of these solutions was prepared identically to that shown above in Table 3. The second solution was made by first centrifuging a combination of surfactant and ethanol, followed by addition of polyacid. Generally, combining ingredients in a manner that provides a homogeneous solution is preferred. The overall composition resulting from combining the two solutions is tabulated below.

[0115] Table 4: composition for second application

[0116] Considering only the solutes of the combined Table 4 solutions, which constitutes that which remains after a fully dried / coalesced coating forms, the resulting weight percentages were polyester - 98.25 surfactant - 0.22 polyacid - 1.53 The Table 3 composition was pipetted onto a stainless steel substrate kept in a petri dish, with that layer being given sufficient time to coalesce at room temperature. Thereafter, the Table 4 composition was applied similarly and also given sufficient time to coalesce. The resulting article was transferred to an oven set to 70° ± 0.5°C for ~18 hours.

[0117] Testing and evaluation consistently indicated that some surfactant from the second layer had migrated into the first layer.

[0118] An established rat model (Rattus norvegicus) of S. aureus was used to evaluate efficacy. Eighteen rats were divided into a control group and a test group. Each rat received an intramedullary inoculation of 2 pLIO3CFU staph bacteria in conjunction with a surgery where a Kirschner wire was employed as an intermedullary nail for a femur. The control group received standard (uncoated) K wire implants while the test group received implants coated as described above. At each of 7, 14 and 42 days post-surgery, a third of the animals in each group were euthanized and the implanted K wires recovered and sonicated. At each time milestone, the coated wires of the test group showed significantly lower CFU / mL counts than did the uncoated wires of the control group.

Claims

CLAIMSThat which is claimed is:

1. An implantable medical device comprising: a metallic or ceramic surface, and a coating overlying or in contact with at least a part of said surface, the coating comprising poly(lactic-co-glycolic acid), cetylpyridinium chloride, and citric acid.

2. The implantable medical device of claim 1, wherein said device comprises a metallic surface and said coating is in direct contact with at least a portion of said metallic surface.

3. The implantable medical device of claim 1, wherein the concentration of the cationic surfactant and optionally the concentration of the organic polyacid are greater at an exterior side of said coating than at a side of the coating closer to or in contact with the metallic or ceramic surface.

4. The implantable medical device of claim 1, wherein said device is a screw, a pin, a wire, a rod, a plate, or an artificial joint component.

5. The implantable medical device of claim 1, wherein said coating has been heat treated, for from 3 to 25 hours.

6. A composition, comprising polylactic-co-glycolic acid, cetylpyridinium chloride, citric acid, and solvent.

7. A coating, comprising compositionally different lower and upper regions, the lower region overlying or contacting at least a portion of a substrate surface, the lower region comprising polylactic-co-glycolic acid and optionally one or both of citric acid and cetylpyridinium chloride, the upper region overlying or contacting at least a portion of said lower region, the upper region comprising polylactic-co-glycolic acid, cetylpyridinium chloride, and citric acid.

8. A method for applying a coating to a substrate comprising: a) applying to a surface of a substrate a composition that comprises solvent, polyester, anionic surfactant, and polyacid; b) permitting at least a portion of said solvent from said composition to evaporate so as to form an initial coating; and c) heat treating said initial coating so as to provide a finished coating.

9. A method of making a coating, comprising: applying on a surface of a bare or coated substrate a first composition that comprises polylactic-co-glycolic acid and a solvent, followed by removing the solvent to form a first coating region, applying on at least a part of a surface of the first coating region a second composition that comprises polylactic-co-glycolic acid, cetylpyridinium chloride, citric acid, and solvent, followed by removing the solvent to form a second coating region in contact with at least part of the first region, and heat treating the first and second regions at 60-85°C for from 3-25 hours, wherein the first and second regions differ compositionally.

10. The method of claim 9, wherein the amount of the cetylpyridinium chloride and the amount of citric acid in the second coating region are greater than in the first region.

11. The method of any of claims 9 to 10 wherein said coating comprises, on a weight percentage basis, at least 98.8% polyester, at least 0.05% surfactant and at least 0.5% polyacid.

12. The method of claim 11 wherein said coating comprises, on a weight percentage basis, no more than 99.4% polyester, no more than 0.15% surfactant and no more than 1% polyacid.

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